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Huangfu R, Hou K, Zhao J, Wu S, Ping Y. Toward the benefit and value of immune treatment beyond progression in lung cancer? Insights from a systematic review and meta-analysis. Front Immunol 2025; 16:1547978. [PMID: 40236709 PMCID: PMC11996641 DOI: 10.3389/fimmu.2025.1547978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/13/2025] [Indexed: 04/17/2025] Open
Abstract
Objective Immune treatment beyond progression (ITBP) has emerged as a novel therapeutic strategy in oncology. This systematic review and meta-analysis aim to evaluate the efficacy and safety of ITBP in patients with lung cancer, while also identifying characteristics of populations that may benefit most from this treatment approach. Methods This study adheres to the PRISMA guidelines. We searched PubMed, Embase, and the Cochrane Library for relevant literature on immunotherapy for lung cancer, using self-constructed databases up until February 1, 2024. The study includes real-world data from patients with lung cancer undergoing ITBP, categorized into two groups: non-ITBP (NTBP) and ITBP. Two authors independently conducted literature screening, quality assessment, and data extraction. The primary efficacy indicators include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). The safety indicator assessed was the incidence of immune-related adverse events (irAEs). Results We included 9 studies with a total of 5,141 patients with lung cancer, comprising 2,051 patients in the ITBP group and 3,090 in the NTBP group. Patients receiving ITBP showed significantly better outcomes than those receiving NTBP, including superior OS and PFS following treatment beyond progression (OS: hazard ratio (HR) 0.72, 95% confidence interval (CI) 0.68-0.77, P < 0.05; PFS: HR 0.63, 95% CI 0.51-0.78, P < 0.05). Additionally, the ITBP group demonstrated higher ORR and DCR (ORR: odds ratio (OR) 0.48, 95% CI 0.31-0.75, P < 0.05; DCR: OR 0.37, 95% CI 0.24-0.57, P < 0.05). No significant difference in the incidence of irAEs was found between the two groups (OR 1.24, 95% CI 0.83-1.85, P > 0.05). Subgroup analysis revealed that factors such as age, gender, lung cancer subtype, and smoking history significantly influenced OS outcomes in the ITBP group. Conclusion Our findings suggest that ITBP is an effective treatment strategy for patients with lung cancer. Further research should focus on identifying specific patient populations that benefit from ITBP and exploring the potential efficacy of combining ITBP with other therapeutic regimens. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024513475.
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Affiliation(s)
- Rui Huangfu
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, China
| | - Kun Hou
- Department of Pharmacy, Peking University Cancer Hospital Inner Mongolia Hospital, Hohhot, China
| | - Jie Zhao
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, China
| | - Shikui Wu
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, China
| | - Yaodong Ping
- Department of Pharmacy, Peking University Cancer Hospital Inner Mongolia Hospital, Hohhot, China
- Department of Pharmacy, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
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2
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Yang G, Tian L, Wang Y. Hyperprogressive disease induced by PD-1 inhibitor monotherapy in lung adenocarcinoma with HER2 exon 20 insertion: report of two cases and review of literature. Discov Oncol 2025; 16:12. [PMID: 39760792 PMCID: PMC11703795 DOI: 10.1007/s12672-025-01749-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025] Open
Abstract
Monotherapy with anti-programmed cell death protein 1 (PD-1) monoclonal antibody has been approved for the treatment of advanced non-small cell lung cancer with positive programmed cell death-ligand 1 (PD-L1) expression and oncogene wild type, which revealed survival benefit compared with chemotherapy. Nevertheless, certain patients develop rapid progression on anti-PD-1 inhibitor monotherapy. This novel pattern is called hyperprogressive disease (HPD), and the underlying mechanism and molecular characteristics still leaves not clear. Here, we reported two heavily pretreated advanced lung adenocarcinoma cases with HER2 exon 20 insertion who presented HPD after two cycles of anti-PD-1 inhibitor sintilimab monotherapy, and they both carried co-alterations in the PI3K/AKT/mTOR and cell cycle signaling pathway. We speculated that HER2 exon 20 insertion might be viewed as a potential biomarker to avoid single-agent immunotherapy in certain patients with driver mutations, or timely guide proper treatment strategies.
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Affiliation(s)
- Guangjian Yang
- Department of Respiratory Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People's Republic of China
| | - Linyan Tian
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
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3
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Li S, Yuan T, Yuan J, Zhu B, Chen D. Opportunities and challenges of using circulating tumor DNA to predict lung cancer immunotherapy efficacy. J Cancer Res Clin Oncol 2024; 150:501. [PMID: 39545998 PMCID: PMC11568038 DOI: 10.1007/s00432-024-06030-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
Immune checkpoint inhibitors (ICIs), particularly anti-programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) antibodies, have led to significant progress in lung cancer treatment. However, only a minority of patients have responses to these therapies. Detecting peripheral blood of circulating tumor DNA (ctDNA) allows minimally invasive diagnosis, characterization, and monitoring of lung cancer. ctDNA has potential to be a prognostic biomarker and a predictor of the response to ICI therapy since it can indicate the genomic status and tumor burden. Recent studies on lung cancer have shown that pretreatment ctDNA analysis can detect residual proliferative disease in the adjuvant immunotherapy setting and evaluate tumor burden in patients with metastatic disease. Early ctDNA dynamics can not only predict the clinical outcome of ICI therapy but also help distinguish between pseudoprogression and real progression. Furthermore, in addition to quantitative assessment, ctDNA can also detect genetic predictors of response to ICI therapy. However, barriers still exist in the application of ctDNA analysis in clinical lung cancer treatment. The predictive value of ctDNA in lung cancer immunotherapy requires further identification and resolution of these challenges. This review aims to summarize the existing data of ctDNA analysis in patients receiving immunotherapy for lung cancer, understand the limitations of clinical treatment, and discuss future research directions.
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Affiliation(s)
- Shanshan Li
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Ting Yuan
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Jing Yuan
- Center for Joint Surgery, Department of Orthopedic Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Bo Zhu
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
- Chongqing Key Laboratory of Immunotherapy, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
| | - Degao Chen
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
- Chongqing Key Laboratory of Immunotherapy, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
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4
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Masse M, Chardin D, Tricarico P, Ferrari V, Martin N, Otto J, Darcourt J, Comte V, Humbert O. [ 18F]FDG-PET/CT atypical response patterns to immunotherapy in non-small cell lung cancer patients: long term prognosis assessment and clinical management proposal. Eur J Nucl Med Mol Imaging 2024; 51:3696-3708. [PMID: 38896129 PMCID: PMC11457717 DOI: 10.1007/s00259-024-06794-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/05/2024] [Indexed: 06/21/2024]
Abstract
AIM To determine the long-term prognosis of immune-related response profiles (pseudoprogression and dissociated response), not covered by conventional PERCIST criteria, in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs). METHODS 109 patients were prospectively included and underwent [18F]FDG-PET/CT at baseline, after 7 weeks (PETinterim1), and 3 months (PETinterim2) of treatment. On PETinterim1, tumor response was assessed using standard PERCIST criteria. In the event of PERCIST progression at this time-point, the study design provided for continued immunotherapy for 6 more weeks. Additional response patterns were then considered on PETinterim2: pseudo-progression (PsPD, subsequent metabolic response); dissociated response (DR, coexistence of responding and non-responding lesions), and confirmed progressive metabolic disease (cPMD, subsequent homogeneous progression of lesions). Patients were followed up for at least 12 months. RESULTS Median follow-up was 21 months. At PETinterim1, PERCIST progression was observed in 60% (66/109) of patients and ICPI was continued in 59/66. At the subsequent PETinterim2, 14% of patients showed PsPD, 11% DR, 35% cPMD, and 28% had a sustained metabolic response. Median overall survival (OS) and progression-free-survival (PFS) did not differ between PsPD and DR (27 vs 29 months, p = 1.0; 17 vs 12 months, p = 0.2, respectively). The OS and PFS of PsPD/DR patients were significantly better than those with cPMD (29 vs 9 months, p < 0.02; 16 vs 2 months, p < 0.001), but worse than those with sustained metabolic response (p < 0.001). This 3-group prognostic stratification enabled better identification of true progressors, outperforming the prognostic value of standard PERCIST criteria (p = 0.03). CONCLUSION [18F]FDG-PET/CT enables early assessment of response to immunotherapy. The new wsPERCIST ("wait and see") PET criteria proposed, comprising immune-related atypical response patterns, can refine conventional prognostic stratification based on PERCIST criteria. TRIAL REGISTRATION HDH F20230309081206. Registered 20 April 2023. Retrospectively registered.
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Affiliation(s)
- Mathilde Masse
- Centre Antoine Lacassagne, Nuclear Medicine Department, 33 Avenue de Valombrose, 06100, Nice, France.
- Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France.
| | - David Chardin
- Centre Antoine Lacassagne, Nuclear Medicine Department, 33 Avenue de Valombrose, 06100, Nice, France
- Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France
| | - Pierre Tricarico
- Centre Antoine Lacassagne, Nuclear Medicine Department, 33 Avenue de Valombrose, 06100, Nice, France
| | - Victoria Ferrari
- Centre Antoine Lacassagne, Oncology Department, 33 Avenue de Valombrose, 06100, Nice, France
| | - Nicolas Martin
- Centre Antoine Lacassagne, Oncology Department, 33 Avenue de Valombrose, 06100, Nice, France
| | - Josiane Otto
- Centre Antoine Lacassagne, Oncology Department, 33 Avenue de Valombrose, 06100, Nice, France
| | - Jacques Darcourt
- Centre Antoine Lacassagne, Nuclear Medicine Department, 33 Avenue de Valombrose, 06100, Nice, France
- TIRO-UMR E 4320, UCA/CEA, 28 Avenue de Valombrose, 06100, Nice, France
| | - Victor Comte
- Centre Antoine Lacassagne, Nuclear Medicine Department, 33 Avenue de Valombrose, 06100, Nice, France
- Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France
| | - Olivier Humbert
- Centre Antoine Lacassagne, Nuclear Medicine Department, 33 Avenue de Valombrose, 06100, Nice, France
- Université Côte D'Azur, CNRS, Inserm, iBV, Nice, France
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Hutchings K, Al Zaki A, Bhadkamkar N, Willis J. Symptomatic pseudoprogression in metastatic colorectal cancer. BMJ Case Rep 2024; 17:e258816. [PMID: 38871645 DOI: 10.1136/bcr-2023-258816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2024] Open
Abstract
A man in his 70s with metastatic colorectal cancer presented with worsening clinical symptoms and imaging studies concerning for disease progression. He had received two cycles of pembrolizumab, but due to his symptomatic presentation and significant decline in performance status, there was concern for worsening disease. Transitioning to hospice was briefly considered, given his clinical decline and the notable increase in tumour size. Despite the presence of clinical symptoms and radiographic findings, pseudoprogression-defined as an increase in the size(s) of and/or visual appearance of new lesion(s), followed by a response-was also considered as part of the diagnostic possibilities. Consequently, the decision was made to proceed with a third cycle of pembrolizumab. During his subsequent outpatient follow-up, the patient showed significant symptomatic improvement and reported a decrease in his palpable right flank mass. With further immunotherapy, the patient continued to demonstrate symptomatic and radiological improvement.
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Affiliation(s)
- Kasen Hutchings
- Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ajlan Al Zaki
- General Oncology, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USA
| | - Nishin Bhadkamkar
- General Oncology, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USA
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USA
| | - Jason Willis
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USA
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Gupta M, Stukalin I, Meyers DE, Heng DYC, Monzon J, Cheng T, Navani V. Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: a retrospective observational cohort study. Front Oncol 2024; 14:1385425. [PMID: 38884085 PMCID: PMC11176500 DOI: 10.3389/fonc.2024.1385425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 05/13/2024] [Indexed: 06/18/2024] Open
Abstract
Background The association between objective imaging response and first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in routine practice. Methods We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from August 2013-May 2020 in Alberta, Canada. The primary outcome was likelihood of RECIST v1.1 assessed objective imaging response between patients receiving anti-programmed cell death protein 1 (anti-PD1) monotherapy and those receiving combination ipilimumab-nivolumab. Secondary outcomes were identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT). Results 198 patients were included, 41/198 (20.7%) had complete response, 86/198 (43.4%) had partial response, 23/198 (11.6%) had stable disease, and 48/198 (24.2%) had progressive disease. Median OS was not reached (NR) (95% CI 49.0-NR) months for complete responders, NR (95%CI 52.9-NR) months for partial responders, 33.7 (95%CI 15.8-NR) months for stable disease, and 6.4 (95%CI 5.2-10.1) months for progressive disease (log-rank p<0.001). Likelihood of objective imaging response remained similar between anti-PD1 monotherapy and ipilimumab-nivolumab groups (OR 1.95 95%CI 0.85-4.63, p=0.121). Elevated LDH level (OR 0.46; 95%CI 0.21-0.98, p=0.043), mucosal primary site (OR 0.14; 95%CI 0.03-0.48, p=0.003), and BRAF V600E mutation status (OR 0.31; 95%CI 0.13-0.72, p=0.007) were associated with decreased likelihood of response. Conclusion No significant difference in likelihood of imaging response between anti-PD1 monotherapy and combination ipilimumab-nivolumab was observed. Elevated LDH level, mucosal primary site, and BRAF V600E mutation status were associated with decreased likelihood of response. Given that pivotal clinical trials of ipilimumab-nivolumab did not formally compare ipilimumab-nivolumab with nivolumab monotherapy, this work adds context to differences in outcomes when these agents are used. These results may inform treatment selection, and aid in counseling of patients treated with first-line ICI therapy in routine clinical practice settings.
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Affiliation(s)
- Mehul Gupta
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Igor Stukalin
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel E Meyers
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Daniel Y C Heng
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Jose Monzon
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Tina Cheng
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
| | - Vishal Navani
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Tom Baker Cancer Centre, Calgary, AB, Canada
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7
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Uhara H, Kiyohara Y, Isei T, Nagase K, Kambe A, Sato M, Tanaka Y, Yamazaki N. Safety and effectiveness of avelumab in patients with Merkel cell carcinoma in general clinical practice in Japan: Post-marketing surveillance. J Dermatol 2024; 51:475-483. [PMID: 38433375 PMCID: PMC11484154 DOI: 10.1111/1346-8138.17096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 12/11/2023] [Accepted: 12/18/2023] [Indexed: 03/05/2024]
Abstract
Avelumab, a programmed cell death ligand 1 blocking antibody, was approved for its first indication in Japan in September 2017 to treat unresectable Merkel cell carcinoma (MCC). Given that the pivotal JAVELIN Merkel 200 study only included a few Japanese patients, this post-marketing surveillance (PMS) evaluated the safety and effectiveness outcomes of patients with MCC who received avelumab in general clinical practice in Japan. This prospective, non-comparative, multicenter PMS included data from all patients with unresectable MCC who received avelumab between November 22, 2017 (avelumab launch date) and October 31, 2019. The primary objective was to evaluate avelumab safety (i.e., adverse events [AEs], adverse drug reactions [ADRs], and ADRs of safety specifications). The secondary objective was to evaluate avelumab effectiveness (i.e., objective response rate and overall survival [OS] rate). Seventy-five evaluable patients were included, of whom 81.3% experienced AEs of any grade (57.3% experienced AEs of grade ≥ 3; 41.3% experienced AEs of grade 5) and 61.3% experienced ADRs (14.7% experienced ADRs of grade ≥ 3; no grade 5 ADRs were observed). The most common ADRs were pyrexia (18.7%), infusion related reaction (10.7%), and chills (6.7%). The most common ADRs of safety specifications were infusion reactions (any grade: n = 21 [28.0%]; grade 3 or 4: n = 3 [4.0%]), thyroid dysfunction (n = 7 [9.3%]), and hepatic function disorders (n = 4 [5.3%]). The median observation period was 51 weeks. An objective response was achieved by 34/75 patients (45.3%; complete response, 24.0%; partial response, 21.3%) and 6- and 12-month OS rates were 77.7% and 59.6%, respectively. This PMS confirmed the clinical tolerability and effectiveness of avelumab in patients with MCC, with no new safety concerns. The risk-benefit profile of avelumab was comparable with that observed in clinical trials and remains favorable for use in general clinical practice in Japan.
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Affiliation(s)
- Hisashi Uhara
- Sapporo Medical University School of MedicineSapporoHokkaidoJapan
| | - Yoshio Kiyohara
- Shizuoka Cancer Center Hospital and Research InstituteShizuokaJapan
| | - Taiki Isei
- Osaka International Cancer InstitutionOsakaJapan
| | - Kotaro Nagase
- Department of DermatologySaga‐Ken Medical Centre KoseikanSagaJapan
| | - Anzu Kambe
- Merck Biopharma Co., Ltd.TokyoJapan, an affiliate of Merck KGaA
| | - Masashi Sato
- Merck Biopharma Co., Ltd.TokyoJapan, an affiliate of Merck KGaA
| | - Yutaro Tanaka
- Merck Biopharma Co., Ltd.TokyoJapan, an affiliate of Merck KGaA
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8
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Sia TY, Wan V, Finlan M, Zhou QC, Iasonos A, Zivanovic O, Sonoda Y, Chi DS, Long Roche K, Jewell E, Tew WP, O'Cearbhaill RE, Cohen S, Makker V, Liu YL, Friedman CF, Kyi C, Zamarin D, Gardner G. Procedural interventions for oligoprogression during treatment with immune checkpoint blockade in gynecologic malignancies: a case series. Int J Gynecol Cancer 2024; 34:594-601. [PMID: 38296517 PMCID: PMC11108643 DOI: 10.1136/ijgc-2023-004842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/01/2023] [Indexed: 04/04/2024] Open
Abstract
OBJECTIVE To evaluate the feasibility and outcomes of performing procedural interventions, defined as surgical resection, tumor ablation, or targeted radiation therapy, for oligoprogressive disease among patients with gynecologic malignancies who are treated with immune checkpoint blockade. METHODS Patients with gynecologic cancers treated with immune checkpoint blockade between January 2013 and October 2021 who underwent procedural interventions including surgical resection, interventional radiology ablation, or radiation therapy for oligoprogressive disease were identified. Procedures performed before immune checkpoint therapy initiation or ≥6 months after therapy completion were excluded. Long immunotherapy duration prior to intervention was defined as ≥6 months. Progression-free survival and overall survival were calculated from procedure date until disease progression or death, respectively. RESULTS During the study period, 886 patients met inclusion criteria and received immune checkpoint blockade therapy. Of these, 34 patients underwent procedural interventions for oligoprogressive disease; 7 underwent surgical resection, 3 underwent interventional radiology ablation, and 24 underwent radiation therapy interventions. Primary disease sites included uterus (71%), ovary (24%), and cervix (6%). Sites of oligoprogression included abdomen/pelvis (26%), bone (21%), lung (18%), distant lymph node (18%), brain (9%), liver (6%), and vagina (3%). Most tumors (76%) did not exhibit microsatellite instability or mismatch repair deficiency. Approximately half (53%) of the patients had long immune checkpoint therapy duration prior to intervention. Median progression-free survival following the procedure was 5.3 months (95% CI, 3.1-9.9), and median overall survival was 21.7 months (95% CI, 14.9-not estimable). Long versus short immune checkpoint therapy duration prior to procedure and length of immune checkpoint therapy had no effect on progression-free or overall survival. CONCLUSIONS Procedural interventions for patients with oligoprogression on immune checkpoint blockade therapy are feasible and demonstrate favorable outcomes. With expanding use of immune checkpoint therapy, it is important to investigate combined modalities to maximize therapeutic benefit for patients with gynecologic cancers.
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Affiliation(s)
- Tiffany Y Sia
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Vivian Wan
- Obstetrics & Gynecology, Brooklyn Hospital Center, Brooklyn, New York, USA
| | - Michael Finlan
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Qin C Zhou
- Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Alexia Iasonos
- Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Oliver Zivanovic
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
| | - Yukio Sonoda
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
| | - Dennis S Chi
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
| | - Kara Long Roche
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
| | - Elizabeth Jewell
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
| | - William P Tew
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Roisin E O'Cearbhaill
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Seth Cohen
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Vicky Makker
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ying L Liu
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Claire F Friedman
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Chrisann Kyi
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dmitriy Zamarin
- Medicine, Weill Cornell Medical College, New York, New York, USA
- Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ginger Gardner
- Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
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9
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Xiang Y, Tang W, Wang J, Wang Z, Bi N. Pseudoprogression of thoracic tumor after radiotherapy in the era of immunotherapy: a case series. Front Oncol 2023; 13:1021253. [PMID: 37576884 PMCID: PMC10419187 DOI: 10.3389/fonc.2023.1021253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 07/18/2023] [Indexed: 08/15/2023] Open
Abstract
Pseudoprogression is rarely mentioned after radiotherapy except for central nervous system tumors. With the widespread of immunotherapy, the incidence of pseudoprogression of thoracic tumor after radiotherapy is increasing. This study summarized the clinical features of pseudoprogression in 4 patients who had underwent thoracic radiotherapy after and/or followed by immunotherapy. All of them had received chemotherapy and immunotherapy before thoracic radiotherapy. After radiotherapy, pseudoprogression occurred within 3 months after initiation of immune consolidation/rechallenge therapy. At least a 20% increase in the sum of the longest diameter of target lesions were measured on their chest image. During this period, patients' ECOG PS scores remained stable, specific serum tumor markers did not increase significantly. Treatment strategies did not change after pseudoprogression. The causes of radiographic pseudoprogression in this case series may be attributed to disturbances such as pneumonitis, atelectasis, mucus blockages and infection. In the era of immunotherapy, pseudoprogression of thoracic tumors after chest radiotherapy might become a common phenomenon. It is important for us to identify pseudoprogression based on patient's general status, radiological changes, and laboratory tests.
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Affiliation(s)
- Yongbo Xiang
- Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Tang
- Center for National Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianyang Wang
- Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhijie Wang
- Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Nan Bi
- Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Pawłowska A, Rekowska A, Kuryło W, Pańczyszyn A, Kotarski J, Wertel I. Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors. Int J Mol Sci 2023; 24:10859. [PMID: 37446039 DOI: 10.3390/ijms241310859] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
The standard treatment of ovarian cancer (OC) patients, including debulking surgery and first-line chemotherapy, is unsatisfactory because of recurrent episodes in the majority (~70%) of patients with advanced OC. Clinical trials have shown only a modest (10-15%) response of OC individuals to treatment based on immune checkpoint inhibitors (ICIs). The resistance of OC to therapy is caused by various factors, including OC heterogeneity, low density of tumor-infiltrating lymphocytes (TILs), non-cellular and cellular interactions in the tumor microenvironment (TME), as well as a network of microRNA regulating immune checkpoint pathways. Moreover, ICIs are the most efficient in tumors that are marked by high microsatellite instability and high tumor mutation burden, which is rare among OC patients. The great challenge in ICI implementation is connected with distinguishing hyper-, pseudo-, and real progression of the disease. The understanding of the immunological, molecular, and genetic mechanisms of OC resistance is crucial to selecting the group of OC individuals in whom personalized treatment would be beneficial. In this review, we summarize current knowledge about the selected factors inducing OC resistance and discuss the future directions of ICI-based immunotherapy development for OC patients.
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Affiliation(s)
- Anna Pawłowska
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Anna Rekowska
- Students' Scientific Association, Independent Laboratory of Cancer Diagnostics and Immunology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Weronika Kuryło
- Students' Scientific Association, Independent Laboratory of Cancer Diagnostics and Immunology, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Anna Pańczyszyn
- Institute of Medical Sciences, Department of Biology and Genetics, Faculty of Medicine, University of Opole, Oleska 48, 45-052 Opole, Poland
| | - Jan Kotarski
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
| | - Iwona Wertel
- Independent Laboratory of Cancer Diagnostics and Immunology, Department of Oncological Gynaecology and Gynaecology, Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
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11
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Mönch S, Heimer MM, Winkelmann M, Guertler A, Schlaak M, Tufman A, Ben Khaled N, de Toni E, Westphalen CB, von Bergwelt-Baildon M, Dinkel J, Kazmierczak PM, Ingrisch M, Mansour N, Unterrainer M, Heinzerling L, Ricke J, Kunz WG. Patterns of pseudoprogression across different cancer entities treated with immune checkpoint inhibitors. Cancer Imaging 2023; 23:58. [PMID: 37291665 DOI: 10.1186/s40644-023-00580-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/29/2023] [Indexed: 06/10/2023] Open
Abstract
BACKGROUND Pseudoprogression (PsPD) is a rare response pattern to immune checkpoint inhibitor (ICI) therapy in oncology. This study aims to reveal imaging features of PsPD, and their association to other relevant findings. METHODS Patients with PsPD who had at least three consecutive cross-sectional imaging studies at our comprehensive cancer center were retrospectively analyzed. Treatment response was assessed according to immune Response Evaluation Criteria in Solid Tumors (iRECIST). PsPD was defined as the occurrence of immune unconfirmed progressive disease (iUPD) without follow-up confirmation. Target lesions (TL), non-target lesions (NTL), new lesions (NL) were analyzed over time. Tumor markers and immune-related adverse events (irAE) were correlated. RESULTS Thirty-two patients were included (mean age: 66.7 ± 13.6 years, 21.9% female) with mean baseline STL of 69.7 mm ± 55.6 mm. PsPD was observed in twenty-six patients (81.3%) at FU1, and no cases occurred after FU4. Patients with iUPD exhibited the following: TL increase in twelve patients, (37.5%), NTL increase in seven patients (21.9%), NL appearance in six patients (18.8%), and combinations thereof in four patients (12.5%). The mean and maximum increase for first iUPD in sum of TL was 19.8 and 96.8 mm (+ 700.8%). The mean and maximum decrease in sum of TL between iUPD and consecutive follow-up was - 19.1 mm and - 114.8 mm (-60.9%) respectively. The mean and maximum sum of new TL at first iUPD timepoint were 7.6 and 82.0 mm respectively. In two patients (10.5%), tumor-specific serologic markers were elevated at first iUPD, while the rest were stable or decreased among the other PsPD cases (89.5%). In fourteen patients (43.8%), irAE were observed. CONCLUSIONS PsPD occurred most frequently at FU1 after initiation of ICI treatment. The two most prevalent reasons for PsPD were TL und NTL progression, with an increase in TL diameter commonly below + 100%. In few cases, PsPD was observed even if tumor markers were rising compared to baseline. Our findings also suggest a correlation between PsPD and irAE. These findings may guide decision-making of ICI continuation in suspected PsPD.
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Affiliation(s)
- Sebastian Mönch
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Maurice M Heimer
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Michael Winkelmann
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Anne Guertler
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Max Schlaak
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
- Department of Dermatology, Venerology and Allergology, Charité - University hospital Berlin, Berlin, Germany
| | - Amanda Tufman
- Department of Medicine V, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Enrico de Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Christoph B Westphalen
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Julien Dinkel
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Philipp M Kazmierczak
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Michael Ingrisch
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
- Clinical Data Science, LMU Munich, Munich, Germany
| | - Nabeel Mansour
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Marcus Unterrainer
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany
| | - Wolfgang G Kunz
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, Munich, 81377, Germany.
- Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Munich, Munich, Germany.
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12
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Bazzacco G, Zelin E, Toffoli L, Conforti C, di Meo N, Fedele D, Zalaudek I. Dichotomic response patterns to PD-1 blockade with cemiplimab in a patient with multiple squamous cell carcinomas. J Eur Acad Dermatol Venereol 2023; 37:e547-e549. [PMID: 36305888 DOI: 10.1111/jdv.18705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/25/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Giulia Bazzacco
- Skin Cancer Unit, Department of Dermatology, University Hospital of Trieste, Trieste, Italy
| | - Enrico Zelin
- Skin Cancer Unit, Department of Dermatology, University Hospital of Trieste, Trieste, Italy
| | - Ludovica Toffoli
- Skin Cancer Unit, Department of Dermatology, University Hospital of Trieste, Trieste, Italy
| | - Claudio Conforti
- Skin Cancer Unit, Department of Dermatology, University Hospital of Trieste, Trieste, Italy
| | - Nicola di Meo
- Skin Cancer Unit, Department of Dermatology, University Hospital of Trieste, Trieste, Italy
| | - Dahlia Fedele
- Skin Cancer Unit, Department of Medical Oncology, Maggiore Hospital of Trieste, Trieste, Italy
| | - Iris Zalaudek
- Skin Cancer Unit, Department of Dermatology, University Hospital of Trieste, Trieste, Italy
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13
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Fu J, Yu W, Qian X, Wang Y, Ji J. A photocatalytic carbon monoxide-generating effervescent microneedle patch for improved transdermal chemotherapy. J Mater Chem B 2023. [PMID: 36946621 DOI: 10.1039/d2tb02613a] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
Carbon monoxide (CO) is regarded as a promising therapeutic agent for chemotherapy sensitization. To simultaneously achieve controllable in situ CO production and efficient chemotherapeutics delivery is of great significance. Here, we presented a polyvinylpyrrolidone (PVP) core-shell microneedle (MN) system that encapsulated the effervescent component, photocatalyst, and doxorubicin hydrochloride (Dox·HCl) for CO-sensitized chemotherapy. Upon the insertion of MNs, the effervescent component, composed of sodium bicarbonate and tartaric acid, was exposed to interstitial fluid, leading to the burst release of carbon dioxide (CO2). The generated gas not only enhanced the diffusion of Dox·HCl but also served as a substrate for the photocatalytic generation of CO. From the experimental results, the photocatalyst CuS atomic layers (CAL) displayed an effective CO2 photoreduction performance, which could realize an irradiation time/intensity-dependent CO-controlled release. Ex vivo permeation studies demonstrated that effervescent CO2 production markedly enhanced the intradermal diffusion of Dox·HCl. Eventually, the robust antitumor efficacy of this versatile MN platform was proved in B16F10-bearing nude mice. This CO-sensitized chemotherapeutic MN system offered a novel strategy for transdermal gas/drug delivery, which might provide a new direction in tumor suppression.
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Affiliation(s)
- Junzhe Fu
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 310027, P. R. China.
| | - Weijiang Yu
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 310027, P. R. China.
| | - Xuedan Qian
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 310027, P. R. China.
| | - Youxiang Wang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 310027, P. R. China.
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 310027, P. R. China.
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Dai J, Wu M, Xu Y, Yao H, Lou X, Hong Y, Zhou J, Xia F, Wang S. Platelet membrane camouflaged AIEgen-mediated photodynamic therapy improves the effectiveness of anti-PD-L1 immunotherapy in large-burden tumors. Bioeng Transl Med 2023; 8:e10417. [PMID: 36925700 PMCID: PMC10013814 DOI: 10.1002/btm2.10417] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/20/2022] [Accepted: 08/08/2022] [Indexed: 11/11/2022] Open
Abstract
Although immunotherapy has achieved recent clinical success in antitumor therapy, it is less effective for solid tumors with large burdens. To overcome this challenge, herein, we report a new strategy based on platelet membrane-camouflaged aggregation-induced emission (AIE) luminogen (Plt-M@P) combined with the anti-programmed death ligand 1 (anti-PD-L1) for tumoral photodynamic-immunotherapy. Plt-M@P is prepared by using poly lactic-co-glycolic acid (PLGA)/PF3-PPh3 complex as a nanocore, and then by co-extrusion with platelet membranes. PF3-PPh3 is an AIE-active conjugated polyelectrolyte with photosensitizing capability for photodynamic therapy (PDT). Plt-M@P exhibits superior tumor targeting capacity in vivo. When applied in small tumor-bearing (~40 mm3) mice, Plt-M@P-mediated PDT significantly inhibits tumor growth. In tumor models with large burdens (~200 mm3), using Plt-M@P-mediated PDT or anti-PD-L1 alone is less effective, but the combination of both is effective in inhibiting tumor growth. Importantly, this combination therapy has good biocompatibility, as demonstrated by the absence of damage to the major organs, especially the reproductive system. In conclusion, we show that Plt-M@P-mediated PDT can improve anti-PD-L1 immunotherapy by enhancing antitumor effects, providing a promising strategy for the treatment of tumors with large burdens.
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Affiliation(s)
- Jun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yating Xu
- College of Material, Chemistry and Chemical EngineeringHangzhou Normal UniversityHangzhouChina
| | - Hongming Yao
- College of Material, Chemistry and Chemical EngineeringHangzhou Normal UniversityHangzhouChina
| | - Xiaoding Lou
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano‐Geomaterials of Ministry of Education, Faculty of Materials Science and ChemistryChina University of GeosciencesWuhanChina
| | - Yuning Hong
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVictoriaAustralia
| | - Jian Zhou
- College of Material, Chemistry and Chemical EngineeringHangzhou Normal UniversityHangzhouChina
| | - Fan Xia
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano‐Geomaterials of Ministry of Education, Faculty of Materials Science and ChemistryChina University of GeosciencesWuhanChina
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Haaker L, Baldewijns M, Wever LD, Albersen M, Debruyne PR, Wynendaele W, Meerleer GD, Beuselinck B. PSEUDOPROGRESSION AND MIXED RESPONSES IN METASTATIC RENAL CELL CARCINOMA PATIENTS TREATED WITH NIVOLUMAB: A RETROSPECTIVE ANALYSIS. Clin Genitourin Cancer 2023:S1558-7673(23)00062-9. [PMID: 36997468 DOI: 10.1016/j.clgc.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/04/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICI) are part of the current standard of care for metastatic clear-cell renal cell carcinoma (m-ccRCC). ICI can elicit diverse tumor response, including atypical responses such as pseudoprogression (psPD), mixed responses (MR) and late responses. We aimed to analyze the occurrence and prognostic impact of atypical responses in m-ccRCC patients treated with nivolumab. MATERIALS AND METHODS A retrospective analysis of m-ccRCC patients treated with nivolumab in first or subsequent therapy line between November 2012 and July 2022 was performed. All radiographic evaluations of eligible patients were analyzed using the iRECIST consensus guideline. RESULTS We assessed 247 baseline target lesions in 94 eligible patients. MR occurred in 11 (11.7%) patients: in 7 at first CT (computed tomography) evaluation (CT1) and in 4 at second CT evaluation (CT2). In 8 patients (73%), MR evolved to confirmed PD. In 3 patients (27%), MR evolved towards a partial response (PR) and was thus a psPD. psPD occurred in 8 (8.5%) patients: with psPD features at CT1 in 3 patients, with psPD features at CT2 in 2 patients, and with MR features at CT1 in 3 patients. psPD patients had similar progression-free survival and overall survival compared to patients displaying PR as best response without a phase of psPD. 76 patients were treated beyond immune unconfirmed progressive disease (iUPD) at any moment: 12 (16%) of them evolved towards PR or stable disease (SD). Treatment beyond immune confirmed PD (iCPD) in 20 patients did not lead to PR or SD. CONCLUSION Atypical responses such as psPD and MR occurred in 8.5% and 11.7% of m-ccRCC patients treated with nivolumab at CT1 and CT2. Patients with psPD had favorable outcomes, while MR most often evolved to progression. Treatment with nivolumab beyond iCPD did not lead to tumor stabilization or regression.
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16
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Zhang Z, Xie C, Gao T, Yang Y, Yang Y, Zhao L. Identification on surrogating overall survival with progression-free survival of first-line immunochemotherapy in advanced esophageal squamous cell carcinoma-an exploration of surrogate endpoint. BMC Cancer 2023; 23:145. [PMID: 36765311 PMCID: PMC9921746 DOI: 10.1186/s12885-023-10613-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Overall survival (OS) is the gold standard to assess novel therapeutics to treat cancer. However, to identify early efficacy and speed up drug approval, trials have used progression-free survival (PFS) as a surrogate endpoint (SE). Herein, we aimed to examine if PFS could function as an OS surrogate in advanced Esophageal Squamous Cell Carcinoma (ESCC) treated with first-line immunochemotherapy. METHODS Two hundred ninety-two advanced ESCC patients treated using inhibitors of PD-1/PD-L1 + chemotherapy or chemotherapy alone were collected. In addition, six phase III randomized clinical trials were eligible for inclusion. Bayesian normal-induced-copula-estimation model in retrospective patient data and regression analysis in the published trial data were used to determine the PFS-OS correlation. RESULTS PFS correlated moderately with OS in the retrospective cohort (Kendall's Tau = 0.684, τ = 0.436). In trial-level, treatments effects for PFS correlated weakly with those for OS in intention-to-treat population (R2 = 0.436, adj.R2 = 0.249, P > 0.05) and in PD-L1-enriched population (R2 = 0.072). In arm-level, median PFS also correlated weakly with median OS. Moreover, analysis of the retrospective cohort demonstrated that the annual death risk after progression in the continued immunotherapy group was considerably lower than that in the discontinued group. CONCLUSION In trials of anti-PD-1 agents to treat advanced ESCC, the current results provide only weak support for PFS as an OS surrogate; OS cannot be substituted completely by PFS in these cases. The results also suggest that qualified patients with advanced ESCC might benefit from continuous immunotherapy beyond progression to achieve a decreased risk of death.
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Affiliation(s)
- Zewei Zhang
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chunxia Xie
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Tiantian Gao
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuxian Yang
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yong Yang
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Lei Zhao
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
- State Key Laboratory of Oncology in South China, Guangzhou, China.
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Jiang S, Zhang J, Chu L, Chu X, Yang X, Li Y, Guo T, Zhou Y, Xu D, Mao J, Zheng Z, An Y, Sun H, Dong H, Yu S, Ye R, Hu J, Chu Q, Ni J, Zhu Z. Atypical Response in Metastatic Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors: Radiographic Patterns and Clinical Value of Local Therapy. Cancers (Basel) 2022; 15:cancers15010180. [PMID: 36612176 PMCID: PMC9818210 DOI: 10.3390/cancers15010180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
PURPOSE To explore the clinical characteristics, management, and survival outcomes of advanced NSCLC patients treated with PD-1/PD-L1 inhibitors who presented with an atypical response (AR). METHODS A total of 926 PD-1/PD-L1-inhibitor-treated patients with metastatic NSCLC from three academic centers were retrospectively reviewed. All measurable lesions were evaluated by RECIST version 1.1. RESULTS Fifty-six (6.1%) patients developed AR. The median time to the occurrence of AR was 2.0 months. Patients with no fewer than 3 metastatic organs at baseline were more prone to develop AR in advanced NSCLC (p = 0.038). The common sites of progressive lesions were lymph nodes (33.8%) and lungs (29.7%). The majority (78.2%) of patients with AR had only 1-2 progressive tumor lesions, and most (89.1%) of the progressive lesions developed from originally existing tumor sites. There was no significance in terms of survival between patients with AR and those with typical response (TR). Local therapy was an independent predictor for PFS of patients with AR (p = 0.025). CONCLUSIONS AR was not an uncommon event in patients with metastatic NSCLC treated with PD-1/PD-L1 inhibitors, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive lesions without discontinuing original PD-1/PD-L1 inhibitors may improve patient survival.
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Affiliation(s)
- Shanshan Jiang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Jinmeng Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Li Chu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Xiao Chu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Xi Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Yida Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Tiantian Guo
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Yue Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Dayu Xu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Jiuang Mao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Zhiqin Zheng
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Yulin An
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Hua Sun
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Huiling Dong
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Silai Yu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Ruiting Ye
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
| | - Jie Hu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jianjiao Ni
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
- Correspondence: (J.N.); (Z.Z.); Tel.: +86-137-6197-4092 (J.N.); +86-180-1731-2901 (Z.Z.); Fax: +86-216-417-5242 (J.N. & Z.Z.)
| | - Zhengfei Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai 200032, China
- Correspondence: (J.N.); (Z.Z.); Tel.: +86-137-6197-4092 (J.N.); +86-180-1731-2901 (Z.Z.); Fax: +86-216-417-5242 (J.N. & Z.Z.)
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Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer. Br J Cancer 2022; 127:2227-2233. [PMID: 36229579 PMCID: PMC9726864 DOI: 10.1038/s41416-022-02004-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 09/21/2022] [Accepted: 09/27/2022] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. METHODS Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. RESULTS Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3-19.7) and 3.9 months (95% CI, 2.3-5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9-14.7) for control arm patients (N = 31). CONCLUSIONS Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases. TRIAL REGISTRATION ClinicalTrials.gov number, NCT03388190 (02/01/2018).
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Wang Z, Mu L, Feng H, Yao J, Wang Q, Yang W, Zhou H, Li Q, Xu L. Expression patterns of platinum resistance-related genes in lung adenocarcinoma and related clinical value models. Front Genet 2022; 13:993322. [PMID: 36506331 PMCID: PMC9730711 DOI: 10.3389/fgene.2022.993322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 10/21/2022] [Indexed: 11/25/2022] Open
Abstract
The purpose of this study was to explore platinum resistance-related biomarkers and mechanisms in lung adenocarcinoma. Through the analysis of gene expression data of lung adenocarcinoma patients and normal patients from The Cancer Genome Atlas, Gene Expression Omnibus database, and A database of genes related to platinum resistance, platinum resistance genes in lung adenocarcinoma and platinum resistance-related differentially expressed genes were obtained. After screening by a statistical significance threshold, a total of 252 genes were defined as platinum resistance genes with significant differential expression, of which 161 were up-regulated and 91 were down-regulated. The enrichment results of up-regulated gene Gene Ontology (GO) showed that TOP3 entries related to biological processes (BP) were double-strand break repair, DNA recombination, DNA replication, the down-regulated gene GO enriches the TOP3 items about biological processes (BP) as a response to lipopolysaccharide, muscle cell proliferation, response to molecule of bacterial origin. Gene Set Enrichment Analysis showed that the top three were e2f targets, g2m checkpoint, and rgf beta signaling. A prognostic model based on non-negative matrix factorization classification showed the characteristics of high- and low-risk groups. The prognostic model established by least absolute shrinkage and selection operator regression and risk factor analysis showed that genes such as HOXB7, NT5E, and KRT18 were positively correlated with risk score. By analyzing the differences in m6A regulatory factors between high- and low-risk groups, it was found that FTO, GPM6A, METTL3, and YTHDC2 were higher in the low-risk group, while HNRNPA2B1, HNRNPC, TGF2BP1, IGF2BP2, IGF2BP3, and RBM15B were higher in the high-risk group. Immune infiltration and drug sensitivity analysis also showed the gene characteristics of the platinum-resistant population in lung adenocarcinoma. ceRNA analysis showed that has-miR-374a-5p and RP6-24A23.7 were lower in the tumor expression group, and that the survival of the low expression group was worse than that of the high expression group. In conclusion, the results of this study show that platinum resistance-related differentially expressed genes in lung adenocarcinoma are mainly concentrated in biological processes such as DNA recombination and response to lipopolysaccharide. The validation set proved that the high-risk group of our prognostic model had poor survival. M6A regulatory factor analysis, immune infiltration, and drug sensitivity analysis all showed differences between high and low-risk groups. ceRNA analysis showed that has-miR-374a-5p and RP6-24A23.7 could be protective factors. Further exploration of the potential impact of these genes on the risk and prognosis of drug-resistant patients with lung adenocarcinoma would provide theoretical support for future research.
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Affiliation(s)
- Zhe Wang
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Mu
- Department of Ophthalmology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - He Feng
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Zhejiang, China
| | - Jialin Yao
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qin Wang
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenxiao Yang
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huiling Zhou
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qinglin Li
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Zhejiang, China,*Correspondence: Qinglin Li, ; Ling Xu,
| | - Ling Xu
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Qinglin Li, ; Ling Xu,
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20
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Kuo WK, Weng CF, Lien YJ. Treatment beyond progression in non-small cell lung cancer: A systematic review and meta-analysis. Front Oncol 2022; 12:1023894. [PMID: 36465371 PMCID: PMC9713814 DOI: 10.3389/fonc.2022.1023894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/26/2022] [Indexed: 09/30/2023] Open
Abstract
OBJECTIVES Treatment beyond progression (TBP) is defined as treatment continuing in spite of disease progression, according to the Response Evaluation Criteria In Solid Tumors. We performed a systematic review and meta-analysis to provide evidence for the effects of TBP on lung cancer survival. MATERIALS AND METHODS This study has been conducted following the PRISMA guidelines. A systematic review of PubMed, MEDLINE, Embase, and Cochrane Collaboration Central Register of Controlled Clinical Trials from the inception of each database to December 2021 was conducted. Two authors independently reviewed articles for inclusion and extract data from all the retrieved articles. Random-effects meta-analysis was performed using Comprehensive Meta-Analysis software, version 3 (Biostat, Englewood, NJ, USA). Hazard ratios (HRs) with the corresponding 95% confidence intervals (CI) were used for survival outcomes. RESULTS We identified five (15.6%) prospective randomized trials and twenty-seven (84.4%) retrospective observational studies of a total of 9,631 patients for the meta-analysis. 3,941 patients (40.9%) were in a TBP group and 5,690 patients (59.1%) were in a non-TBP group. There is a statistically significant advantage for patients who received TBP compared with those who did not in post progression progression-free survival (ppPFS), post progression overall survival (ppOS), and overall survival (OS) from initiation of drugs (ppPFS: HR, 0.746; 95% CI, 0.644-0.865; P<0.001; ppOS: HR, 0.689; 95% CI, 0.596-0.797; P<0.001; OS from initiation of drugs: HR, 0.515; 95% CI, 0.387-0.685; P<0.001). CONCLUSION This study provides further evidence in support of TBP for NSCLC, however, these results require cautious interpretation. Large, randomized, controlled trials investigating the efficacy of TBP in lung cancer treatment are warranted. SYSTEMIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021285147.
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Affiliation(s)
- Wei-Ke Kuo
- Division of Respiratory Therapy and Chest Medicine, Sijhih Cathay General Hospital, Taipei, Taiwan
| | - Ching-Fu Weng
- Division of Pulmonary Medicine, Department of Internal Medicine, Hsinchu Cathay General Hospital, Hsinchu, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Yin-Ju Lien
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
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21
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Moreno V, Roda D, Pikiel J, Trigo J, Bosch-Barrera J, Drew Y, Kristeleit R, Hiret S, Bajor DL, Cruz P, Beck JT, Ghosh S, Dabrowski C, Antony G, Duan T, Veneris J, Zografos E, Subramanian J. Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non-small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial. Clin Lung Cancer 2022; 23:e415-e427. [PMID: 35729005 DOI: 10.1016/j.cllc.2022.05.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Dostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non-small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284). MATERIALS AND METHODS Here, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety. RESULTS As of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients. CONCLUSION Dostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile.
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Affiliation(s)
- Victor Moreno
- START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain
| | | | | | - Jose Trigo
- Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain
| | - Joaquim Bosch-Barrera
- Catalan Institute of Oncology (ICO), Hospital Universitari Dr Josep Trueta, Girona, Spain
| | - Yvette Drew
- Clinical and Translational Institute, Newcastle University, Newcastle, UK
| | | | - Sandrine Hiret
- Institut de Cancérologie de l'Ouest, René Gauducheau, St Herblain, France
| | - David L Bajor
- University Hospitals Cleveland Medical Centre, Cleveland, OH
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Schomburg L, Malouhi A, Grimm MO, Ingwersen M, Foller S, Leucht K, Teichgräber U. iRECIST-based versus non-standardized free text reporting of CT scans for monitoring metastatic renal cell carcinoma: a retrospective comparison. J Cancer Res Clin Oncol 2022; 148:2003-2012. [PMID: 35420348 PMCID: PMC9294024 DOI: 10.1007/s00432-022-03997-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/26/2022] [Indexed: 12/02/2022]
Abstract
PURPOSE Therapy decision for patients with metastatic renal cell carcinoma (mRCC) is highly dependent on disease monitoring based on radiological reports. The purpose of the study was to compare non-standardized, common practice free text reporting (FTR) on disease response with reporting based on response evaluation criteria in solid tumors modified for immune-based therapeutics (iRECIST). METHODS Fifty patients with advanced mRCC were included in the retrospective, single-center study. CT scans had been evaluated and FTR prepared in accordance with center's routine practice. For study purposes, reports were re-evaluated using a dedicated computer program that applied iRECIST. Patients were followed up over a period of 22.8 ± 7.9 months in intervals of 2.7 ± 1.8 months. Weighted kappa statistics was run to assess strength of agreement. Logistic regression was used to identify predictors for different rating. RESULTS Agreement between FTR and iRECIST-based reporting was moderate (kappa 0.38 [95% CI 0.2-0.6] to 0.70 [95% CI 0.5-0.9]). Tumor response or progression according to FTR were not confirmed with iRECIST in 19 (38%) or 11 (22%) patients, respectively, in at least one follow-up examination. With FTR, new lesions were frequently not recognized if they were already identified in the recent prior follow-up examination (odds ratio for too favorable rating of disease response compared to iRECIST: 5.4 [95% CI 2.9-10.1]. CONCLUSIONS Moderate agreement between disease response according to FTR or iRECIST in patients with mRCC suggests the need of standardized quantitative radiological assessment in daily clinical practice.
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Affiliation(s)
- Laura Schomburg
- Department of Diagnostic and Interventional Radiology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Amer Malouhi
- Department of Diagnostic and Interventional Radiology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Marc-Oliver Grimm
- Department of Urology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07743, Jena, Germany
| | - Maja Ingwersen
- Department of Diagnostic and Interventional Radiology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Susan Foller
- Department of Urology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07743, Jena, Germany
| | - Katharina Leucht
- Department of Urology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07743, Jena, Germany
| | - Ulf Teichgräber
- Department of Diagnostic and Interventional Radiology, Friedrich-Schiller-University, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany.
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18FDG PET Assessment of Therapeutic Response in Patients with Advanced or Metastatic Melanoma Treated with First-Line Immune Checkpoint Inhibitors. Cancers (Basel) 2022; 14:cancers14133190. [PMID: 35804963 PMCID: PMC9264956 DOI: 10.3390/cancers14133190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 12/21/2022] Open
Abstract
Simple Summary In a retrospective study of patients with advanced or metastatic melanoma treated with first-line immune checkpoint inhibitors, we investigated the value of metabolic criteria, PERCIST 5 (criteria used for conventional chemotherapy), and imPERCIST5 (criteria adapted for immunotherapy therapeutic evaluation). Responding patients according to both criteria had better overall survival than that of not-responding patients, with a 2 years OS of 91% versus 39%, respectively. Combining different approaches to assess response could help improve the confidence in the test aiming at evaluating the response to immunotherapy. Abstract Background: Immune checkpoint inhibitors (ICI) are currently the first-line treatment for patients with metastatic melanoma. We investigated the value of positron emission tomography (PET) response criteria to assess the therapeutic response to first-line ICI in this clinical context and explore the potential contribution of total tumor metabolic volume (TMTV) analysis. Methods: We conducted a retrospective study in patients treated with first-line ICI for advanced or metastatic melanoma, with 18F-FDG PET/CT performed at baseline and 3 months after starting treatment. Patients’ metabolic response was classified according to PERCIST5 and imPERCIST 5 criteria. TMTV was recorded for each examination. Results: Twenty-nine patients were included. The median overall survival (OS) was 51.2 months (IQR 13.6—not reached), and the OS rate at 2 years was 58.6%. Patients classified as responders (complete and partial response) had a 90.9% 2-year OS rate versus 38.9% for non-responders (stable disease and progressive disease) (p = 0.03), for PERCIST5 and imPERCIST 5 criteria. The median change in metabolic volume was 9.8% (IQR −59–+140%). No significant correlation between OS and changes in TMTV was found. Conclusion: The evaluation of response to immunotherapy using metabolic imaging with PERCIST5 and imPERCIST5 was significantly associated with OS in patients with advanced or metastatic melanoma.
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Govindan R, Aggarwal C, Antonia SJ, Davies M, Dubinett SM, Ferris A, Forde PM, Garon EB, Goldberg SB, Hassan R, Hellmann MD, Hirsch FR, Johnson ML, Malik S, Morgensztern D, Neal JW, Patel JD, Rimm DL, Sagorsky S, Schwartz LH, Sepesi B, Herbst RS. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma. J Immunother Cancer 2022; 10:jitc-2021-003956. [PMID: 35640927 PMCID: PMC9157337 DOI: 10.1136/jitc-2021-003956] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2022] [Indexed: 12/24/2022] Open
Abstract
Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)— either as monotherapy or in combination with other ICIs or chemotherapy—have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC’s 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma.
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Affiliation(s)
- Ramaswamy Govindan
- Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in Saint Louis, St Louis, Missouri, USA
| | - Charu Aggarwal
- Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Scott J Antonia
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute Center for Cancer Immunotherapy, Durham, North Carolina, USA
| | - Marianne Davies
- Yale School of Nursing, Yale Cancer Center, New Haven, Connecticut, USA
| | - Steven M Dubinett
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
| | | | - Patrick M Forde
- Upper Aerodigestive Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Edward B Garon
- Division of Hematology/Oncology, Department of Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
| | - Sarah B Goldberg
- Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut, USA
| | - Raffit Hassan
- Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Fred R Hirsch
- Center for Thoracic Oncology, Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Melissa L Johnson
- Sarah Cannon Research Institute, Nashville, Tennessee, USA
- Tennessee Oncology/One Oncology, Nashville, Tennessee, USA
| | - Shakun Malik
- Division of Cancer Treatment & Diagnosis, CTEP, National Cancer Institute, Rockville, Maryland, USA
| | - Daniel Morgensztern
- Department of Medicine, Oncology Division, Medical Oncology, Washington University School of Medicine in Saint Louis, St Louis, Missouri, USA
| | - Joel W Neal
- Stanford Cancer Institute, Stanford University, Stanford, California, USA
| | - Jyoti D Patel
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois, USA
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Sarah Sagorsky
- Upper Aerodigestive Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lawrence H Schwartz
- Department of Radiology, Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
| | - Boris Sepesi
- Department of Thoracic and Cardiovascular Surgery, Division of Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Roy S Herbst
- Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut, USA
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25
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Lopci E, Hicks RJ, Dimitrakopoulou-Strauss A, Dercle L, Iravani A, Seban RD, Sachpekidis C, Humbert O, Gheysens O, Glaudemans AWJM, Weber W, Wahl RL, Scott AM, Pandit-Taskar N, Aide N. Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [ 18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0. Eur J Nucl Med Mol Imaging 2022; 49:2323-2341. [PMID: 35376991 PMCID: PMC9165250 DOI: 10.1007/s00259-022-05780-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/22/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE The goal of this guideline/procedure standard is to assist nuclear medicine physicians, other nuclear medicine professionals, oncologists or other medical specialists for recommended use of [18F]FDG PET/CT in oncological patients undergoing immunotherapy, with special focus on response assessment in solid tumors. METHODS In a cooperative effort between the EANM, the SNMMI and the ANZSNM, clinical indications, recommended imaging procedures and reporting standards have been agreed upon and summarized in this joint guideline/procedure standard. CONCLUSIONS The field of immuno-oncology is rapidly evolving, and this guideline/procedure standard should not be seen as definitive, but rather as a guidance document standardizing the use and interpretation of [18F]FDG PET/CT during immunotherapy. Local variations to this guideline should be taken into consideration. PREAMBLE The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology and practical application of nuclear medicine. The Australian and New Zealand Society of Nuclear Medicine (ANZSNM), founded in 1969, represents the major professional society fostering the technical and professional development of nuclear medicine practice across Australia and New Zealand. It promotes excellence in the nuclear medicine profession through education, research and a commitment to the highest professional standards. EANM, SNMMI and ANZSNM members are physicians, technologists, physicists and scientists specialized in the research and clinical practice of nuclear medicine. All three societies will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the EANM/SNMMI/ANZSNM, has undergone a thorough consensus process, entailing extensive review. These societies recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents based on current knowledge. They are not intended to be inflexible rules or requirements of practice, nor should they be used to establish a legal standard of care. For these reasons and those set forth below, the EANM, SNMMI and ANZSNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an action differing from what is laid out in the guidelines/procedure standards, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines/procedure standards. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/ guidelines will not ensure a successful outcome. All that should be expected is that practitioners follow a reasonable course of action, based on their level of training, current knowledge, clinical practice guidelines, available resources and the needs/context of the patient being treated. The sole purpose of these guidelines is to assist practitioners in achieving this objective. The present guideline/procedure standard was developed collaboratively by the EANM, the SNMMI and the ANZSNM, with the support of international experts in the field. They summarize also the views of the Oncology and Theranostics and the Inflammation and Infection Committees of the EANM, as well as the procedure standards committee of the SNMMI, and reflect recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.
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Affiliation(s)
- E Lopci
- Nuclear Medicine Unit, IRCCS - Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milano, Italy.
| | - R J Hicks
- The Department of Medicine, St Vincent's Medical School, the University of Melbourne, Melbourne, Australia
| | - A Dimitrakopoulou-Strauss
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69210, Heidelberg, Germany
| | - L Dercle
- Department of Radiology, New York Presbyterian, Columbia University Irving Medical Center, New York, NY, USA
| | - A Iravani
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - R D Seban
- Department of Nuclear Medicine and Endocrine Oncology, Institut Curie, 92210, Saint-Cloud, France
- Laboratoire d'Imagerie Translationnelle en Oncologie, Inserm, Institut Curie, 91401, Orsay, France
| | - C Sachpekidis
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69210, Heidelberg, Germany
| | - O Humbert
- Department of Nuclear Medicine, Centre Antoine-Lacassagne, Université Côte d'Azur, Nice, France
- TIRO-UMR E 4320, Université Côte d'Azur, Nice, France
| | - O Gheysens
- Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - A W J M Glaudemans
- Nuclear Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - W Weber
- Department of Nuclear Medicine, Klinikum Rechts Der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - R L Wahl
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - A M Scott
- Department of Molecular Imaging and Therapy, Austin Health, Studley Rd, Heidelberg, Victoria, 3084, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- Faculty of Medicine, University of Melbourne, Melbourne, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - N Pandit-Taskar
- Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10021, USA
| | - N Aide
- Nuclear Medicine Department, University Hospital, Caen, France
- INSERM ANTICIPE, Normandie University, Caen, France
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Relationship between Patients’ Baseline Characteristics and Survival Benefits in Immunotherapy-Treated Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. JOURNAL OF ONCOLOGY 2022; 2022:3601942. [PMID: 35646119 PMCID: PMC9135521 DOI: 10.1155/2022/3601942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/21/2022] [Accepted: 04/30/2022] [Indexed: 11/17/2022]
Abstract
Background The difference of patients' baseline characteristics such as sex, age, Eastern Cooperative Oncology Group performance status (ECOG PS), and smoking status may influence the immune response. However, little is known about whether these factors affect the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we performed this systematic review and meta-analysis to investigate the relationship between patients' baseline characteristics and survival benefits in immunotherapy-treated NSCLC. Materials and Methods We performed a systematic search of PubMed, the Cochrane Library, and Embase for randomized controlled trials (RCTs) of NSCLC immunotherapy. We also searched abstracts and presentations from the proceedings of the American Society of Clinical Oncology and the European Society of Medical Oncology to identify unpublished studies. These studies have available data based on patients' baseline characteristics (such as sex, age, ECOG PS, and smoking status). We take the hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS) as the effect index and use the random effect model to pool the results. Results We included 18 phase II/III RCTs with a total of 14,189 participants. The benefits of ICIs were found for both male (pooled OS-HR 0.77, 95% CI 0.72-0.82, P < 0.05) and female patients (pooled OS-HR 0.77, 95% CI 0.67-0.87, P < 0.05); for both younger (<65 y: pooled OS-HR 0.74, 95% CI 0.68-0.81, P < 0.05) and older patients (≥65 y: pooled OS-HR 0.80, 95% CI 0.75-0.86, P < 0.05); and for both patients with ECOG PS = 0 (pooled OS-HR 0.77, 95% CI 0.71-0.84, P < 0.05) and ECOG PS ≥ 1 (pooled OS-HR 0.76, 95% CI 0.70-0.82, P < 0.05). Moreover, there was no significant difference in the efficacy of ICIs among different sex (P value for interaction = 0.955), age (P value for interaction = 0.17), or ECOG PS (P value for interaction = 0.765). However, in patients with different smoking status, the application of ICIs significantly prolonged the OS of smokers (pooled OS-HR 0.77, 95% CI 0.71-0.83, P < 0.05) but could not significantly improve the OS of never smokers (pooled OS-HR 0.85, 95% CI 0.70-1.03, P > 0.05). Conclusions ICIs could significantly improve prognosis in patients with advanced NSCLC, regardless of sex, age, or ECOG PS. But among patients with different smoking status, the survival benefits of never smokers treated with ICIs were no better than that of controls. The impact of these factors on immunotherapy should be considered in the future clinical practice and guidelines.
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Ipilimumab, Pembrolizumab, or Nivolumab in Combination with BBI608 in Patients with Advanced Cancers Treated at MD Anderson Cancer Center. Cancers (Basel) 2022; 14:cancers14051330. [PMID: 35267638 PMCID: PMC8909492 DOI: 10.3390/cancers14051330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/26/2022] [Accepted: 03/01/2022] [Indexed: 12/10/2022] Open
Abstract
Background: BBI608 is an investigational reactive oxygen species generator that affects several molecular pathways. We investigated BBI608 combined with immune checkpoint inhibitors in patients with advanced cancers. Methods: BBI608 (orally twice daily) was combined with ipilimumab (3 mg/kg IV every 3 weeks); pembrolizumab (2 mg/kg IV every 3 weeks); or nivolumab (3 mg/kg IV every 4 weeks). We assessed the safety, antitumor activity and the pharmacokinetic profile of BBI combined with immunotherapy. Results: From 1/2017 to 3/2017, 12 patients were treated (median age, 54 years; range, 31–78; 6 men). Treatment was overall well tolerated. No dose-limiting toxicity was observed. The most common adverse events were diarrhea (5 patients: grade (G)1–2, n = 3; G3, n = 2) and nausea (4 patients, all G1). Prolonged disease stabilization was noted in five patients treated with BBI608/nivolumab lasting for 12.1, 10.1, 8.0, 7.7 and 7.4 months. The median progression-free survival was 2.73 months. The median overall survival was 7.56 months. Four patients had prolonged overall survival (53.0, 48.7, 51.9 and 48.2 months). Conclusions: Checkpoint inhibitors combined with BBI608 were well tolerated. Several patients had prolonged disease stabilization and overall survival. Prospective studies to elucidate the mechanisms of response and resistance to BBI608 are warranted.
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Dercle L, Zhao B, Gönen M, Moskowitz CS, Firas A, Beylergil V, Connors DE, Yang H, Lu L, Fojo T, Carvajal R, Karovic S, Maitland ML, Goldmacher GV, Oxnard GR, Postow MA, Schwartz LH. Early Readout on Overall Survival of Patients With Melanoma Treated With Immunotherapy Using a Novel Imaging Analysis. JAMA Oncol 2022; 8:385-392. [PMID: 35050320 PMCID: PMC8778619 DOI: 10.1001/jamaoncol.2021.6818] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
IMPORTANCE Existing criteria to estimate the benefit of a therapy in patients with cancer rely almost exclusively on tumor size, an approach that was not designed to estimate survival benefit and is challenged by the unique properties of immunotherapy. More accurate prediction of survival by treatment could enhance treatment decisions. OBJECTIVE To validate, using radiomics and machine learning, the performance of a signature of quantitative computed tomography (CT) imaging features for estimating overall survival (OS) in patients with advanced melanoma treated with immunotherapy. DESIGN, SETTING, AND PARTICIPANTS This prognostic study used radiomics and machine learning to retrospectively analyze CT images obtained at baseline and first follow-up and their associated clinical metadata. Data were prospectively collected in the KEYNOTE-002 (Study of Pembrolizumab [MK-3475] Versus Chemotherapy in Participants With Advanced Melanoma; 2017 analysis) and KEYNOTE-006 (Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab [MK-3475] Compared to Ipilimumab in Participants With Advanced Melanoma; 2016 analysis) multicenter clinical trials. Participants included 575 patients with a diagnosis of advanced melanoma who were randomly assigned to training and validation sets. Data for the present study were collected from November 20, 2012, to June 3, 2019, and analyzed from July 1, 2019, to September 15, 2021. INTERVENTIONS KEYNOTE-002 featured trial groups testing intravenous pembrolizumab, 2 mg/kg or 10 mg/kg every 2 or every 3 weeks based on randomization, or investigator-choice chemotherapy; KEYNOTE-006 featured trial groups testing intravenous ipilimumab, 3 mg/kg every 3 weeks and intravenous pembrolizumab, 10 mg/kg every 2 or 3 weeks based on randomization. MAIN OUTCOMES AND MEASURES The performance of the signature CT imaging features for estimating OS at the month 6 posttreatment landmark in patients who received pembrolizumab was measured using an area under the time-dependent receiver operating characteristics curve (AUC). RESULTS A random forest model combined 25 imaging features extracted from tumors segmented on CT images to identify the combination (signature) that best estimated OS with pembrolizumab in 575 patients. The signature combined 4 imaging features, 2 related to tumor size and 2 reflecting changes in tumor imaging phenotype. In the validation set (287 patients treated with pembrolizumab), the signature reached an AUC for estimation of OS status of 0.92 (95% CI, 0.89-0.95). The standard method, Response Evaluation Criteria in Solid Tumors 1.1, achieved an AUC of 0.80 (95% CI, 0.75-0.84) and classified tumor outcomes as partial or complete response (93 of 287 [32.4%]), stable disease (90 of 287 [31.3%]), or progressive disease (104 of 287 [36.2%]). CONCLUSIONS AND RELEVANCE The findings of this prognostic study suggest that the radiomic signature discerned from conventional CT images at baseline and on first follow-up may be used in clinical settings to provide an accurate early readout of future OS probability in patients with melanoma treated with single-agent programmed cell death 1 blockade.
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Affiliation(s)
- Laurent Dercle
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
| | - Binsheng Zhao
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chaya S. Moskowitz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmed Firas
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
| | - Volkan Beylergil
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
| | - Dana E. Connors
- Foundation for the National Institutes of Health, North Bethesda, Maryland
| | - Hao Yang
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
| | - Lin Lu
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
| | - Tito Fojo
- Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York
| | - Richard Carvajal
- Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York
| | - Sanja Karovic
- Inova Center for Personalized Health and Schar Cancer Institute, Fairfax, Virginia
| | - Michael L. Maitland
- Inova Center for Personalized Health and Schar Cancer Institute, Fairfax, Virginia,University of Virginia Cancer Center, Charlottesville
| | | | - Geoffrey R. Oxnard
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Michael A. Postow
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York,Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Lawrence H. Schwartz
- Department of Radiology, Columbia University Medical Center, New York, New York,Department of Radiology, New York Presbyterian Hospital, New York, New York
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Zhou M, Zhang C, Nie J, Sun Y, Xu Y, Wu F, Huang Y, Li S, Wang Y, Zhou Y, Zheng T. Response Evaluation and Survival Prediction Following PD-1 Inhibitor in Patients With Advanced Hepatocellular Carcinoma: Comparison of the RECIST 1.1, iRECIST, and mRECIST Criteria. Front Oncol 2021; 11:764189. [PMID: 34956885 PMCID: PMC8697350 DOI: 10.3389/fonc.2021.764189] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background Precise evaluation of the efficacy of immunotherapy is critical in the effective management and treatment of advanced hepatocellular carcinoma (HCC). Therefore, the purpose of this study was to compare the response assessments achieved by different criteria and to evaluate the correlation between survival outcome and response assessment in HCC treated with programmed cell death protein 1 (PD-1) inhibitor. Methods Fifty patients with advanced HCC treated with first-line PD-1 inhibitor with baseline and follow‐up CT images were analyzed. The patients were categorized into responders and nonresponders according to the criteria. Results When the response assessments between RECIST 1.1 and mRECIST were compared, no statistically significant differences were observed. Overall response rate was 16% by RECIST 1.1 and iRECIST and was 24% by mRECIST. According to RECIST 1.1 and mRECIST, overall survival (OS) and progression-free survival (PFS) were not statistically different between the complete response (CR) and partial response (PR) groups and the stable disease (SD) and progressive disease (PD) groups. The OS and PFS were significantly different between responders and nonresponders according to mRECIST. The Cohen’s Kappa for RECIST 1.1, iRECIST, and mRECIST was 0.534, 0.438, and 0.363, respectively. Conclusion The mRECIST criteria have a powerful ability to discriminate between responders and nonresponders and demonstrated significantly longer OS and PFS in responders than in nonresponders. However, mRECIST needs to be further improved in order for it to be widely used in the clinical evaluation of immunotherapy in HCC.
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Affiliation(s)
- Meng Zhou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunhui Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jianhua Nie
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yajuan Sun
- Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ye Xu
- Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Fangfang Wu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuhong Huang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shun Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuan Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Zhou
- Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.,Department of Phase 1 Trials Center, Harbin Medical University Cancer Hospital, Harbin, China.,Key Laboratory of Molecular Oncology, Heilongjiang Cancer Institute, Harbin, China
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Zhu G, Yang K, Tang S, Peng L. Progression-free survival assessed per immune-related or conventional response criteria, which is the better surrogate endpoint for overall survival in trials of immune-checkpoint inhibitors in lung cancer: A systematic review and meta-analysis. Cancer Med 2021; 10:8272-8287. [PMID: 34668660 PMCID: PMC8633231 DOI: 10.1002/cam4.4347] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/14/2021] [Accepted: 09/29/2021] [Indexed: 12/19/2022] Open
Abstract
Progression-free survival (PFS) has been used as a surrogate endpoint for overall survival (OS) in lung cancer trials. The pattern of response to immune-checkpoint inhibitors (ICIs) differs from that to conventional chemotherapy, so immune-related response evaluation criteria were proposed. This study aims at determining which PFS measure, PFS assessed per immune-related response evaluation criteria (iPFS), or conventional criteria (cPFS), is the better surrogate endpoint for OS in trials of ICIs in lung cancer. We selected clinical trials in lung cancer that administered ICIs to at least one arm and reported both median OS and median PFS from PubMed, Embase, and The Cochrane Library. We compared the correlation between treatment effect (hazard ratio) on OS and cPFS or iPFS and the correlation between median OS and median cPFS or iPFS using weighted linear regression at trial level. We analyzed 78 ICI arms (13,438 patients) from 54 studies, including 66 arms with cPFS, seven arms with iPFS, and five arms with both kinds of PFS. We demonstrated an excellent correlation between treatment effect (hazard ratio) on OS and iPFS (RWLS2 = 0.91), while the correlation was moderate for cPFS (RWLS2 = 0.38). Similarly, the correlation between median OS and median iPFS was also strong (RWLS2 ranging from 0.86 to 0.96) across different phases of trials and different types of lung cancer, ICI, and treatment modalities, while it was much weaker for median cPFS (RWLS2 ranging from 0.28 to 0.88). In conclusion, iPFS provides better trial-level surrogacy for OS than cPFS in trials of ICIs in lung cancer.
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Affiliation(s)
- Guang‐Li Zhu
- Department of Otorhinolaryngology Head and Neck Surgerythe First Affiliated Hospital of Sun Yat‐sen UniversityInstitute of Otorhinolaryngology Head and Neck SurgerySun Yat‐sen UniversityGuangzhouP. R. China
- Department of Radiation OncologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Kai‐Bin Yang
- Department of Radiation OncologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Si‐Qi Tang
- Department of Radiation OncologySun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Liang Peng
- Department of Otorhinolaryngology Head and Neck Surgerythe First Affiliated Hospital of Sun Yat‐sen UniversityInstitute of Otorhinolaryngology Head and Neck SurgerySun Yat‐sen UniversityGuangzhouP. R. China
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Boutros A, Bruzzone M, Tanda ET, Croce E, Arecco L, Cecchi F, Pronzato P, Ceppi M, Lambertini M, Spagnolo F. Health-related quality of life in cancer patients treated with immune checkpoint inhibitors in randomised controlled trials: A systematic review and meta-analysis. Eur J Cancer 2021; 159:154-166. [PMID: 34753012 DOI: 10.1016/j.ejca.2021.10.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/30/2021] [Accepted: 10/07/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionised clinical practice in oncology in the last years, leading to a survival benefit in several tumour types. To investigate whether these benefits are associated with improved quality of life, we conducted a systematic review and meta-analysis comparing patient-reported outcomes (PROs) between ICIs and standard chemotherapy (CT) in patients with advanced solid tumours. METHODS Clinical trials comparing the efficacy of ICIs (either programmed death receptor-1 and programmed death-ligand 1 inhibitors or cytotoxic T-lymphocyte antigen 4 inhibitors, as single agent or in combination) versus CT were included. Trials evaluating treatment with ICIs plus CT versus CT alone were also included, whereas studies in which the control arm included other anticancer agents (such as targeted therapy and other ICIs) or placebo alone were excluded. The aim of our meta-analysis was to compare PROs in subjects treated with ICIs or ICIs plus CT (intervention) with those reported by patients receiving CT (control). The co-primary endpoints were time from baseline to first deterioration in PROs, defined as the time from baseline to the first clinically significant deterioration in PROs, and the changes in PROs from baseline to follow-up between ICI and CT treatment groups (PROSPERO registration number CRD42021247440). RESULTS A total of 8341 patients from 17 randomised trials of ICI versus CT were included in the analysis. Treatment with ICI delayed clinical deterioration over standard CT in Global Health Status/QoL EORTC QLQ-C30 (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.74-0.89), and in both EQ-5D utility index (HR 0.65; 95% CI, 0.52-0.82) and EQ-5D visual analogue scale (VAS; HR 0.70; 95% CI, 0.61-0.80). The difference in mean change between the ICI-treated group and the CT-treated group was 5.82 (95% CI, 4.11-7.53) in favour of ICI. Similarly, in the EQ-5D, the mean change differences favoured treatment with ICIs in both Utility Index and VAS, with differences of 0.05 (95% CI, 0.03-0.07) and 5.41 (95% CI, 3.39-7.43), respectively. CONCLUSIONS ICIs are associated with higher levels of quality of life and longer time to clinical deterioration on several PROs scales compared with CT in different types of solid tumours.
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Affiliation(s)
- Andrea Boutros
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Genoa, Italy.
| | - Marco Bruzzone
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Enrica T Tanda
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Elena Croce
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Genoa, Italy
| | - Luca Arecco
- Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Genoa, Italy; U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Federica Cecchi
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Paolo Pronzato
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Marcello Ceppi
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genoa, Genoa, Italy; U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Francesco Spagnolo
- Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Mohammed N, Zhou RR, Xiong Z. Imaging evaluation of lung cancer treated with PD-1/PD-L1 inhibitors. Br J Radiol 2021; 94:20210228. [PMID: 34541867 DOI: 10.1259/bjr.20210228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Immunotherapy (PD-1/PD-L1 inhibitors) has attracted attention for lung cancer treatment and recasted the administration of immunotherapeutics to patients who have advanced/metastatic diseases. Whether in combination or as monotherapy, these medications have become common therapies for certain patients with lung cancer. Moreover, their usage is expected to expand widely in the future. This review aims to discuss the imaging evaluation of lung cancer response to PD-1/PD-L1 therapy with focus on new radiological criteria for immunotherapy response. Abnormal radiological responses (pseudoprogression, dissociative responses, and hyperprogression) and immune-related adverse events are also described.
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Affiliation(s)
- Nader Mohammed
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
| | - Rong Rong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Zeng Xiong
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
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He S, Feng Y, Lin Q, Wang L, Wei L, Tong J, Zhang Y, Liu Y, Ye Z, Guo Y, Yu T, Luo Y. CT-Based Peritumoral and Intratumoral Radiomics as Pretreatment Predictors of Atypical Responses to Immune Checkpoint Inhibitor Across Tumor Types: A Preliminary Multicenter Study. Front Oncol 2021; 11:729371. [PMID: 34733781 PMCID: PMC8560023 DOI: 10.3389/fonc.2021.729371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/23/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To develop and validate a new strategy based on radiomics features extracted from intra- and peritumoral regions on CT images for the prediction of atypical responses to the immune checkpoint inhibitor (ICI) in cancer patients. METHODS In total, 135 patients derived from five hospitals with pathologically confirmed malignancies receiving ICI were included in this retrospective study. Atypical responses including pseudoprogression (PsP) and hyperprogression disease (HPD) were identified as their definitions. A subgroup of standard progression disease (sPD) in 2018 was also involved in this study. Based on pretreatment CT imaging, a total of 107 features were extracted from intra- and peri-tumoral regions, respectively. The least absolute shrinkage and selection operator (Lasso) algorithm was used for feature selection, and multivariate logistic analysis was used to develop radiomics signature (RS). Finally, a total of nine RSs, derived from intra-tumoral, peri-tumoral, and combination of both regions, were built respectively to distinguish PsP vs. HPD, PsP vs. sPD, and HPD vs. sPD. The performance of the RSs was evaluated with discrimination, calibration, and clinical usefulness. RESULTS No significant difference was found when compared in terms of clinical characteristics of PsP, HPD, and sPD. RS based on combined regions outperformed those from either intra-tumoral or peri-tumoral alone, yielding an AUC (accuracy) of 0.834 (0.827) for PsP vs. HPD, 0.923 (0.868) for PsP vs. sPD, and 0.959 (0.894) for HPD vs. sPD in the training datasets, and 0.835 (0.794) for PsP vs. HPD, 0.919 (0.867) for PsP vs. sPD, and 0.933 (0.842) for HPD vs. sPD in the testing datasets. The combined RS showed good fitness (Hosmer-Lemeshow test p > 0.05) and provided more net benefit than the treat-none or treat-all scheme by decision curve analysis in both training and testing datasets. CONCLUSION Pretreatment radiomics are helpful to predict atypical responses to ICI across tumor types. The combined RS outperformed those from either intra- or peri-tumoral alone which may provide a more comprehensive characterization of atypical responses to ICI.
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Affiliation(s)
- Shuai He
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yuqing Feng
- Department of Oncology, The Fifth People’s Hospital of Shenyang, Shenyang, China
| | - Qi Lin
- Department of Radiology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Lihua Wang
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Lijun Wei
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Jing Tong
- Department of Radiology, General Hospital of Northern Theater Command, Shenyang, China
| | - Yuwei Zhang
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ying Liu
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhaoxiang Ye
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yan Guo
- Prognostic Diagnosis, GE Healthcare China, Beijing, China
| | - Tao Yu
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Yahong Luo
- Department of Medical Imaging, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
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Lennartz S, Persigehl T. [Radiological monitoring of immunotherapy in renal cell carcinoma]. Aktuelle Urol 2021; 52:474-480. [PMID: 34428827 DOI: 10.1055/a-1489-2163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The Response Evaluation Criteria in Solid Tumours (RECIST 1.1) currently represent the most widely established evaluation criteria for standardised therapy monitoring in solid tumours treated with traditional cytostatic and cytotoxic tumour therapies. The increasing use of immune checkpoint inhibitors in the therapy of metastatic renal cell carcinoma poses special challenges for radiological therapy monitoring due to the presence of atypical response patterns and immunotherapy-specific side-effects. Adapted criteria such as immune RECIST (iRECIST) can help in the follow-up assessment of renal cell carcinoma to detect atypical courses of disease under immune checkpoint inhibitor therapy both within and outside of clinical trials.
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Affiliation(s)
- Simon Lennartz
- Institut für Diagnostische und Interventionelle Radiologie, Uniklinik Köln, Köln, Deutschland
| | - Thorsten Persigehl
- Institut für Diagnostische und Interventionelle Radiologie, Uniklinik Köln, Köln, Deutschland
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Lau D, McLean MA, Priest AN, Gill AB, Scott F, Patterson I, Carmo B, Riemer F, Kaggie JD, Frary A, Milne D, Booth C, Lewis A, Sulikowski M, Brown L, Lapointe JM, Aloj L, Graves MJ, Brindle KM, Corrie PG, Gallagher FA. Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma. J Immunother Cancer 2021; 9:e003125. [PMID: 34561275 PMCID: PMC8475139 DOI: 10.1136/jitc-2021-003125] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI. METHODS Fifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T2-weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year. RESULTS Differential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (Dapp) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (Kapp), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve, and vp) detected after 12 weeks of immunotherapy (p<0.05). CONCLUSIONS Multiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma.
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Affiliation(s)
- Doreen Lau
- Department of Radiology, University of Cambridge, Cambridge, UK
- Cancer Research UK Cambridge Centre, Cambridge, UK
| | - Mary A McLean
- Department of Radiology, University of Cambridge, Cambridge, UK
- Cancer Research UK Cambridge Centre, Cambridge, UK
| | - Andrew N Priest
- Department of Radiology, University of Cambridge, Cambridge, UK
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | - Andrew B Gill
- Department of Radiology, University of Cambridge, Cambridge, UK
- Cancer Research UK Cambridge Centre, Cambridge, UK
| | - Francis Scott
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Ilse Patterson
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | - Bruno Carmo
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | - Frank Riemer
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Joshua D Kaggie
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Amy Frary
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Doreen Milne
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Catherine Booth
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Arthur Lewis
- Clinical Pharmacology & Safety Sciences, AstraZeneca PLC, Cambridge, Cambridgeshire, UK
| | - Michal Sulikowski
- Clinical Pharmacology & Safety Sciences, AstraZeneca PLC, Cambridge, Cambridgeshire, UK
| | - Lee Brown
- Clinical Pharmacology & Safety Sciences, AstraZeneca PLC, Cambridge, Cambridgeshire, UK
| | - Jean-Martin Lapointe
- Clinical Pharmacology & Safety Sciences, AstraZeneca PLC, Cambridge, Cambridgeshire, UK
| | - Luigi Aloj
- Department of Radiology, University of Cambridge, Cambridge, UK
- Department of Nuclear Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Martin J Graves
- Department of Radiology, University of Cambridge, Cambridge, UK
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | - Kevin M Brindle
- Cancer Research UK Cambridge Research Institute, Cambridge, UK
| | - Pippa G Corrie
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Ferdia A Gallagher
- Department of Radiology, University of Cambridge, Cambridge, UK
- Cancer Research UK Cambridge Centre, Cambridge, UK
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36
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Iyalomhe O, Farwell MD. Immune PET Imaging. Radiol Clin North Am 2021; 59:875-886. [PMID: 34392924 PMCID: PMC8371717 DOI: 10.1016/j.rcl.2021.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Fluorodeoxyglucose (FDG) PET/CT is sensitive to metabolic, immune-related, and structural changes that can occur in tumors in cancer immunotherapy. Unique mechanisms of immune checkpoint inhibitors (ICIs) occasionally make response evaluation challenging, because tumors and inflammatory changes are both FDG avid. These response patterns and sequelae of ICI immunotherapy, such as immune-related adverse events, are discussed. Immune-specific PET imaging probes at preclinical stage or in early clinical trials, which may help guide clinical management of cancer patients treated with immunotherapy and likely have applications outside of oncology for other diseases in which the immune system plays a role, are reviewed.
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Affiliation(s)
- Osigbemhe Iyalomhe
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael D. Farwell
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
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37
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Schaafsma E, Fugle CM, Wang X, Cheng C. Pan-cancer association of HLA gene expression with cancer prognosis and immunotherapy efficacy. Br J Cancer 2021; 125:422-432. [PMID: 33981015 PMCID: PMC8329209 DOI: 10.1038/s41416-021-01400-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/27/2021] [Accepted: 04/09/2021] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND The function of major histocompatibility complex (MHC) molecules is to bind peptide fragments derived from genomic mutations or pathogens and display them on the cell surface for recognition by cognate T cells to initiate an immune response. METHODS In this study, we provide a comprehensive investigation of HLA gene expression in a pan-cancer manner involving 33 cancer types. We utilised gene expression data from several databases and immune checkpoint blockade-treated patient cohorts. RESULTS We show that MHC expression varies strongly among cancer types and is associated with several genomic and immunological features. While immune cell infiltration was generally higher in tumours with higher HLA gene expression, CD4+ T cells showed significantly different correlations among cancer types, separating them into two clusters. Furthermore, we show that increased HLA gene expression is associated with prolonged survival in the majority of cancer types. Lastly, HLA gene expression is associated with patient response to immune checkpoint blockade, which is especially prominent for HLA class II expression in tumour biopsies taken during treatment. CONCLUSION We show that HLA gene expression is an important feature of tumour biology that has significant impact on patient prognosis.
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Affiliation(s)
- Evelien Schaafsma
- Department of Molecular and Systems Biology, Dartmouth College, Hanover, NH, USA
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Chloe M Fugle
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Xiaofeng Wang
- Department of Molecular and Systems Biology, Dartmouth College, Hanover, NH, USA
| | - Chao Cheng
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- The Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
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38
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Emens LA, Adams S, Cimino-Mathews A, Disis ML, Gatti-Mays ME, Ho AY, Kalinsky K, McArthur HL, Mittendorf EA, Nanda R, Page DB, Rugo HS, Rubin KM, Soliman H, Spears PA, Tolaney SM, Litton JK. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer. J Immunother Cancer 2021; 9:e002597. [PMID: 34389617 PMCID: PMC8365813 DOI: 10.1136/jitc-2021-002597] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2021] [Indexed: 12/17/2022] Open
Abstract
Breast cancer has historically been a disease for which immunotherapy was largely unavailable. Recently, the use of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for the treatment of advanced/metastatic triple-negative breast cancer (TNBC) has demonstrated efficacy, including longer progression-free survival and increased overall survival in subsets of patients. Based on clinical benefit in randomized trials, ICIs in combination with chemotherapy for the treatment of some patients with advanced/metastatic TNBC have been approved by the United States (US) Food and Drug Administration (FDA), expanding options for patients. Ongoing questions remain, however, about the optimal chemotherapy backbone for immunotherapy, appropriate biomarker-based selection of patients for treatment, the optimal strategy for immunotherapy treatment in earlier stage disease, and potential use in histological subtypes other than TNBC. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew upon the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for breast cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence-based and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with breast cancer.
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Affiliation(s)
- Leisha A Emens
- Department of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sylvia Adams
- Perlmutter Cancer Center, New York University Langone, New York, New York, USA
| | - Ashley Cimino-Mathews
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mary L Disis
- Cancer Vaccine Institute, University of Washington, Seattle, Washington, USA
| | - Margaret E Gatti-Mays
- Pelotonia Institute for Immuno-Oncology, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Alice Y Ho
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kevin Kalinsky
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | | | - Elizabeth A Mittendorf
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Breast Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Rita Nanda
- Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
| | - David B Page
- Earle A Chiles Research Institute, Portland, Oregon, USA
| | - Hope S Rugo
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA
| | - Krista M Rubin
- Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Hatem Soliman
- Department of Breast Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Patricia A Spears
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Jennifer K Litton
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Tumor Growth Rate Decline despite Progressive Disease May Predict Improved Nivolumab Treatment Outcome in mRCC: When RECIST Is Not Enough. Cancers (Basel) 2021; 13:cancers13143492. [PMID: 34298702 PMCID: PMC8304626 DOI: 10.3390/cancers13143492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 06/25/2021] [Accepted: 07/09/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary The treatment scenario of metastatic renal cell carcinoma has drastically changed in recent years, with the advent of immunotherapy. Since 2015 immune-checkpoint inhibitors, either alone or in combination with other compounds, are constantly enriching the treatment scenario, with a drastic change of patients’ outcomes. The benefit from immunotherapy is difficult to capture with the currently available assessment radiological criteria. Often, with rhe use of immunotherapy, we can observe atypical patterns of response, such as hyperprogression or pseudoprogression. Pseudoprogression consists of an initial increase in tumor burden followed by a response to therapy, while hyperprogression is defined as a tumor growth rate that was at least 2-fold greater in patients with disease progression during immunotherapy. We performed a retrospective monocentric study to explore the impact of tumor growth rate change after immunotherapy administration as second or later line of treatment in patients with metastatic renal cell carcinoma. Abstract Treatment response is usually assessed by the response evaluation criteria in solid tumors (RECIST). These criteria may not be adequate to evaluate the response to immunotherapy, considering the peculiar patterns of response reported with this therapy. With the advent of immunotherapy these criteria have been modified to include the evaluation of the peculiar responses seen with this type of therapy (iRECIST criteria), including pseudoprogressions and hyperprogressions. Tumor growth rate (TGR) is a dynamic evaluation that takes into account the kinetics of response to treatment and may help catch the real efficacy of an immunotherapy approach. We performed a retrospective monocentric study to explore the impact of TGR change after nivolumab administration as the second or later line of treatment in patients with metastatic renal cell carcinoma (RCC). We evaluated 27 patients, divided into three categories: Disease control (DC) if there was no PD; lower velocity PD (LvPD) if disease progressed but the TGR at second assessment (TGR2) was lower than the TGR at first assessment (TGR1); higher velocity PD (HvPD) if TGR2 was higher than TGR1. The median OS for the DC group was 11.0 months (95% CI 5.0–17.0) (reference) vs. (not reached) NR (95% CI NR-NR) for LvPD (HR 0.27; 95% CI 0.06–1.30; p 0.102) vs. NR (95% CI NR–NR) for HvPD (HR 0.23; 95% CI 0.06–0.88; p 0.032). There was no difference between LvPD and DC (HR 1.21; 95% CI 0.20–7.28; p 0.838). In patients with metastatic RCC, the second or later line of nivolumab treatment may lead to a deceleration in TGR resulting in an improved survival outcome similar to that observed in patients experiencing tumor regression. In this subgroup, especially in the presence of a clinical benefit, continuing the treatment beyond progression can be recommended.
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40
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Okwundu N, Grossman D, Hu-Lieskovan S, Grossmann KF, Swami U. The dark side of immunotherapy. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1041. [PMID: 34277841 PMCID: PMC8267325 DOI: 10.21037/atm-20-4750] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Immunotherapy has broadened the therapeutic scope and response for many cancer patients with drugs that are generally of higher efficacy and less toxicity than prior therapies. Multiple classes of immunotherapies such as targeted antibodies and immune checkpoint inhibitors (ICI), cell-based immunotherapies, immunomodulators, vaccines, and oncolytic viruses have been developed to help the immune system target and destroy malignant tumors. ICI targeting programmed cell death protein-1 (PD-1) or its ligand (PD-L1) are among the most effective immunotherapy agents and are a major focus of current investigations. They have received approval for at least 16 different tumor types as well as for unresectable or metastatic tumors with microsatellite instability-high (MSI-H) or mismatch repair deficiency or with high tumor mutational burden (defined as ≥10 mutations/megabase). However, it is important to recognize that immunotherapy may be associated with significant adverse events. To summarize these events, we conducted a PubMed and Google Scholar database search through April 2020 for manuscripts evaluating treatment-related adverse events and knowledge gaps associated with the use of immunotherapy. Reviewed topics include immune-related adverse events (irAEs), toxicities on combining immunotherapy with other agents, disease reactivation such as tuberculosis (TB) and sarcoid-like granulomatosis, tumor hyperprogression (HPD), financial toxicity, challenges in special patient populations such as solid organ transplant recipients and those with auto-immune diseases. We also reviewed reports of worse or even lethal outcomes compared to other oncologic therapies in certain scenarios and summarized biomarkers predicting adverse events.
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Affiliation(s)
- Nwanneka Okwundu
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Douglas Grossman
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.,Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Siwen Hu-Lieskovan
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.,Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Kenneth F Grossmann
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.,Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Umang Swami
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.,Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
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41
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Lei K, Li J, Tu Z, Liu F, Ye M, Wu M, Zhu Y, Luo M, Lin L, Tao C, Huang K, Zhu X. Prognostic and Predictive Value of Immune-Related Gene Pair Signature in Primary Lower-Grade Glioma Patients. Front Oncol 2021; 11:665870. [PMID: 34123829 PMCID: PMC8190397 DOI: 10.3389/fonc.2021.665870] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022] Open
Abstract
Immune-related gene pairs (IRGPs) have been associated with prognosis in various cancer types, but few studies have examined their prognostic capabilities in glioma patients. Here, we gathered the gene expression and clinical profile data of primary lower-grade glioma (LGG) patients from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA, containing CGGAseq1 and CGGAseq2), the Gene Expression Omnibus (GEO: GSE16011), and Rembrandt datasets. In the TCGA dataset, univariate Cox regression was performed to detect overall survival (OS)-related IRGs, Lasso regression, and multivariate Cox regression were used to screen robust prognosis-related IRGs, and 19 IRGs were selected for the construction of an IRGP prognostic signature. All patients were allotted to high- and low-risk subgroups based on the TCGA dataset median value risk score. Validation analysis indicated that the IRGP signature returned a stable prognostic value among all datasets. Univariate and multivariate Cox regression analyses indicated that the IRG -signature could efficiently predict the prognosis of primary LGG patients. The IRGP-signature-based nomogram model was built, revealing the reliable ability of the IRGP signature to predict clinical prognosis. The single-sample gene set enrichment analysis (ssGSEA) suggested that high-risk samples contained higher numbers of immune cells but featured lower tumor purity than low-risk samples. Finally, we verified the prognostic ability of the IRGP signature using experiments performed in LGG cells. These results indicated that the IRGP signature could be regarded as a stable prognostic assessment predictor for identifying high-risk primary LGG patients.
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Affiliation(s)
- Kunjian Lei
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jingying Li
- Department of Comprehensive Intensive Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zewei Tu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,East China Institute of Digital Medical Engineering, Shangrao, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Feng Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Minhua Ye
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Miaojing Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Yue Zhu
- Department of Medical Social Work, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Min Luo
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,East China Institute of Digital Medical Engineering, Shangrao, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Li Lin
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,East China Institute of Digital Medical Engineering, Shangrao, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Chuming Tao
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,East China Institute of Digital Medical Engineering, Shangrao, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Kai Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,East China Institute of Digital Medical Engineering, Shangrao, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
| | - Xingen Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Institute of Neuroscience, Nanchang University, Nanchang, China
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42
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Zhang Y, Li Y, Chen K, Qian L, Wang P. Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy. Cancer Cell Int 2021; 21:262. [PMID: 33985527 PMCID: PMC8120729 DOI: 10.1186/s12935-021-01972-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/05/2021] [Indexed: 02/07/2023] Open
Abstract
It has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.
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Affiliation(s)
- Yalei Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ye Li
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
| | - Kun Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Qian
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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43
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He H, Shi L, Meng D, Zhou H, Ma J, Wu Y, Wu Y, Gu Y, Xie W, Zhang J, Zhu Y. PD-1 blockade combined with IL-33 enhances the antitumor immune response in a type-1 lymphocyte-mediated manner. Cancer Treat Res Commun 2021; 28:100379. [PMID: 33951555 DOI: 10.1016/j.ctarc.2021.100379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 04/19/2021] [Indexed: 01/01/2023]
Abstract
PD-1 immune checkpoint blockade and cytokine IL-33 have shown significant therapeutic effects in tumor immunotherapy. These therapies promote CD8+ T cell activation, proliferation, and effector functions. However, there were few research about the combined therapy efficacy. In this study, we established B16-empty vector and B16-IL33 melanoma mouse models and treated with PD-1 monoclonal antibody. We reported that PD-1 blockade combined with cytokine IL-33 further inhibited tumor progression and prolonged the survival of tumor-bearing mice. Mechanistically, the combination therapy was found to further facilitate CD4+ and CD8+ T lymphocytes accumulation, and enhance the antitumor effects of CD4+or CD8+tumor-infiltrating lymphocytes by promoting type-1 immune response within the tumor microenvironment using flow cytometry and quantitative real time polymerase chain reaction. Thus, PD-1 blockade combined with IL-33 has application potential in tumor immunotherapy. Further, this study provides a new promising strategy and theoretical basis for tumor combination immunotherapy.
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MESH Headings
- Animals
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- Cell Line, Tumor
- Drug Synergism
- Female
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Immunotherapy
- Interleukin-33/pharmacology
- Interleukin-33/therapeutic use
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/immunology
- Melanoma, Experimental/drug therapy
- Melanoma, Experimental/immunology
- Melanoma, Experimental/pathology
- Mice, Transgenic
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Skin Neoplasms/drug therapy
- Skin Neoplasms/immunology
- Skin Neoplasms/pathology
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/immunology
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Affiliation(s)
- Honghong He
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China; Suzhou Blood Center, Suzhou 215006, China
| | - Liyan Shi
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China; Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Dan Meng
- Suzhou Junmeng Biopharm Co., Ltd, Suzhou 215200, China
| | - Huijun Zhou
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Jingshu Ma
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yixian Wu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yanshi Wu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yanzheng Gu
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou 215006, China; Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wei Xie
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China
| | - Jing Zhang
- Suzhou Junmeng Biopharm Co., Ltd, Suzhou 215200, China
| | - Yibei Zhu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou 215006, China; Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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Spagnolo F, Boutros A, Cecchi F, Croce E, Tanda ET, Queirolo P. Treatment beyond progression with anti-PD-1/PD-L1 based regimens in advanced solid tumors: a systematic review. BMC Cancer 2021; 21:425. [PMID: 33865350 PMCID: PMC8052683 DOI: 10.1186/s12885-021-08165-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/09/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Treatment beyond progression with immunotherapy may be appropriate in selected patients based on the potential for late responses. The aim of this systematic review was to explore the impact of treatment beyond progression in patients receiving an anti-PD-1/PD-L1 based regimen for an advanced solid tumor. METHODS A systematic literature search was performed to identify prospective clinical trials reporting data on overall response rate by immune-related criteria and/or the number of patients treated beyond conventional criteria-defined PD and/or the number of patients achieving a clinical benefit after an initial PD with regimens including an anti-PD-1/PD-L1 agent which received the FDA approval for the treatment of an advanced solid tumor. RESULTS 254 (4.6%) responses after an initial RECIST-defined progressive disease were observed among 5588 patients, based on 35 trials included in our analysis reporting this information. The overall rate of patients receiving treatment beyond progressive disease was 30.2%, based on data on 5334 patients enrolled in 36 trials, and the rate of patients who achieved an unconventional response among those treated beyond progressive disease was 19.7% (based on 25 trials for a total of 853 patients). CONCLUSION The results of our systematic review support the clinical relevance of unconventional responses to anti-PD-1/PD-L1-based regimens; however, most publications provided only partial information regarding immune-related clinical activity, or did not provide any information at all, highlighting the need of a more comprehensive report of such data in trials investigating immunotherapy for the treatment of patients with advanced tumors.
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Affiliation(s)
- Francesco Spagnolo
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy.
| | - Andrea Boutros
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy
| | - Federica Cecchi
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy
| | - Elena Croce
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy
| | - Enrica Teresa Tanda
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy
| | - Paola Queirolo
- Melanoma, Sarcoma & Rare Tumors Division, European Institute of Oncology (IEO), Milan, Italy
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Tong BC, Gu L, Wang X, Wigle DA, Phillips JD, Harpole DH, Klapper JA, Sporn T, Ready NE, D'Amico TA. Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2021; 163:427-436. [PMID: 33985811 DOI: 10.1016/j.jtcvs.2021.02.099] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 02/28/2021] [Accepted: 02/28/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Pembrolizumab is a programmed death receptor-1 masking antibody approved for metastatic non-small cell lung cancer. This Phase 2 study (NCT02818920) of neoadjuvant pembrolizumab in non-small cell lung cancer had a primary end point of safety and secondary end points of efficacy and correlative science. METHODS Patients with untreated clinical stage IB to IIIA non-small cell lung cancer were enrolled. Two cycles of pembrolizumab (200 mg) were administered before surgery. Standard adjuvant chemotherapy and radiation were encouraged but not required. Four cycles of adjuvant pembrolizumab were provided. RESULTS Of 35 patients enrolled, 30 received neoadjuvant pembrolizumab and 25 underwent lung resection. Only 1 patient had a delay before surgery attributed to pembrolizumab; this was due to thyroiditis. All patients underwent anatomic resection and mediastinal lymph node dissection; the majority (18/25%, 72%) of patients underwent lobectomy. Of the 25 patients, 23 had an initial minimally invasive approach (92%); 5 of these were converted to thoracotomy (21.7%). R0 resection was achieved in 22 patients (88%), and major pathologic response was observed in 7 of 25 patients (28%). The most common postoperative adverse event was atrial fibrillation, affecting 6 of 25 patients (24%). Median chest tube duration and length of stay were 3 and 4 days, respectively. One patient required readmission to the hospital within 30 days. There was no mortality within 90 days of surgery. CONCLUSIONS In this study, pembrolizumab was safe and well tolerated in the neoadjuvant setting, and its use was not associated with excess surgical morbidity or mortality. Minimally invasive approaches are feasible in this patient population, but may be more challenging than in cases without neoadjuvant immunotherapy. Pathologic response was higher than typically observed with standard neoadjuvant chemotherapy.
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Affiliation(s)
- Betty C Tong
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC.
| | - Lin Gu
- Duke Cancer Institute Biostatistics Shared Resource, Duke University School of Medicine, Durham, NC
| | - Xiaofei Wang
- Duke Cancer Institute Biostatistics Shared Resource, Duke University School of Medicine, Durham, NC
| | - Dennis A Wigle
- Department of Thoracic Surgery, Mayo Clinic, Rochester, Minn
| | - Joseph D Phillips
- Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - David H Harpole
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
| | - Jacob A Klapper
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
| | - Thomas Sporn
- Department of Pathology, Duke University Medical Center, Durham, NC
| | - Neal E Ready
- Division of Medical Oncology, Duke University Medical Center, Durham, NC
| | - Thomas A D'Amico
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC
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Zhang T, Merle P, Wang H, Zhao H, Kudo M. Combination therapy for advanced hepatocellular carcinoma: do we see the light at the end of the tunnel? Hepatobiliary Surg Nutr 2021; 10:180-192. [PMID: 33898559 DOI: 10.21037/hbsn-2021-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Importance Combination therapies of anti-PD-1 and anti-angiogenesis regimens are emerging rapidly and exhibit more promising anti-tumor efficacy for advanced hepatocellular carcinoma (HCC), and consistently it is the hotspot in clinical studies. Objective To elaborate several issues which are warranted further consideration as more regimens are being investigated in combination therapies. Evidence Review We searched PubMed, MEDLINE, Cochrane Library and Google Scholar by 2021 February for publications on combination therapies for HCC. Findings Several clinical issues are worth reconsidering, such as the evaluation on appropriate primary endpoints in phase III clinical trials as for different practical problems, the translation of surrogate endpoint objective response rate (ORR) benefits into overall survival (OS) benefits, and whether conversion surgery contributes to initial expectations of long-term survival or not. New concepts in novel immunotherapy and targeted therapy in combination with loco-regional therapies may improve overall survival for HCC. Conclusions and Relevance for Reviews Comprehensive understanding of the mechanism of immunotherapy and targeted therapy contributes to better prognosis of advanced HCC and more explorative combination therapies are needed.
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Affiliation(s)
- Ti Zhang
- Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Philippe Merle
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université Lyon 1, 103 Grande rue de la Croix Rousse, Lyon, France
| | - Huaqi Wang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Xu Y, Li H, Fan Y. Progression Patterns, Treatment, and Prognosis Beyond Resistance of Responders to Immunotherapy in Advanced Non-Small Cell Lung Cancer. Front Oncol 2021; 11:642883. [PMID: 33747966 PMCID: PMC7973268 DOI: 10.3389/fonc.2021.642883] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 01/19/2021] [Indexed: 12/26/2022] Open
Abstract
Introduction Immune checkpoint inhibitors (ICIs) have changed the management of non-small cell lung cancer (NSCLC). However, resistance is inevitable. The disease progression patterns, sequential treatment, and prognosis beyond ICI resistance are not completely understood. Methods We retrospectively analyzed stage IV NSCLC patients who underwent ICI treatment at Zhejiang Cancer Hospital between January 2016 and January 2020 and who suffered disease progression after at least stable disease on immunotherapy for more than 3 months (at least two cycles). Oligoprogression and systematic progression were defined as previous reports. The main outcome measures were progression-free survival (PFS), second PFS (PFS2), and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis. Results Totally 1,014 NSCLC patients were administered immunotherapy. Of them, 208 NSCLC patients were included in this retrospective study. The estimated PFS, PFS2 and OS were 6.3 months (95% CI 5.6–7.0 months), 10.7 months (95% CI 10.1–12.7 months), and 21.4 months (95% CI 20.6–26.4 months), respectively. After resistance, 55.3% (N = 115) patients developed oligoprogression, and 44.7% (N = 93) systemic progression. For patients with systemic progression, chemotherapy (N = 35, 37.6%), best supportive care (N = 30, 32.3%), and antiangiogenic therapy alone (N = 11, 11.8%) were the major strategies. A combination of local radiotherapy (N = 38, 33.0%) with continued ICIs was the most common treatment used in oligoprogression group, followed by continued immunotherapy with antiangiogenic therapy (N = 19, 16.5%) and local radiotherapy only (N = 17, 14.9%). For patients with oligoprogression, continued immunotherapy plus local radiotherapy can lead to a significantly longer PFS2 (12.9 vs. 10.0 months; p = 0.006) and OS (26.3 vs. 18.5 months, p = 0.001). The PFS2 and OS of patients with oligoprogression were superior to those of patients with systemic progression (PFS2: 13.1 vs. 10.0 months, p = 0.001; OS: 25.8 vs. 19.1 months, p = 0.003). Conclusions The major progression pattern after acquired resistance from immunotherapy is oligoprogression. Local radiotherapy with continued immunotherapy beyond oligoprogression in responders was feasible and led to prolonged PFS2 and OS in advanced NSCLC patients.
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Affiliation(s)
- Yanjun Xu
- Department of Medical Thoracic Oncology, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Hangzhou, China
| | - Hui Li
- Department of Medical Thoracic Oncology, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Hangzhou, China
| | - Yun Fan
- Department of Medical Thoracic Oncology, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Hangzhou, China
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Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel) 2021; 13:651. [PMID: 33561950 PMCID: PMC7915546 DOI: 10.3390/cancers13040651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/26/2021] [Accepted: 02/03/2021] [Indexed: 02/08/2023] Open
Abstract
Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
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Affiliation(s)
- Mojun Zhu
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; (Z.J.); (J.M.H.)
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Jin Z, Zhang B, Zhang L, Huang W, Mo X, Chen Q, Wang F, Chen Z, Li M, Zhang S. Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for treatment of recurrent or metastatic head and neck squamous cell carcinoma: a systematic review and network meta-analysis. Ther Adv Med Oncol 2020; 12:1758835920983717. [PMID: 33488783 PMCID: PMC7768319 DOI: 10.1177/1758835920983717] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Multiple therapies including immune-checkpoint inhibitors are emerging as effective treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSSC). However, the optimal first-line and second-line treatments remains controversial. Methods: We systematically searched databases and conducted a systematic review of phase II/III randomized controlled trials (RCTs) that compared two or more treatments for R/M HNSSC. Progression-free survival (PFS), overall survival (OS) and adverse events (AEs) ⩾3 with hazard ratios (HRs) were extracted and synthesized based on a frequentist network meta-analysis. Results: Twenty-six trials involving 8908 patients were included. Of first-line treatments, pembrolizumab plus cisplatin plus 5-fluorouracil is associated with significantly improved OS (P-score = 0.91) and TPEx ranked first for prolonging PFS (0.91). EXTREME plus docetaxel (0.18) ranked lowest for AEs ⩾3. Of second-line treatments, nivolumab was the highest-ranked treatment for prolonging OS (0.95), while buparlisib plus paclitaxel was the highest-ranked treatment for PFS (0.94). Subgroup analyses suggested that nivolumab was significantly associated with improvement of OS in patients with high PD-L1 expression (HR 0.55, 0.43–0.70), whereas its OS benefit is similar with conventional chemotherapy for those with low PD-L1 expression. Buparlisib plus paclitaxel showed the best OS benefit in subgroups of patients with HPV-negative status, and with oral cavity or larynx as primary tumor sites. Conclusions: Pembrolizumab plus cisplatin plus 5-fluorouracil is likely to be the best first-line treatment when OS is a priority. Otherwise, TPEx should be the optimal first-line option due to its superior PFS prolongation efficacy, best safety profile, and similar OS benefit with pembrolizumab plus cisplatin plus 5-fluorouracil. Nivolumab appears to be the best second-line option with best OS prolongation efficacy and outstanding safety profile in the overall population. Future RCTs with meticulous grouping of patients and detailed reporting are urgently needed for individualized treatment.
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Affiliation(s)
- Zhe Jin
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bin Zhang
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lu Zhang
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wenhui Huang
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaokai Mo
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Qiuyin Chen
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Fei Wang
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhuozhi Chen
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Minmin Li
- The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Shuixing Zhang
- The First Affiliated Hospital of Jinan University, No. 613, West Huangpu Avenue, Guangzhou, Guangdong Province 510630, PR China
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Ge X, Zhang Z, Zhang S, Yuan F, Zhang F, Yan X, Han X, Ma J, Wang L, Tao H, Li X, Zhi X, Huang Z, Hofman P, Prelaj A, Banna GL, Mutti L, Hu Y, Wang J. Immunotherapy beyond progression in patients with advanced non-small cell lung cancer. Transl Lung Cancer Res 2020; 9:2391-2400. [PMID: 33489801 PMCID: PMC7815351 DOI: 10.21037/tlcr-20-1252] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background Immune checkpoint inhibitors (ICIs) represent a great breakthrough in the treatment of advanced non-small cell lung cancer (aNSCLC). However, whether immunotherapy beyond progression (IBP) is effective for aNSCLC has yet to be established. Therefore, a retrospective clinical study was conducted to investigate the efficacy of IBP in patients with aNSCLC under real-world conditions. Methods A total of 125 Chinese patients with aNSCLC who experienced progressive disease (PD) after receiving monotherapy or combination therapy (combined with chemotherapy or/and antiangiogenic therapy) with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors between January 2015 and March 2019 were enrolled. Patients who were treated with ICIs for more than 6 weeks after PD were defined as IBP (n=39), while those who received ICI treatment for less than 6 weeks or discontinued it due to PD were defined as non-IBP (n=86). Patient clinical characteristics were evaluated. An optimization-based method was applied to balance the clinical baseline characteristics between the two groups. Results In total population, the IBP group had longer overall survival (median OS, 26.6 vs. 9.5 months; HR, 0.40; 95% CI: 0.23–0.69; P<0.001) and progression-free survival (median PFS, 8.9 vs. 4.1 months; HR, 0.41; 95% CI: 0.26–0.65; P<0.001), compared with the non-IBP group. Despite no significant difference in objective response rate (ORR, 15.4% vs. 11.6%, P=0.560), disease control rate (DCR) was significantly higher in the IBP group (89.7% vs. 61.6%, P<0.001). After balancing baseline covariates, the IBP group also had longer OS (median: 26.6 vs. 10.7 months; HR, 0.40; 95% CI: 0.19–0.84; P=0.015) and PFS (median: 9.7 vs. 4.3 months; HR, 0.28; 95% CI: 0.15–0.51; P<0.001), with a benefit in either of patients previously treated with ICI monotherapy or in combination therapy and with non-response to the previously ICI. Conclusions IBP is associated with longer OS and PFS in patients with aNSCLC. Our findings may suggest new therapeutic options for patients with aNSCLC who experienced disease progression after initial immunotherapy.
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Affiliation(s)
- Xiangwei Ge
- Medical School of Chinese PLA, Beijing, China.,Department of Oncology, the Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhibo Zhang
- Department of Oncology, the Second Medical Center, Chinese PLA General Hospital, Beijing, China.,The 78th Group Army Hospital of Chinese PLA, Mudanjiang, China
| | - Sujie Zhang
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Fang Yuan
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Fan Zhang
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xiang Yan
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xiao Han
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Junxun Ma
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Lijie Wang
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Haitao Tao
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xiaoyan Li
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Xiaoyu Zhi
- Medical School of Chinese PLA, Beijing, China.,Department of Oncology, the Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | | | - Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France
| | - Arsela Prelaj
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.,Department of Electronics, Information, and Bioengineering, Polytechnic University of Milan, Milan, Italy
| | - Giuseppe Luigi Banna
- Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK
| | - Luciano Mutti
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Yi Hu
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Jinliang Wang
- Department of Oncology, the Second Medical Center, Chinese PLA General Hospital, Beijing, China.,Department of Oncology, Chinese PLA General Hospital, Beijing, China
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