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1
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Wang PJ, Wang J, Yao XM, Cheng WL, Sun L, Yan J, Yu YL, Li SY, Li DP, Jia JH. Evaluation of efficacy and safety of targeted therapy and immune checkpoint inhibitors in metastatic colorectal cancer. World J Gastrointest Oncol 2025; 17:105027. [DOI: 10.4251/wjgo.v17.i5.105027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/07/2025] [Accepted: 03/25/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is among the most prevalent and deadly cancers globally, particularly in China. Treatment challenges remain in advanced and metastatic cases, especially in third- and fourth-line settings. The combination of targeted therapies with immune checkpoint inhibitors (ICIs) has shown potential in addressing the limitations of single-agent treatments.
AIM To evaluate the efficacy and safety of targeted therapy (TT) alone and in combination with ICIs for metastatic CRC (mCRC).
METHODS A multicenter retrospective observational study was conducted to evaluate the efficacy and safety of TT alone and in combination with ICIs for mCRC. A total of 99 patients treated with regorafenib or fruquintinib, with or without ICIs, were enrolled. Propensity score matching (PSM) and inverse probability weighting (IPW) were employed to balance baseline characteristics. The primary endpoint was progression-free survival (PFS), while overall survival (OS) and safety were secondary.
RESULTS Patients who received combined therapy showed significantly longer median PFS rates compared to those who underwent TT in all analyses (original: 6.0 vs 3.4 months, P < 0.01; PSM: 6.15 vs 4.25 months, P < 0.05; IPW: 5.6 vs 3.3 months, P < 0.01). Although the median OS showed a trend toward improvement in the combination group, the difference was insignificant. Cox regression analysis revealed that combining TT with ICIs significantly reduced the risk of disease progression (hazard ratio = 0.38, P < 0.001). Adverse events (AEs) were generally manageable with both regimens, while serious AEs (grade 3-4) were primarily hypertension, fatigue, and reduced platelet counts. All AEs were controlled effectively by symptomatic treatment or discontinuation of the drug, and no treatment-related deaths were observed.
CONCLUSION The combination of TT with ICIs offers a significant advantage in terms of PFS for patients with advanced mCRC, accompanied by a favorable safety profile. These findings underscore the benefits of combination therapy in this setting, warranting further investigation in larger prospective clinical trials.
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Affiliation(s)
- Peng-Jian Wang
- Clinical Medical School, North China University of Science and Technology, Tangshan 063000, Hebei Province, China
| | - Jing Wang
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Xue-Min Yao
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Wei-Li Cheng
- Department of Digestive Oncology, Tianjin Tumor Hospital Qinhuangdao Hospital, Qinhuangdao 066000, Hebei Province, China
| | - Lu Sun
- Department of Radiochemotherapy, Tangshan People’s Hospital, Tangshan 063000, Hebei Province, China
| | - Jie Yan
- Clinical Medical School, North China University of Science and Technology, Tangshan 063000, Hebei Province, China
| | - Yong-Ling Yu
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Su-Yao Li
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Da-Peng Li
- Department of Digestive Oncology, Tianjin Tumor Hospital Qinhuangdao Hospital, Qinhuangdao 066000, Hebei Province, China
| | - Jing-Hao Jia
- Department of Radiochemotherapy, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
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Furukawa J, Kato T, Yamasaki T, Monji K, Tanaka T, Tsuchiya N, Miyagawa T, Yaegashi H, Sano T, Karashima T, Fujita K, Hori JI, Ito T, Kajita M, Tomita Y, Shinohara N, Eto M, Oya M, Uemura H. Real-world outcomes with avelumab + axitinib in patients with advanced renal cell carcinoma in Japan: subgroup analyses from the J-DART2 study by International Metastatic Renal Cell Carcinoma Database Consortium risk classification. Int J Clin Oncol 2025; 30:749-760. [PMID: 39934514 PMCID: PMC11946980 DOI: 10.1007/s10147-024-02655-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/31/2024] [Indexed: 02/13/2025]
Abstract
BACKGROUND Avelumab + axitinib was approved for the treatment of advanced renal cell carcinoma (aRCC) in Japan in December 2019. We report long-term real-world subgroup analyses with first-line avelumab + axitinib in patients with aRCC by International Metastatic RCC Database Consortium (IMDC) risk classification from the J-DART2 study in Japan. METHODS J-DART2 was a multicenter, noninterventional, retrospective study examining characteristics, treatment patterns, and outcomes in patients with aRCC who started first-line avelumab + axitinib in Japan between December 2019 and October 2022. RESULTS Data from 150 patients across 19 sites were analyzed. IMDC risk was favorable in 39 patients (26.0%), intermediate (1 risk factor) in 46 (30.7%), intermediate (2 risk factors) in 36 (24.0%), and poor in 29 (19.3%). Baseline characteristics were generally consistent across IMDC risk subgroups. In subgroups with favorable, intermediate (1 risk factor), intermediate (2 risk factors), and poor risk, median progression-free survival was 31.0, 15.3, 16.4, and 8.1 months; median overall survival (OS) was not reached, but 24-month OS rates were 95.2%, 91.3%, 85.3%, and 57.6%, respectively. Objective response rates were 54.5%, 56.8%, 47.1%, and 54.2%, respectively. High-dose corticosteroid treatment for immune-related adverse events was administered in 5.1%, 8.7%, 8.3%, and 6.9% of patients, respectively. CONCLUSION Subgroup analyses from J-DART2 confirm the long-term real-world effectiveness of first-line avelumab + axitinib across IMDC risk groups in patients with aRCC in Japan. Our findings were consistent with previous analyses by IMDC risk and support the favorable benefit-risk profile of avelumab + axitinib in clinical practice in Japan.
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Affiliation(s)
- Junya Furukawa
- Department of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe, 650-0017, Japan
- Department of Urology, Tokushima University, Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Toshinari Yamasaki
- Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima Minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Keisuke Monji
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Toshiaki Tanaka
- Department of Urology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Norihiko Tsuchiya
- Department of Urology, Faculty of Medicine, Yamagata University, 2-2-2, Iida-Nishi, Yamagata, 990-9585, Japan
| | - Tomoaki Miyagawa
- Department of Urology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama-shi, Saitama, 330-8503, Japan
| | - Hiroshi Yaegashi
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takaramachi, Kanazawa City, Ishikawa, 920-8641, Japan
| | - Tomoyasu Sano
- Department of Urology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takashi Karashima
- Department of Urology, Kochi Medical School, Kohasu, Oku-cho, Nankoku, Kochi, 783-8505, Japan
| | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama City, Osaka, 589-8511, Japan
| | - Jun-Ichi Hori
- Department of Renal and Urologic Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido, 078-8510, Japan
| | - Takayuki Ito
- Medical Department, Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA, 1-8-1 Shimomeguro, Meguro-ku, Tokyo, 153-8926, Japan
| | - Masahiro Kajita
- Medical Department, Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA, 1-8-1 Shimomeguro, Meguro-ku, Tokyo, 153-8926, Japan
| | - Yoshihiko Tomita
- Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori Chuo-ku, Niigata, 951-8510, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Kita15, Nishi7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama City, Osaka, 589-8511, Japan.
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Park S, Park K, Kim C, Rhie SJ. Optimization of immunotherapy-based combinations for metastatic renal cell carcinoma: A network meta-analysis. Crit Rev Oncol Hematol 2025; 208:104630. [PMID: 39864536 DOI: 10.1016/j.critrevonc.2025.104630] [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: 12/10/2024] [Revised: 01/17/2025] [Accepted: 01/20/2025] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Despite numerous meta-analyses comparing the efficacy and safety of immunotherapy-based combination therapies, the optimal therapeutic combinations remain unclear. This study aims to evaluate the optimal application of all immunotherapy-based combination therapy for advanced/metastatic renal cell carcinoma, focusing on efficacy and safety. METHODS We systemically searched the Web of Science, Cochrane Library, and PubMed for studies regarding the first-line immunotherapy-based combination therapy in patients with advanced or metastatic renal cell carcinoma until April 15, 2024. We used network meta-analysis using a random effect model to facilitate direct and indirect treatment comparisons across outcomes. RESULTS Seven clinical studies, including 5542 patients with metastatic renal cell carcinoma, were included in the network meta-analysis analysis. Regarding progression-free survival and overall survival, combined Toripalimab + Axitinib significantly outperformed other immunotherapy-based combination therapies. This regimen significantly improved progression-free survival in the intermediate/poor risk group when stratified by prognosis prediction risks compared to sunitinib alone. For the objective response rate, Avelumab + Axitinib was the most preferred strategy in the favorable-risk group, while Nivolumab + Cabozantinib was favored in the intermediate/poor-risk group compared to other immunotherapy-based combinations. The combinations of Nivolumab + Ipilimumab and Atezolizumab + Bevacizumab had favorable safety profiles. CONCLUSIONS Immunotherapy-based combination therapies significantly improved progression-free survival, overall survival and objective response rate in patients with metastatic renal cell carcinoma compared to sunitinib monotherapy. However, careful monitoring and personalized treatment strategies are required to balance efficacy and safety in patients with underlying conditions. Future research should focus on optimizing treatment protocols and elucidating the mechanisms of adverse events.
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Affiliation(s)
- Sohyeon Park
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| | - Kalynn Park
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| | - Chaeyoon Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| | - Sandy Jeong Rhie
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
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Ohba K, Osawa T, Kojima T, Hara T, Sugimoto M, Eto M, Minami K, Nakai Y, Ueda K, Naito S, Nonomura N, Murai S, Nishiyama H, Nakanishi H, Mukae Y, Mitsunari K, Matsuo T, Imamura R, Shinohara N. Characteristics of patients with metastatic renal cell carcinoma who do not respond to axitinib treatment. Int J Clin Oncol 2025; 30:781-788. [PMID: 39951188 PMCID: PMC11947068 DOI: 10.1007/s10147-025-02715-3] [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: 12/10/2024] [Accepted: 01/28/2025] [Indexed: 03/27/2025]
Abstract
BACKGROUND Axitinib is a widely used tyrosine kinase inhibitor (TKI) in metastatic renal cell carcinoma (mRCC) treatment. Here, we analyzed the characteristics of patients who did not respond to axitinib and evaluated alternative options for their treatment. METHODS We retrospectively analyzed data for 449 patients with mRCC who were administered axitinib following another TKI as initial therapy. Patients with progressive disease (PD) at their first assessment were defined as showing early-PD. We analyzed the characteristics of patients at risk of early-PD and evaluated the relationship between the treatment following axitinib and their prognosis. RESULTS Early-PD was diagnosed in 102 patients, and was more common in those who had not undergone nephrectomy (p < 0.001), those treated with a TKI for a short period (p < 0.001), and those in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) poor risk category for mRCC (p < 0.001). Multivariate analysis showed that these were independent risk factors for early-PD (all p < 0.001). Of those with early-PD, 52 changed to next-line treatment. The progression-free survival periods were 5.5 (95% confidence interval (CI) 2.4-8.6) months for patients administered TKIs, 4.2 (95% CI 0.3-8.1) months for those on nivolumab, and 2.2 (1.8-2.6) months for those on mammalian target of rapamycin inhibitors (p = 0.030). CONCLUSION Patients who have not undergone nephrectomy, those previously treated with another TKI for a short period, and those in the IMDC poor risk category are more likely to experience early-PD when taking axitinib. Furthermore, TKIs are the best treatment for patients with early-PD who have previously been administered axitinib.
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Affiliation(s)
- Kojiro Ohba
- Department of Urology and Renal Transplantation, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Takahiro Osawa
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | | | - Tomohiko Hara
- Office of Research Administration, Center for Regulatory Science, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan
| | | | - Masatoshi Eto
- Department of Urology, Kyushu University, Fukuoka, Japan
| | - Keita Minami
- Department of Urology, Sapporo City General Hospital, Sapporo, Japan
| | - Yasutomo Nakai
- Department of Urology, Osaka International Cancer Institute, Osaka, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University Hospital, Kurume, Japan
| | - Sei Naito
- Department of Urology, Yamagata University, Yamagata, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Hospital, Osaka, Japan
| | - Sachiyo Murai
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | | | - Hiromi Nakanishi
- Department of Urology and Renal Transplantation, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yuta Mukae
- Department of Urology and Renal Transplantation, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kensuke Mitsunari
- Department of Urology and Renal Transplantation, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Tomohiro Matsuo
- Department of Urology and Renal Transplantation, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ryoichi Imamura
- Department of Urology and Renal Transplantation, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Nobuo Shinohara
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
- Department of Urology, Kushiro Rosai Hospital, Kushiro, Japan
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Choueiri TK, Penkov K, Uemura H, Campbell MT, Pal S, Kollmannsberger C, Lee JL, Venugopal B, van den Eertwegh AJM, Negrier S, Gurney H, Albiges L, Berger R, Haanen JBAG, Oyervides Juárez V, Rini BI, Larkin J, Nolè F, Schmidinger M, Atkins MB, Tomita Y, Ellers-Lenz B, Hoffman J, Sandner R, Wang J, di Pietro A, Motzer RJ. Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN Renal 101 trial. Ann Oncol 2025; 36:387-392. [PMID: 39706335 DOI: 10.1016/j.annonc.2024.12.008] [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: 10/11/2024] [Revised: 11/25/2024] [Accepted: 12/06/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND In the phase III JAVELIN Renal 101 trial (NCT02684006), first-line treatment with avelumab + axitinib resulted in significantly longer progression-free survival (PFS) and a higher objective response rate (ORR) versus sunitinib in patients with advanced renal cell carcinoma (aRCC). We report the final analysis, including the primary analysis of overall survival (OS). PATIENTS AND METHODS Patients with untreated aRCC (any prognostic risk score) were enrolled. The primary endpoints were OS and PFS in the programmed death-ligand 1-positive (PD-L1+) population. ORR, duration of response, safety, and patient-reported outcomes (PROs) were also assessed. RESULTS The minimum follow-up was 68 months in all patients. The median OS with avelumab + axitinib versus sunitinib, respectively, was 43.2 months [95% confidence interval (CI) 36.5-51.7 months] versus 36.2 months (95% CI 29.8-44.2 months) in the PD-L1+ population [hazard ratio (HR) 0.86 (95% CI 0.701-1.057); P = 0.0755] and 44.8 months (95% CI 39.7-51.1 months) versus 38.9 months (95% CI 31.4-45.2 months) in the overall population [HR 0.88 (95% CI 0.749-1.039); P = 0.0669]. Investigator-assessed PFS remained prolonged with avelumab + axitinib versus sunitinib [5-year event-free rate in the overall population, 12.0% (95% CI 8.9% to 15.6%) versus 4.4% (95% CI 2.5% to 7.3%)]. ORR in the overall population was 59.7% (95% CI 55.0% to 64.3%) with avelumab + axitinib versus 32.0% (95% CI 27.7% to 36.5%) with sunitinib; duration of response was ≥5 years in 16.4% (95% CI 12.0% to 21.4%) versus 9.2% (95% CI 4.6% to 15.7%), respectively. Rates of grade ≥3 treatment-related adverse events were 66.8% versus 61.5%, respectively. PROs were similar between arms. CONCLUSIONS JAVELIN Renal 101 provides the longest follow-up to date for immune checkpoint inhibitor + tyrosine kinase inhibitor combination treatment from a phase III trial in aRCC. OS analyses favored avelumab + axitinib versus sunitinib but did not reach statistical significance; subsequent treatment may have impacted results. Avelumab + axitinib provided long-term efficacy benefits versus sunitinib, including prolonged PFS, a nearly doubled ORR, and more durable responses, with a manageable long-term safety profile.
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Affiliation(s)
- T K Choueiri
- The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, USA.
| | - K Penkov
- Private Medical Institution, Euromedservice, St. Petersburg, Russian Federation
| | - H Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - M T Campbell
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Pal
- City of Hope, Duarte, USA
| | | | - J L Lee
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - B Venugopal
- Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
| | - A J M van den Eertwegh
- Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - S Negrier
- University of Lyon, Centre Léon Bérard, Lyon, France
| | - H Gurney
- Department of Clinical Medicine, Macquarie University, Sydney, Australia
| | - L Albiges
- Institut Gustave Roussy, Villejuif, France
| | - R Berger
- The Chaim Sheba Medical Center, Ramat Gan, Israel
| | - J B A G Haanen
- Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - V Oyervides Juárez
- Hospital Universitario Dr. Jose Eleuterio Gonzalez, Centro Universitario Contra el Cancer, Monterrey, Mexico
| | - B I Rini
- Vanderbilt-Ingram Cancer Center, Nashville, USA
| | - J Larkin
- Royal Marsden NHS Foundation Trust, London, UK
| | - F Nolè
- Istituto Europeo di Oncologia, Milan, Italy
| | | | - M B Atkins
- Georgetown University Medical Center, Washington, USA
| | - Y Tomita
- Department of Urology, Niigata University Graduate School of Medicine, Niigata, Japan; Department of Molecular Oncology, Niigata University Graduate School of Medicine, Niigata, Japan
| | | | - J Hoffman
- EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, USA
| | | | | | | | - R J Motzer
- Memorial Sloan Kettering Cancer Center, New York, USA.
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Nonomura N, Ito T, Sato M, Morita M, Kajita M, Oya M. Post-marketing surveillance data for avelumab + axitinib treatment in patients with advanced renal cell carcinoma in Japan: Subgroup analyses by pathological classification. Int J Urol 2025; 32:293-299. [PMID: 39699015 PMCID: PMC11923512 DOI: 10.1111/iju.15646] [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: 08/29/2024] [Accepted: 11/21/2024] [Indexed: 12/20/2024]
Abstract
OBJECTIVE Clinical trials have demonstrated the efficacy and safety of avelumab + axitinib in patients with advanced clear cell renal cell carcinoma (ccRCC). However, information is limited regarding the activity of avelumab + axitinib in patients with non-clear cell RCC (nccRCC). In Japan, post-marketing surveillance (PMS) of patients with RCC receiving avelumab + axitinib treatment in general clinical practice was undertaken. We report ad hoc analyses of PMS data according to RCC pathological classification. METHODS Of 328 patients with RCC who received ≥1 dose of avelumab and were enrolled between December 2019 and May 2021, 271 (82.6%) had ccRCC, 22 (6.7%) had nccRCC, and 35 (10.7%) had missing or unknown RCC pathology. Among patients with nccRCC, pathological subtypes were papillary in 12 (3.7%), translocation in 3 (0.9%), acquired cystic disease associated in 3 (0.9%), chromophobe in 2 (0.6%), mucinous tubular and spindle cell in 1 (0.3%), and Bellini duct in 1 (0.3%). RESULTS Among patients with ccRCC or nccRCC, any-grade adverse drug reactions of safety specifications occurred in 140 (51.7%) and 15 (68.2%), and of grade ≥3 in 48 (17.7%) and 6 (27.3%), respectively. The objective response rate in patients with ccRCC or nccRCC was 36.9% and 22.7%, respectively; in patients with papillary tumors, it was 33.3%. Median overall survival was not reached in patients with ccRCC or nccRCC, and 12-month overall survival rates were 86.8% and 76.7%, respectively. CONCLUSIONS Overall, subgroup analyses of PMS data suggest that avelumab + axitinib improved clinical outcomes in nccRCC in addition to ccRCC.
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MESH Headings
- Humans
- Axitinib/administration & dosage
- Axitinib/adverse effects
- Axitinib/therapeutic use
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/mortality
- Male
- Female
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/pathology
- Kidney Neoplasms/mortality
- Japan
- Middle Aged
- Aged
- Product Surveillance, Postmarketing/statistics & numerical data
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged, 80 and over
- Adult
- Treatment Outcome
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Affiliation(s)
- Norio Nonomura
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Taito Ito
- Medical Department, Merck Biopharma Co., Ltd., Tokyo, Japanan affiliate of Merck KGaA
| | - Masashi Sato
- Research and Development, Merck Biopharma Co., Ltd., Tokyo, Japanan affiliate of Merck KGaA
| | - Makiko Morita
- Global Patient Safety Japan, Merck Biopharma Co., Ltd., Tokyo, Japanan affiliate of Merck KGaA
| | - Masahiro Kajita
- Medical Department, Merck Biopharma Co., Ltd., Tokyo, Japanan affiliate of Merck KGaA
| | - Mototsugu Oya
- Department of UrologyKeio University School of MedicineShinjuku‐KuTokyoJapan
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7
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Kato R, Obara W. Persisting challenges in the development of predictive biomarkers for immuno-oncology therapies for renal cell carcinoma. Expert Rev Anticancer Ther 2025; 25:97-103. [PMID: 39835433 DOI: 10.1080/14737140.2025.2457373] [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: 11/26/2024] [Revised: 12/23/2024] [Accepted: 01/20/2025] [Indexed: 01/22/2025]
Abstract
INTRODUCTION Immuno-oncology (IO) therapies have become integral to renal cell carcinoma (RCC) management, RCC remains a complex malignancy with diverse clinical behaviors and a heterogeneous tumor microenvironment, highlighting the need for predictive biomarkers to optimize therapy. AREAS COVERED This review synthesizes recent findings from clinical trials, translational studies, and molecular analyses to provide an updated perspective on biomarker research for IO therapies in RCC. A literature search was conducted using PubMed, Embase, and Web of Science for articles published between January 2010 and November 2024. EXPERT OPINION IO combination therapies have demonstrated significant improvements in progressionfree survival and overall survival compared with sunitinib. However, treatment outcomes vary according to the IMDC risk groups, metastatic sites, and histological subtypes, such as sarcomatoid differentiation. Advances in molecular biology have elucidated the roles of genetic alterations and immune phenotypes in modulating IO efficacy. Emerging biomarkers, including tertiary lymphoid structures, human endogenous retroviruses, and the gut microbiome, show promise but require further validation. Addressing challenges such as intratumoral heterogeneity and dynamic immune responses will be key to identifying actionable biomarkers. Continued integration of clinical and molecular insights is essential for improving patient selection and outcomes in RCC treated with IO therapies.
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Affiliation(s)
- Renpei Kato
- Department of Urology, Iwate Medical University, Shiwa, Iwate, Japan
| | - Wataru Obara
- Department of Urology, Iwate Medical University, Shiwa, Iwate, Japan
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Bölek H, Sertesen E, Kuzu OF, Tural D, Sim S, Nahit Şendur MA, Uçar G, Işık S, Hacıoğlu B, Çiçin İ, Arslan Ç, Göksu SS, Sever ÖN, Karaçin C, Karadurmuş N, Özgüroğlu M, Yekedüz E, Ürün Y. Treatment Patterns and Attrition in Metastatic Renal Cell Carcinoma: Real-Life Experience from the Turkish Oncology Group Kidney Cancer Consortium (TKCC) Database. Clin Genitourin Cancer 2025; 23:102282. [PMID: 39709686 DOI: 10.1016/j.clgc.2024.102282] [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: 07/17/2024] [Revised: 11/24/2024] [Accepted: 11/25/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION Despite the rapid evolution in management of metastatic renal cell carcinoma (mRCC) over the past decade, challenges remain in accessing new therapies in some parts of the world. Despite therapeutic advancements, attrition rates remain persistently high. This study aims to assess the treatment patterns and attrition rates of patients with mRCC in oncology clinics across Turkey. PATIENTS AND METHODS Patients diagnosed with mRCC between January 1, 2008, and December 31, 2022, with first-line systemic treatment data, were retrospectively evaluated using the Turkish Oncology Group Kidney Cancer Consortium (TKCC) Database. RESULTS The final analysis included a total of 1126 patients. The percentages of patients treated in the 2nd, 3rd, 4th, and 5th lines of therapy were 62.8%, 27.4%, 8.9%, and 2.1%, respectively. The drugs that were most commonly used in the groups were tyrosine kinase inhibitors (TKIs) (52.2%) and interferon (IFN)-alpha (43.3%) for the first line, TKIs (66.3%) and immunotherapy (IO) monotherapy (25.9%) for the second line, TKI (41.4%) and mTOR inhibitors (28.8%) for the third line, TKI (44.4%) and mTOR inhibitors (29%) for the fourth line, and IO monotherapy (37.5%) and TKI (25%) for the fifth line. For the first-line treatment, the primary cause of attrition was disease progression (66.4%), followed by toxicity (16.5%), death (11.2%), and patient preference (5.9%). The primary reason for attrition across all treatment lines was disease progression. Over time, the use of TKIs in first-line treatment increased, while IFN-alpha usage declined. IOs began to be utilized in earlier lines, predominantly in second-line treatment, though use of IO-based combination therapies remains limited. CONCLUSION This study underscores that despite significant progress in therapeutic options, the adoption of novel agents remains slow, and attrition rates are still high. These findings indicate a disparity in systemic therapy compared to developed countries.
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Affiliation(s)
- Hatice Bölek
- Ankara University School of Medicine, Department of Medical Oncology, Ankara, Turkey; Ankara University Cancer Institute, Ankara, Turkey
| | - Elif Sertesen
- University of Health Science, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Department of Medical Oncology, Ankara Turkey
| | - Omer Faruk Kuzu
- University of Health Science, Gülhane Training and Research Hospital, Department of Medical Oncology, Ankara Turkey
| | - Deniz Tural
- University of Health Science, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Medical Oncology, Istanbul, Turkey
| | - Saadet Sim
- Ege University School of Medicine, Department of Medical Oncology, İzmir, Turkey
| | | | - Gökhan Uçar
- Bilkent City Hospital, Department of Medical Oncology, Ankara Turkey
| | - Selver Işık
- Marmara University School of Medicine, Department of Medical Oncology, Istanbul, Turkey
| | - Bekir Hacıoğlu
- Trakya University School of Medicine, Department of Medical Oncology, Edirne, Turkey
| | - İrfan Çiçin
- Istinye University, Department of Medical Oncology, Istanbul, Turkey
| | - Çağatay Arslan
- Izmir University of Economics, Medical Point Hospital, Izmir, Turkey
| | - Sema Sezgin Göksu
- Akdeniz University School of Medicine, Department of Medical Oncology, Antalya, Turkey
| | - Özlem Nuray Sever
- Kartal Dr Lutfi Kirdar City Hospital, Department of Medical Oncology, Istanbul, Turkey
| | - Cengiz Karaçin
- University of Health Science, Dr Abdurrahman Yurtaslan Oncology Training and Research Hospital, Department of Medical Oncology, Ankara Turkey
| | - Nuri Karadurmuş
- University of Health Science, Gülhane Training and Research Hospital, Department of Medical Oncology, Ankara Turkey
| | - Mustafa Özgüroğlu
- Cerrahpasa School of Medicine, Department of Medical Oncology, Istanbul, Turkey
| | - Emre Yekedüz
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA
| | - Yüksel Ürün
- Ankara University School of Medicine, Department of Medical Oncology, Ankara, Turkey; Ankara University Cancer Institute, Ankara, Turkey.
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9
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Fawsitt CG, Pan J, Orishaba P, Jackson CH, Thom H. Unanchored simulated treatment comparison on survival outcomes using parametric and Royston-Parmar models with application to lenvatinib plus pembrolizumab in renal cell carcinoma. BMC Med Res Methodol 2025; 25:26. [PMID: 39885377 PMCID: PMC11780865 DOI: 10.1186/s12874-025-02480-x] [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: 12/01/2023] [Accepted: 01/20/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Population-adjusted indirect comparison using parametric Simulated Treatment Comparison (STC) has had limited application to survival outcomes in unanchored settings. Matching-Adjusted Indirect Comparison (MAIC) is commonly used but does not account for violation of proportional hazards or enable extrapolations of survival. We developed and applied a novel methodology for STC in unanchored settings. We compared overall survival (OS) and progression-free survival (PFS) of lenvatinib plus pembrolizumab (LEN + PEM) against nivolumab plus ipilimumab (NIVO + IPI), pembrolizumab plus axitinib (PEM + AXI), avelumab plus axitinib (AVE + AXI), and nivolumab plus cabozontanib (NIVO + CABO) in patients with advanced renal cell carcinoma (RCC). Unanchored comparison was necessitated as the control groups differed in their use of PD-1/PD-L1 rescue therapy. METHODS We fit covariate-adjusted survival models to individual patient data from phase 3 trial of LEN + PEM, including standard parametric distributions and Royston-Parmar spline models with up to 3 knots. We used these models to predict OS and PFS in the population of comparator treatments. The base case model was selected by minimum Akaike Information Criterion (AIC). Treatment effects were measured using difference in restricted mean survival time (RMST), over shortest follow-up of input trials, and hazard ratios at 6, 12, 18, and 24 months. RESULTS The survival model with the lowest AIC was 1-knot spline odds for OS and log-logistic for PFS. Difference in RMST OS was 6.90 months (95% CI: 1.95, 11.36), 5.31 (3.58, 7.28), 5.99 (1.82, 9.42), and 11.59 (8.41, 15.38) versus NIVO + IPI (over 64.8 months follow-up), AVE + AXI (46.7 months), PEM + AXI (64.8 months), NIVO + CABO (53.0 months), respectively. Difference in RMST PFS was 4.50 months (95% CI: 0.92, 8.26), 8.23 (5.60, 10.57), 5.38 (2.06, 9.09), and 4.58 (0.09, 9.44) versus NIVO + IPI (over 57.8 months), AVE + AXI (44.9 months), PEM + AXI (57.8 months), NIVO + CABO (23.8 months), respectively. Hazard ratios indicated strong evidence of greater OS and PFS on LEN + PEM at most timepoints. CONCLUSIONS We developed and applied a novel methodology for comparing survival outcomes in unanchored settings using STC. Pending investigation with a simulation study or further examples, this methodology could be used for clinical decision-making and, if long-term data are available, inform economic models designed to extrapolate outcomes for the evaluation of lifetime cost-effectiveness. TRIAL REGISTRATION NCT02811861 (registered: 23/06/2016).
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Affiliation(s)
| | | | | | | | - Howard Thom
- Clifton Insight, Bristol, UK
- University of Bristol, 1-5 Whiteladies Rd, Clifton, UK
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10
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Kato T, Furukawa J, Hinata N, Ueda K, Hara I, Hongo F, Mizuno R, Okamoto T, Okuno H, Ito T, Kajita M, Oya M, Tomita Y, Shinohara N, Eto M, Uemura H. Real-world outcomes of avelumab plus axitinib in patients with advanced renal cell carcinoma in Japan: long-term follow-up from the J-DART2 retrospective study. Int J Clin Oncol 2025; 30:99-109. [PMID: 39549218 DOI: 10.1007/s10147-024-02618-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 08/28/2024] [Indexed: 11/18/2024]
Abstract
BACKGROUND Avelumab + axitinib was approved for advanced renal cell carcinoma (aRCC) in Japan in December 2019. We report long-term real-world outcomes with first-line avelumab + axitinib from the J-DART2 study in Japan. METHODS J-DART2 was a multicenter, noninterventional, retrospective study examining clinical data from patients with curatively unresectable locally advanced or metastatic RCC who started treatment with first-line avelumab + axitinib in Japan between December 2019 and October 2022. Endpoints included patient characteristics, treatment patterns, and outcomes. RESULTS Data from 150 patients across 19 sites were analyzed; median follow-up was 18.7 months (95% CI, 16.3-20.6 months). Median age was 70.5 years; 26.0% of patients were aged ≤64 years, 42.7% were aged 65-74 years, and 31.3% were aged ≥75 years. International Metastatic RCC Database Consortium risk was favorable in 26.0%, intermediate in 54.7% (1 risk factor in 30.7%; 2 risk factors in 24.0%), and poor in 19.3% of patients. Median progression-free survival (PFS) was 17.1 months, with 1- and 2-year PFS rates of 57.7% and 37.5%, respectively. Median overall survival (OS) was not reached, with 1- and 2-year OS rates of 90.6% and 84.7%, respectively. Objective response rate was 53.3%; disease control rate was 88.9%. Outcomes were similar across age groups, including patients aged ≥75 years. CONCLUSIONS J-DART2 is the largest retrospective study to report long-term real-world outcomes in patients with aRCC treated with avelumab + axitinib in Japan. Findings were similar to those observed in previous studies and support the benefit of avelumab + axitinib in clinical practice in Japan.
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Affiliation(s)
- Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Oska, 565-0871, Japan
| | - Junya Furukawa
- Department of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Nobuyuki Hinata
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University School of Medicine, Asahi-Machi 67, Kurume-shi, Fukuoka, 830-0011, Japan
| | - Isao Hara
- Department of Urology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Fumiya Hongo
- Department of Urology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryuichi Mizuno
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Teppei Okamoto
- Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hiroshi Okuno
- Department of Urology, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa-Mukaihatacho, Fushimiku, Kyoto, 612-8555, Japan
| | - Takayuki Ito
- Medical Department, Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA, 1-8-1 Shimomeguro, Meguro-ku, Tokyo, 153-8926, Japan
| | - Masahiro Kajita
- Medical Department, Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA, 1-8-1 Shimomeguro, Meguro-ku, Tokyo, 153-8926, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yoshihiko Tomita
- Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Street, Chuo Ward, Niigata, 951-8510, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Kita15, Nishi7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan.
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11
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Nonomura N, Ito T, Sato M, Morita M, Ogi M, Kajita M, Oya M. Final Analysis of Post-Marketing Surveillance for Avelumab + Axitinib in Patients With Renal Cell Carcinoma in Japan. Cancer Med 2025; 14:e70275. [PMID: 39838507 PMCID: PMC11750683 DOI: 10.1002/cam4.70275] [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: 03/04/2024] [Revised: 08/20/2024] [Accepted: 09/20/2024] [Indexed: 01/23/2025] Open
Abstract
INTRODUCTION Avelumab, an anti-programmed death ligand 1 antibody, was approved in combination with axitinib for curatively unresectable or metastatic renal cell carcinoma (RCC) in Japan in December 2019. Because the pivotal JAVELIN Renal 101 study included a limited number of Japanese patients, post-marketing surveillance (PMS) was required to evaluate outcomes (safety and effectiveness) in patients with RCC who received avelumab + axitinib treatment in clinical practice in Japan. MATERIALS AND METHODS We report data from prospective, noncomparative, multicenter, observational PMS in patients with RCC who received ≥ 1 dose of avelumab. Patients were enrolled between December 2019 (date of regulatory approval) and May 2021. The primary objective was to evaluate safety, defined as adverse drug reactions (ADRs) of safety specifications occurring during an observation period of ≤ 52 weeks for each patient. The secondary objective was to evaluate effectiveness, including best overall response and overall survival (OS). RESULTS In total, 328 patients were included in the safety and effectiveness analysis sets. Overall, 173 patients (52.7%) had ADRs of safety specifications of any grade, most commonly thyroid dysfunction (n = 69 [21.0%]), infusion reaction (n = 65 [19.8%]), and hepatic disorders (n = 45 [13.7%]). Objective responses occurred in 118 patients (36.0%), including complete or partial responses in 13 (4.0%) and 105 (32.0%), respectively; the disease control rate was 75.6%. The 12-month OS rate was 83.7% (95% CI, 78.9%-87.4%). DISCUSSION This PMS confirmed the safety, tolerability, and effectiveness of avelumab + axitinib in patients with RCC in clinical practice in Japan, with a benefit-risk profile comparable to that observed in clinical trials.
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MESH Headings
- Humans
- Axitinib/administration & dosage
- Axitinib/adverse effects
- Axitinib/therapeutic use
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/mortality
- Carcinoma, Renal Cell/pathology
- Male
- Female
- Middle Aged
- Aged
- Japan
- Product Surveillance, Postmarketing
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/mortality
- Kidney Neoplasms/pathology
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Prospective Studies
- Aged, 80 and over
- Adult
- Treatment Outcome
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Affiliation(s)
- Norio Nonomura
- Department of UrologyOsaka University Graduate School of MedicineOsakaJapan
| | - Taito Ito
- Medical DepartmentMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Masashi Sato
- Research and DevelopmentMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Makiko Morita
- Global Patient Safety JapanMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Mie Ogi
- Global Development OperationsMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Masahiro Kajita
- Medical DepartmentMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Mototsugu Oya
- Department of UrologyKeio University School of MedicineTokyoJapan
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12
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Oya M, Ito T, Sato M, Morita M, Kajita M, Nonomura N. Avelumab + axitinib treatment in older patients with advanced renal cell carcinoma in Japan: Subgroup analyses of post-marketing surveillance data by age. Cancer Med 2025; 14:e70186. [PMID: 39838508 PMCID: PMC11750686 DOI: 10.1002/cam4.70186] [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: 03/06/2024] [Revised: 06/28/2024] [Accepted: 08/21/2024] [Indexed: 01/23/2025] Open
Abstract
INTRODUCTION Avelumab + axitinib was approved in Japan in December 2019 for the treatment of curatively unresectable or metastatic renal cell carcinoma (RCC) based on results from the JAVELIN Renal 101 trial. MATERIALS AND METHODS To evaluate the safety and effectiveness of avelumab + axitinib in older patients in general clinical practice in Japan, an ad hoc analysis of data from post-marketing surveillance (PMS) by age group was conducted. RESULTS The analysis population included 328 patients who had received ≥1 dose of avelumab and were enrolled between December 2019 and May 2021. In total, 100 patients (30.5%) were aged ≤64 years, 130 (39.6%) were aged 65-74 years, and 98 (29.9%) were aged ≥75 years. Within these age groups, adverse drug reactions (ADRs) of safety specifications of any grade occurred in 46 (46.0%), 71 (54.6%), and 56 (57.1%), and of grade ≥3 in 13 (13.0%), 23 (17.7%), and 20 (20.4%), respectively. The most common ADRs of safety specifications across all age groups were thyroid dysfunction, infusion reactions, and hepatic function disorders. Median overall survival (OS) was not reached in any age group; 12-month OS rates in patients aged ≤64, 65-74, or ≥75 years were 83.8%, 86.2%, and 80.0%, and objective response rates were 31.0%, 43.8%, and 30.6%, respectively. DISCUSSION Analyses of PMS data show the safety and effectiveness of avelumab + axitinib across all age groups of patients with RCC in general clinical practice in Japan. The favorable benefit-risk profile was generally consistent with that observed in previous clinical trials.
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MESH Headings
- Humans
- Aged
- Axitinib/administration & dosage
- Axitinib/adverse effects
- Axitinib/therapeutic use
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/mortality
- Carcinoma, Renal Cell/pathology
- Male
- Female
- Japan/epidemiology
- Product Surveillance, Postmarketing
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/pathology
- Kidney Neoplasms/mortality
- Middle Aged
- Aged, 80 and over
- Age Factors
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
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Affiliation(s)
- Mototsugu Oya
- Department of UrologyKeio University School of MedicineTokyoJapan
| | - Taito Ito
- Medical DepartmentMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Masashi Sato
- Research and DevelopmentMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Makiko Morita
- Global Patient Safety JapanMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Masahiro Kajita
- Medical DepartmentMerck Biopharma Co., Ltd., Tokyo, Japan, an Affiliate of Merck KGaADarmstadtGermany
| | - Norio Nonomura
- Department of UrologyOsaka University Graduate School of MedicineOsakaJapan
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13
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Sprokkerieft J, van der Beek JN, Spreafico F, Selle B, Chowdhury T, Graf N, Verschuur AC, Dandis R, Bex A, Geller JI, Tytgat GAM, van den Heuvel-Eibrink MM. Outcome after treatment with axitinib in children, young adults, and adults with renal cell carcinoma: a narrative review. Crit Rev Oncol Hematol 2024; 204:104523. [PMID: 39326645 DOI: 10.1016/j.critrevonc.2024.104523] [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: 05/03/2024] [Accepted: 09/21/2024] [Indexed: 09/28/2024] Open
Abstract
Renal cell carcinoma (RCC) is a very rare type of renal cancer in children and young adults. When metastasized or recurrent, no standards of care are available, and outcome is still poor. The tyrosine kinase inhibitor axitinib is approved for treatment of RCC in adults, but its effects in children and young adults with RCC remains unclear. Due to the histological and biological differences between children and adults, it is difficult to extrapolate knowledge on treatments from the adult to the pediatric and young adult setting. This paper summarizes the clinical characteristics and outcomes of patients with RCC who were treated with axitinib, with the aim to gain insight in the clinical efficacy of this compound in this young patient group.
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Affiliation(s)
- Julia Sprokkerieft
- Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
| | - Justine N van der Beek
- Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Filippo Spreafico
- Pediatric Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Barbara Selle
- Hopp Children's Cancer Center Heidelberg (KiTZ) & Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Tanzina Chowdhury
- Pediatric Oncology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Norbert Graf
- Department of Pediatric Oncology and Hematology, Saarland University, Homburg, Germany
| | - Arnauld C Verschuur
- Department of Pediatric Hematology-Oncology, Hôpital d'Enfants de la Timone, APHM, Marseille, France
| | - Rana Dandis
- Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Axel Bex
- Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam 1066CX, the Netherlands; Division of Surgical and Interventional Science, The Royal Free London NHS Foundation Trust and UCL, London, UK
| | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, USA
| | - Godelieve A M Tytgat
- Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
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14
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Frazer R, Arranz JÁ, Estévez SV, Parikh O, Krabbe LM, Vasudev NS, Doehn C, Marschner N, Waddell T, Ince W, Goebell PJ. Tivozanib Monotherapy in the Frontline Setting for Patients with Metastatic Renal Cell Carcinoma and Favorable Prognosis. Curr Oncol Rep 2024; 26:1639-1650. [PMID: 39565522 PMCID: PMC11646210 DOI: 10.1007/s11912-024-01613-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2024] [Indexed: 11/21/2024]
Abstract
PURPOSE OF REVIEW In this review, we discuss which patients with metastatic clear cell renal cell carcinoma (mRCC) may be most suitable for frontline tyrosine kinase inhibitor (TKI) monotherapy, a treatment option supported by emerging long-term efficacy data including overall survival and quality of life. We specifically focus on tivozanib, a potent and selective inhibitor of vascular endothelial growth factor receptor, which has comparable efficacy to other single-agent TKIs in frontline treatment for mRCC while exhibiting fewer off-target side effects. RECENT FINDINGS Combination therapy with TKIs and checkpoint inhibitors (CPIs) and CPI/CPI combination therapies, as well as TKI monotherapy are recommended frontline treatment options for mRCC. Treatment decisions are complex and based on several factors, including the patient's International Metastatic RCC Database Consortium risk status, age, comorbidities, and personal preferences related to response, tolerability, and quality of life. TKIs not only serve as backbone of most combination therapies for mRCC, but also remain a viable monotherapy option in the first-line setting for patients in favorable risk groups and those with contraindications to CPI combination therapies. Given that overall survival benefits have not yet been confirmed for CPI-containing combination regimens in favorable risk patients, we argue that frontline single-agent TKI treatment remains a standard of care option for these patients. This is supported by treatment guidelines, even in the era of TKI/CPI combination therapies.
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Affiliation(s)
| | | | | | - Omi Parikh
- Lancashire Teaching Hospitals NHS Foundation Trust, Chorley, UK
| | | | | | | | | | - Tom Waddell
- The Christie NHS Foundation Trust, Manchester, UK
| | - Will Ince
- Department of Oncology, Cambridge University NHS Foundation Trust, Cambridge, UK
| | - Peter J Goebell
- Uniklinik Erlangen, Urologische und Kinderurologische Klinik, Erlangen, Germany
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15
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Yanagisawa T, Mori K, Kawada T, Katayama S, Uchimoto T, Tsujino T, Nishimura K, Adachi T, Toyoda S, Nukaya T, Fukuokaya W, Urabe F, Murakami M, Yamanoi T, Bekku K, Komura K, Takahara K, Hashimoto T, Fujita K, Azuma H, Ohno Y, Shiroki R, Uemura H, Araki M, Kimura T. First-line therapy for metastatic renal cell carcinoma: A propensity score-matched comparison of efficacy and safety. Urol Oncol 2024; 42:374.e21-374.e29. [PMID: 39085019 DOI: 10.1016/j.urolonc.2024.06.013] [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: 03/12/2024] [Revised: 05/03/2024] [Accepted: 06/13/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE Immune checkpoint inhibitor (ICI)-based combination therapy is a standard systemic treatment for metastatic renal cell carcinoma (mRCC). Although differential pharmacologic action between ICI+ICI and ICI+tyrosine kinase inhibitor (TKI) combinations may affect outcomes, comparative studies using real-world data are few. METHODS We retrospectively analyzed the records of 447 mRCC patients treated with 1st-line ICI-based combinations at multiple institutions between January 2018 and August 2023, and selected 320 patients diagnosed with clear cell RCC (ccRCC) for further study. Cohorts were matched using one-to-one propensity scores based on IMDC risk classification. Overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), and treatment-related adverse events (TrAE) were compared. RESULTS The matching process yielded 228 metastatic ccRCC patients treated with ICI+ICI (n = 114) or ICI+TKI (n = 114). Median OS was 53 months (95%CI: 33-NA) in patients treated with ICI+ICI and was not reached (95%CI: 43-NA) with ICI+TKI (P = 0.24). Median PFS was significantly shorter for ICI+ICI (13 months, 95%CI: 7-25) than for ICI+TKI (25 months, 95%CI: 13-NA) (P = 0.047). There were no differences in second-line PFS for sequential therapy after 1st-line combinations of ICI+ICI or ICI+TKI (6 vs. 8 months, P = 0.6). There were no differences in ORR between the 2 groups (ICI+ICI: 51% vs. ICI+TKI: 55%, P = 0.8); the progressive disease (PD) rate was significantly higher in patients treated with the ICI+ICI combination (24% vs. 11%, P = 0.029). The rate of any grade TrAE was significantly higher in patients treated with ICI+TKI (71% vs. 85%, P = 0.016), but we found no differences in severe TrAE between the 2 groups (39% vs. 36%, P = 0.8). CONCLUSIONS In a matched cohort of real-world data, we confirmed comparable OS benefits between ICI+ICI and ICI+TKI combinations. However, differential clinical behaviors in terms of PFS, PD rates, and TrAE between ICI-based combinations may enrich clinical decision-making.
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Affiliation(s)
- Takafumi Yanagisawa
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.
| | - Keiichiro Mori
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Tatsushi Kawada
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoshi Katayama
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Taizo Uchimoto
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Takuya Tsujino
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kazuki Nishimura
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Takahiro Adachi
- Department of Urology,Tokyo Medical University, Tokyo, Japan
| | - Shingo Toyoda
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takuhisa Nukaya
- Department of Urology, Fujita Health University School of Medicine, Aichi, Japan
| | - Wataru Fukuokaya
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Fumihiko Urabe
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masaya Murakami
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomoaki Yamanoi
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kensuke Bekku
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazumasa Komura
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kiyoshi Takahara
- Department of Urology, Fujita Health University School of Medicine, Aichi, Japan
| | | | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Haruhito Azuma
- Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Yoshio Ohno
- Department of Urology,Tokyo Medical University, Tokyo, Japan
| | - Ryoichi Shiroki
- Department of Urology, Fujita Health University School of Medicine, Aichi, Japan
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Motoo Araki
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
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16
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Cerrato C, Crocerossa F, Marchioni M, Giannarini G, Gupta S, Albiges L, Brouwer O, Albersen M, Fankhauser C, Grimm MO, Gandaglia G, Roupret M, Mir MC. Effect of Sex on the Oncological Outcomes in Response to Immunotherapy and Antibody-drug Conjugates in Patients with Urothelial and Kidney Cancer: A Systematic Review and a Network Meta-analysis. Eur Urol Oncol 2024; 7:1005-1014. [PMID: 38644155 DOI: 10.1016/j.euo.2024.03.014] [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: 01/28/2024] [Revised: 03/03/2024] [Accepted: 03/26/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND AND OBJECTIVE Immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) herald a transformative era in metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) treatment, amid acknowledged sex-based disparities in these cancers. We conducted a systematic review and network meta-analysis (NMA) to identify sex-specific differences in the efficacy of ICI/ADC monotherapy or combination therapies for RCC and TCC survival, in metastatic and adjuvant settings. METHODS A systematic search was conducted up to October 2023 for English articles on ICIs and ADCs as systemic therapies (ICIs in first-line and adjuvant treatment for RCC, ICIs and ADCs in first- and second-line treatment for TCC). Randomised clinical trials were considered. The primary objective was overall survival (OS) of ICIs and ADCs between males and females. The secondary outcomes included progression-free survival, overall response rate, disease-free survival, and recurrence-free survival. Treatment efficacy was evaluated by sex via odds ratios (ORs) and confidence intervals compared with controls. Log ORs were used for creating a frequentist NMA. This meta-analysis was registered on PROSPERO (CRD42023468632). KEY FINDINGS AND LIMITATIONS Eighteen articles met the inclusion criteria. Females had an advantage for RCC-adjuvant treatment for atezolizumab (log OR [SE] = -0.57 ± 0.25, p = 0.024) in OS. Males showed a survival advantage in TCC second-line treatment for ADC-Nectin 4 (log OR [SE] = 0.65 ± 0.28, p = 0.02). No other significant results were shown. CONCLUSIONS AND CLINICAL IMPLICATIONS The NMA revealed gender-specific variations in ICI and ADC responses for RCC and TCC, offering insights for personalised cancer care and addressing disparities in cancer care and outcomes. PATIENT SUMMARY In this systematic review, we looked at the sex differences for metastatic renal cell carcinoma (RCC) and transitional cell carcinoma (TCC) for antibody-drug conjugates and immune checkpoint inhibitors. In our analysis, female and male sex has better overall survival for adjuvant and second-line therapies for RCC and TCC, respectively. Urgent research on gender-specific cancer therapies is imperative.
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Affiliation(s)
- Clara Cerrato
- University Hospital Southampton NHS Trust, Southampton, UK
| | - Fabio Crocerossa
- Department of Urology, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | | | - Gianluca Giannarini
- Urology Unit, "Santa Maria della Misericordia" University Hospital, Udine, Italy
| | - Shilpa Gupta
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
| | - Laurence Albiges
- Department of Cancer Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Oscar Brouwer
- The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Maarten Albersen
- Department of Urology, University Hospitals Leuven, Leuven, Belgium
| | - Christian Fankhauser
- Department of Urology, Luzerner Kantonsspital, Luzern, Switzerland; University of Lucerne, Lucerne, Switzerland; University of Zurich, Zurich, Switzerland
| | | | - Giorgio Gandaglia
- Department of Urology, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Morgan Roupret
- GRC 5 Predictive Onco-Uro, Department of Urology, AP-HP, Pitié Salpétrière Hospital, Sorbonne University, Paris, France
| | - Maria Carmen Mir
- Department of Urology, Hospital Universitario La Ribera, Valencia, Spain.
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17
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Young M, Jackson-Spence F, Beltran L, Day E, Suarez C, Bex A, Powles T, Szabados B. Renal cell carcinoma. Lancet 2024; 404:476-491. [PMID: 39033764 DOI: 10.1016/s0140-6736(24)00917-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 03/10/2024] [Accepted: 04/30/2024] [Indexed: 07/23/2024]
Abstract
The landscape of the management of renal cell carcinoma has evolved substantially in the last decade, leading to improved survival in localised and advanced disease. We review the epidemiology, pathology, and diagnosis of renal cell carcinoma and discuss the evidence for current management strategies from localised to metastatic disease. Developments in adjuvant therapies are discussed, including use of pembrolizumab-the first therapy to achieve overall survival benefit in the adjuvant setting. The treatment of advanced disease, including landmark trials that have established immune checkpoint inhibition as a standard of care, are also reviewed. We also discuss the current controversies that exist surrounding the management of metastatic renal cell carcinoma, including the use of risk assessment models for disease stratification and treatment selection for frontline therapy. Management of non-clear cell renal cell carcinoma subtypes is also reviewed. Future directions of research, including a discussion of ongoing clinical trials and the need for reliable biomarkers to guide treatment in kidney cancer, are also highlighted.
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Affiliation(s)
- Matthew Young
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - Luis Beltran
- Department of Cellular Pathology, Barts National Health Service Trust, London, UK
| | - Elizabeth Day
- Department of Urology, University College London Hospital National Health Service Foundation Trust, London, UK
| | - Christina Suarez
- Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Axel Bex
- Department of Urology, The Royal Free London National Health Service Foundation Trust, University College London Division of Surgery and Interventional Science, London, UK; The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Thomas Powles
- Barts Cancer Institute, Queen Mary University of London, London, UK.
| | - Bernadett Szabados
- Barts Cancer Institute, Queen Mary University of London, London, UK; Department of Urology, University College London Hospital National Health Service Foundation Trust, London, UK
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18
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Bolek H, Arslan C, Basaran M, Cicin İ, Ozguroglu M, Tural D, Ürün Y. Perceptions and Expectations: A Study on Prognostic Perception and Quality of Life in Patients With Metastatic Renal and Bladder Cancer. JCO Glob Oncol 2024; 10:e2400201. [PMID: 39208383 DOI: 10.1200/go.24.00201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/29/2024] [Accepted: 07/25/2024] [Indexed: 09/04/2024] Open
Abstract
PURPOSE Durable complete response rates for metastatic renal cell carcinoma (mRCC) and metastatic bladder cancer (mBC) are low despite new therapy. Palliative care focuses on life extension and quality of life (QoL), not cure. This study aims to investigate patients' perceptions of treatment outcomes in mRCC and mBC and to assess the influence of QoL and optimism levels on these perceptions. METHODS From March 15, 2023, to January 15, 2024, a multicenter, cross-sectional online survey was carried out, targeting patients diagnosed with mRCC and mBC. The survey comprised structured questions aimed at evaluating perceptions concerning disease cure, symptom improvement, daily activity performance, and life extension due to treatment. Additionally, to evaluate optimism and QoL, the European Organization for Research and Treatment of Cancer 30.3 QoL questionnaire and life orientation test were implemented. Study on patients' perceptions of treatment outcomes in metastatic kidney and bladder cancer shows high optimism, inaccurate cure beliefs. RESULTS In total, 169 patients participated in the survey; the majority of the patients stated their general health status as good (72.2%) and excellent (13.6%). Patients who rated their overall health status as good-excellent had a higher median general QoL and optimism score compared with those who rated it as fair-poor. In all, 85.2% of patients considered the possibility of a cure very likely or likely. Most participants believed treatment could provide symptom relief (30.2% very likely, 49.1% likely), enhanced ability to perform daily activities (28.4% very likely, 55.6% likely), and life extension (32.5% very likely, 53.3% likely). Patients responding very likely and likely to these questions regarding treatment outcomes had higher QoL and optimism scores than those responding a little likely and not possible. CONCLUSION The majority of patients with mRCC and mBC held inaccurate beliefs about treatment outcomes. Better QoL and optimism were associated with increased inaccuracy.
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Affiliation(s)
- Hatice Bolek
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey
- Ankara University Cancer Institute, Ankara, Turkey
| | - Cagatay Arslan
- Department of Medical Oncology, Izmir University of Economics, Medical Point Hospital, Izmir, Turkey
| | - Mert Basaran
- Department of Medical Oncology, Istanbul University School of Medicine, Istanbul, Turkey
| | - İrfan Cicin
- Department of Medical Oncology, Trakya University School of Medicine, Edirne, Turkey
| | - Mustafa Ozguroglu
- Department of Medical Oncology, Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Deniz Tural
- Department of Medical Oncology, University of Health Science, Bakirkoy Dr Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - Yüksel Ürün
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey
- Ankara University Cancer Institute, Ankara, Turkey
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19
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Blas L, Monji K, Mutaguchi J, Kobayashi S, Goto S, Matsumoto T, Shiota M, Inokuchi J, Eto M. Current status and future perspective of immunotherapy for renal cell carcinoma. Int J Clin Oncol 2024; 29:1105-1114. [PMID: 38108981 DOI: 10.1007/s10147-023-02446-3] [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: 10/24/2023] [Accepted: 11/21/2023] [Indexed: 12/19/2023]
Abstract
In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives.
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Affiliation(s)
- Leandro Blas
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Keisuke Monji
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Jun Mutaguchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Satoshi Kobayashi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shunsuke Goto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takashi Matsumoto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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20
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Beecroft N, Gauntner TD, Upadhyay R, Wang SJ, Yang Y, Singer EA, Dason S. Active Surveillance in Metastatic Renal Cell Carcinoma. J Kidney Cancer VHL 2024; 11:27-38. [PMID: 38863736 PMCID: PMC11164654 DOI: 10.15586/jkcvhl.v11i2.309] [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: 12/09/2023] [Accepted: 05/24/2024] [Indexed: 06/13/2024] Open
Abstract
Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with a variable clinical course. While therapies for treatment of this condition have progressed, they are not without toxicity. In some patients, active surveillance (AS) of this disease is increasingly considered to delay its toxicity. This article seeks to review the literature and discuss management of metastatic renal cell carcinoma, specifically regarding upfront AS, the role of radiation therapy in delaying systemic therapy, and surveillance after initial treatment with systemic therapy. Median time on AS prior to initiation of systemic therapy ranged from 14 to 60 months across studies. AS is appropriate to offer in favorable or intermediate risk, asymptomatic, and systemic treatment naïve patients with mRCC.
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Affiliation(s)
- Nicholas Beecroft
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Timothy D. Gauntner
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Rituraj Upadhyay
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Shang-Jui Wang
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Yuanquan Yang
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Eric A Singer
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Shawn Dason
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
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21
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Galarza Fortuna GM, Maughan BL. The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in the modern era. Transl Androl Urol 2024; 13:915-919. [PMID: 38855590 PMCID: PMC11157399 DOI: 10.21037/tau-23-646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/01/2024] [Indexed: 06/11/2024] Open
Affiliation(s)
| | - Benjamin L Maughan
- Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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22
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Powles T, Burotto M, Escudier B, Apolo AB, Bourlon MT, Shah AY, Suárez C, Porta C, Barrios CH, Richardet M, Gurney H, Kessler ER, Tomita Y, Bedke J, George S, Scheffold C, Wang P, Fedorov V, Motzer RJ, Choueiri TK. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open 2024; 9:102994. [PMID: 38642472 PMCID: PMC11046044 DOI: 10.1016/j.esmoop.2024.102994] [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: 10/04/2023] [Revised: 02/07/2024] [Accepted: 03/11/2024] [Indexed: 04/22/2024] Open
Abstract
BACKGROUND Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score. PATIENTS AND METHODS Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability. RESULTS Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN [16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71]; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN [56% (50% to 62%) versus 28% (23% to 33%)]; 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN. CONCLUSIONS After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC. TRIAL REGISTRATION ClinicalTrials.gov, NCT03141177.
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Affiliation(s)
- T Powles
- Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, London; Royal Free National Health Service Trust, London, UK.
| | - M Burotto
- Bradford Hill Clinical Research Center, Santiago, Chile
| | | | - A B Apolo
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - M T Bourlon
- Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - A Y Shah
- MD Anderson Cancer Center, Houston, USA
| | - C Suárez
- Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - C Porta
- Department of Internal Medicine, University of Pavia, Pavia, Italy
| | - C H Barrios
- Centro de Pesquisa em Oncologia, Hospital São Lucas, PUCRS, Latin American Cooperative Oncology Group, Porto Alegre, Brazil
| | - M Richardet
- Fundación Richardet Longo, Instituto Oncológico de Córdoba, Córdoba, Argentina
| | - H Gurney
- Westmead Hospital and Macquarie University, Westmead and Sydney, Australia
| | - E R Kessler
- Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, USA
| | - Y Tomita
- Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - J Bedke
- Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - S George
- Roswell Park Comprehensive Cancer Center, Buffalo
| | | | - P Wang
- Bristol Myers Squibb, Princeton
| | | | - R J Motzer
- Memorial Sloan Kettering Cancer Center, New York
| | - T K Choueiri
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston; Brigham and Women's Hospital, Harvard Medical School, Boston, USA
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23
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Yang S, Yang X, Hou Z, Zhu L, Yao Z, Zhang Y, Chen Y, Teng J, Fang C, Chen S, Jia M, Liu Z, Kang S, Chen Y, Li G, Niu Y, Cai Q. Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma. Heliyon 2024; 10:e29215. [PMID: 38623200 PMCID: PMC11016731 DOI: 10.1016/j.heliyon.2024.e29215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 04/02/2024] [Accepted: 04/02/2024] [Indexed: 04/17/2024] Open
Abstract
Renal cell carcinoma (RCC) is a frequent urological malignancy characterized by a high rate of metastasis and lethality. The treatment strategy for advanced RCC has moved through multiple iterations over the past three decades. Initially, cytokine treatment was the only systemic treatment option for patients with RCC. With the development of medicine, antiangiogenic agents targeting vascular endothelial growth factor and mammalian target of rapamycin and immunotherapy, immune checkpoint inhibitors (ICIs) have emerged and received several achievements in the therapeutics of advanced RCC. However, ICIs have still not brought completely satisfactory results due to drug resistance and undesirable side effects. For the past years, the interests form researchers have been attracted by the combination of ICIs and targeted therapy for advanced RCC and the angiogenesis and immunogenic tumor microenvironmental variations in RCC. Therefore, we emphasize the potential principle and the clinical progress of ICIs combined with targeted treatment of advanced RCC, and summarize the future direction.
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Affiliation(s)
- Siwei Yang
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xianrui Yang
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zekai Hou
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Liang Zhu
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhili Yao
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | | | - Yanzhuo Chen
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Jie Teng
- Affiliated Hospital of Hebei University, Baoding, China
| | - Cheng Fang
- Taihe County People's Hospital, Anhui, China
| | - Songmao Chen
- Department of Urology, Fujian Provincial Hospital, Fujian, China
- Provincial Clinical Medical College of Fujian Medical University, Fujian, China
| | - Mingfei Jia
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Hebei, China
| | - Zhifei Liu
- Department of Urology, Tangshan People's Hospital, Hebei, China
| | - Shaosan Kang
- Department of Urology, North China University of Science and Technology Affiliated Hospital, Hebei, China
| | - Yegang Chen
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Gang Li
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yuanjie Niu
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
| | - Qiliang Cai
- Department of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, China
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24
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Soares A, Monteiro FSM, da Trindade KM, Silva AGE, Cardoso APG, Sasse AD, Fay AP, Carneiro APCD, Alencar Junior AM, de Andrade Mota AC, Santucci B, da Motta Girardi D, Herchenhorn D, Araújo DV, Jardim DL, Bastos DA, Rosa DR, Schutz FA, Kater FR, da Silva Marinho F, Maluf FC, de Oliveira FNG, Vidigal F, Morbeck IAP, Rinck Júnior JA, Costa LAGA, Maia MCDF, Zereu M, Freitas MRP, Dias MSF, Tariki MS, Muniz P, Beato PMM, Lages PSM, Velho PI, de Carvalho RS, Mariano RC, de Araújo Cavallero SR, Oliveira TM, Souza VC, Smaletz O, de Cássio Zequi S. Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update. J Cancer Res Clin Oncol 2024; 150:183. [PMID: 38594593 PMCID: PMC11003910 DOI: 10.1007/s00432-024-05663-z] [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: 12/27/2023] [Accepted: 02/22/2024] [Indexed: 04/11/2024]
Abstract
PURPOSE Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.
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Affiliation(s)
- Andrey Soares
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil.
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
- Centro Paulista de Oncologia/Oncoclínicas, São Paulo, SP, Brazil.
| | - Fernando Sabino Marques Monteiro
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Sírio-Libanês, Brasília, DF, Brazil
| | - Karine Martins da Trindade
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Oncologia D'Or, Fortaleza, CE, Brazil
| | - Adriano Gonçalves E Silva
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Instituto do Câncer e Transplante de Curitiba/PR (ICTr Curitiba), Curitiba, PR, Brazil
| | - Ana Paula Garcia Cardoso
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - André Deeke Sasse
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo SONHE de Campinas, Campinas, SP, Brazil
| | - André P Fay
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Escola de Medicina da Pontifícia, Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - André Paternò Castello Dias Carneiro
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Hospital Municipal Vila Santa Catarina, São Paulo, SP, Brazil
| | - Antonio Machado Alencar Junior
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital São Domingos, São Luís, MA, Brazil
- Dasa Oncologia, Brasília, DF, Brazil
- Hospital Universitário da Universidade Federal do Maranhão (UFMA), São Luís, MA, Brazil
| | - Augusto César de Andrade Mota
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Clínica AMO-DASA, Feira de Santana, BA, Brazil
| | - Bruno Santucci
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Instituto Paulista de Cancerologia, São Paulo, SP, Brazil
| | - Daniel da Motta Girardi
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Sírio-Libanês, Brasília, DF, Brazil
| | - Daniel Herchenhorn
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Oncologia D'Or, Rio de Janeiro, RJ, Brazil
| | - Daniel Vilarim Araújo
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital de Base de São José do Rio Preto/SP, São José do Rio Preto, São Paulo, SP, Brazil
| | - Denis Leonardo Jardim
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, São Paulo, São Paulo, SP, Brazil
| | - Diogo Assed Bastos
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Sirio-Libanês de São Paulo, São Paulo, SP, Brazil
| | - Diogo Rodrigues Rosa
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Rio de Janeiro, RJ, Brazil
| | - Fabio A Schutz
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Fábio Roberto Kater
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Felipe da Silva Marinho
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Recife, PE, Brazil
| | - Fernando Cotait Maluf
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Fernando Nunes Galvão de Oliveira
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Salvador, BA, Brazil
| | - Fernando Vidigal
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Dasa Oncologia, Brasília, DF, Brazil
| | - Igor Alexandre Protzner Morbeck
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Brasília, DF, Brazil
| | - Jose Augusto Rinck Júnior
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Leonardo Atem G A Costa
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Oncologia D'Or, Fortaleza, CE, Brazil
| | - Manuel Caitano Dias Ferreira Maia
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital do Câncer Porto Dias, Belém, PA, Brazil
| | - Manuela Zereu
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brazil
| | - Marcelo Roberto Pereira Freitas
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Centro Especializado de Oncologia de Florianópolis, Florianópolis, SC, Brazil
| | - Mariane Sousa Fontes Dias
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Rio de Janeiro, RJ, Brazil
| | - Milena Shizue Tariki
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Pamela Muniz
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, São Paulo, São Paulo, SP, Brazil
- Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | - Patrícia Medeiros Milhomem Beato
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Amaral Carvalho, Jaú, SP, Brazil
| | - Paulo Sérgio Moraes Lages
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Grupo Oncoclínicas, Brasília, DF, Brazil
| | - Pedro Isaacsson Velho
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Moinhos de Vento, Porto Alegre, RS, Brazil
- Johns Hopkins University, Baltimore, MD, USA
| | - Ricardo Saraiva de Carvalho
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Rodrigo Coutinho Mariano
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Sandro Roberto de Araújo Cavallero
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Adventista de Belém, Belém, PA, Brazil
| | - Thiago Martins Oliveira
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital São Rafael, Salvador, BA, Brazil
| | - Vinicius Carrera Souza
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Instituto D'Or de Ensino e Pesquisa, Salvador, BA, Brazil
| | - Oren Smaletz
- Latin American Cooperative Oncology Group, Genitourinary Group (LACOG-GU), Av. Brigadeiro Faria Lima, Vila Olímpia, São Paulo, SP, 4300, Brazil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Stênio de Cássio Zequi
- AC Camargo Cancer Center, São Paulo, SP, Brazil
- National Institute for Science and Technology in Oncogenomics and Therapeutic Innovation, AC Camargo Cancer Center, São Paulo, SP, Brazil
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25
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Ohba K, Imamura R. The final report of KEYNOTE-426 showed the efficacy and safety as a treatment for advanced renal cell carcinoma. Transl Androl Urol 2024; 13:353-355. [PMID: 38481862 PMCID: PMC10932633 DOI: 10.21037/tau-23-588] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/16/2024] [Indexed: 05/09/2025] Open
Affiliation(s)
| | - Ryoichi Imamura
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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26
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Yan XQ, Ye MJ, Zou Q, Chen P, He ZS, Wu B, He DL, He CH, Xue XY, Ji ZG, Chen H, Zhang S, Liu YP, Zhang XD, Fu C, Xu DF, Qiu MX, Lv JJ, Huang J, Ren XB, Cheng Y, Qin WJ, Zhang X, Zhou FJ, Ma LL, Guo JM, Ding DG, Wei SZ, He Y, Guo HQ, Shi BK, Liu L, Liu F, Hu ZQ, Jin XM, Yang L, Zhu SX, Liu JH, Huang YH, Xu T, Liu B, Sun T, Wang ZJ, Jiang HW, Yu DX, Zhou AP, Jiang J, Luan GD, Jin CL, Xu J, Hu JX, Huang YR, Guo J, Zhai W, Sheng XN. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol 2024; 35:190-199. [PMID: 37872020 DOI: 10.1016/j.annonc.2023.09.3108] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.
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Affiliation(s)
- X Q Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing
| | - M J Ye
- Department of Urology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha
| | - Q Zou
- Department of Urology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing
| | - P Chen
- Department of Urology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi
| | - Z S He
- Department of Urology, First Hospital of Peking University, Beijing
| | - B Wu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang
| | - D L He
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an
| | - C H He
- Department of Urology, Cancer Hospital of Henan Province, Zhengzhou
| | - X Y Xue
- Department of Urology, The First Affiliated Hospital, Fujian Medical University, Fuzhou
| | - Z G Ji
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
| | - H Chen
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin
| | - S Zhang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu
| | - Y P Liu
- Department of Oncology, The First Hospital of China Medical University, Shenyang
| | - X D Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing
| | - C Fu
- Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang
| | - D F Xu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai
| | - M X Qiu
- Department of Urology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu
| | - J J Lv
- Department of Urology, Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - J Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou
| | - X B Ren
- Department of Immunology and Biotherapy, Cancer Institute & Hospital, Tianjin Medical University, Tianjin
| | - Y Cheng
- Department of Medical Thoracic Oncology, Jilin Provincial Cancer Hospital, Changchun
| | - W J Qin
- Department of Urology, Xijing Hospital of Air Force Military Medical University, Xi'an
| | - X Zhang
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing
| | - F J Zhou
- Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou
| | - L L Ma
- Department of Urology, Peking University Third Hospital, Beijing
| | - J M Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai
| | - D G Ding
- Department of Urology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou
| | - S Z Wei
- Department of Urology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
| | - Y He
- Department of Urology, The Affiliated Hospital of Jiaxing University, Jiaxing
| | - H Q Guo
- Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing
| | - B K Shi
- Department of Urology, Qilu Hospital of Shandong University, Jinan
| | - L Liu
- Department of Urology, Qilu Hospital of Shandong University, Jinan
| | - F Liu
- Department of Urology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou
| | - Z Q Hu
- Department of Urology, Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan
| | - X M Jin
- Department of Oncology, General Hospital of Ningxia Medical University, Yinchuan
| | - L Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou
| | - S X Zhu
- Department of Urology, Fujian Medical University Union Hospital, Fuzhou
| | - J H Liu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming
| | - Y H Huang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou
| | - T Xu
- Department of Urology, Peking University People's Hospital, Beijing
| | - B Liu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou
| | - T Sun
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang
| | - Z J Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing
| | - H W Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai
| | - D X Yu
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei
| | - A P Zhou
- 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
| | - J Jiang
- Department of Urology, The PLA General Hospital Army Characteristic Medical Center, Chongqing
| | - G D Luan
- Shanghai Junshi Biosciences Co., Ltd., Shanghai
| | - C L Jin
- Shanghai Junshi Biosciences Co., Ltd., Shanghai
| | - J Xu
- Shanghai Junshi Biosciences Co., Ltd., Shanghai
| | - J X Hu
- Shanghai Junshi Biosciences Co., Ltd., Shanghai
| | - Y R Huang
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - J Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing
| | - W Zhai
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - X N Sheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing.
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27
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Yanagisawa T, Mori K, Matsukawa A, Kawada T, Katayama S, Bekku K, Laukhtina E, Rajwa P, Quhal F, Pradere B, Fukuokaya W, Iwatani K, Murakami M, Bensalah K, Grünwald V, Schmidinger M, Shariat SF, Kimura T. Updated systematic review and network meta-analysis of first-line treatments for metastatic renal cell carcinoma with extended follow-up data. Cancer Immunol Immunother 2024; 73:38. [PMID: 38289361 PMCID: PMC10827892 DOI: 10.1007/s00262-023-03621-1] [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: 10/26/2023] [Accepted: 12/20/2023] [Indexed: 02/01/2024]
Abstract
Immune checkpoint inhibitor (ICI)-based combination therapies are the recommended first-line treatment for metastatic renal cell carcinoma (mRCC). However, no head-to-head phase-3 randomized controlled trials (RCTs) have compared the efficacy of different ICI-based combination therapies. Here, we compared the efficacy of various first-line ICI-based combination therapies in patients with mRCC using updated survival data from phase-3 RCTs. Three databases were searched in June 2023 for RCTs that analyzed oncologic outcomes in mRCC patients treated with ICI-based combination therapies as first-line treatment. A network meta-analysis compared outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. Subgroup analyses were based on the International mRCC Database Consortium risk classification. The treatment ranking analysis of the entire cohort showed that nivolumab + cabozantinib (81%) had the highest likelihood of improving OS, followed by nivolumab + ipilimumab (75%); pembrolizumab + lenvatinib had the highest likelihood of improving PFS (99%), ORR (97%), and CR (86%). These results remained valid even when the analysis was limited to patients with intermediate/poor risk, except that nivolumab + ipilimumab had the highest likelihood of achieving CR (100%). Further, OS benefits of ICI doublets were not inferior to those of ICI + tyrosine kinase inhibitor combinations. Recommendation of combination therapies with ICIs and/or tyrosine kinase inhibitors based on survival benefits and patient pretreatment risk classification will help advance personalized medicine for mRCC.
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Affiliation(s)
- Takafumi Yanagisawa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Keiichiro Mori
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria.
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan.
| | - Akihiro Matsukawa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Tatsushi Kawada
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Satoshi Katayama
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Kensuke Bekku
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Ekaterina Laukhtina
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Pawel Rajwa
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, Medical University of Silesia, Zabrze, Poland
| | - Fahad Quhal
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Benjamin Pradere
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Department of Urology, La Croix Du Sud Hospital, Quint Fonsegrives, France
| | - Wataru Fukuokaya
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Kosuke Iwatani
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masaya Murakami
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Karim Bensalah
- Department of Urology, University of Rennes, Rennes, France
| | - Viktor Grünwald
- Clinic for Medical Oncology and Clinic for Urology, West German Cancer Center Essen, University Hospital Essen, Essen, Germany
| | - Manuela Schmidinger
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
| | - Shahrokh F Shariat
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria
- Division of Urology, Department of Special Surgery, The University of Jordan, Amman, Jordan
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
- Department of Urology, Weill Cornell Medical College, New York, NY, USA
- Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
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Bolek H, Yekedüz E, Ürün Y. Combination therapies in patients with favorable risk metastatic renal cell Carcinoma: A Systematic Review and Meta-Analysis. Cancer Treat Rev 2024; 122:102667. [PMID: 38101099 DOI: 10.1016/j.ctrv.2023.102667] [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: 08/22/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
INTRODUCTION Immunotherapy (IO)-based combination therapies have emerged as the standard of care for first-line treatment of metastatic renal cell carcinoma (mRCC) among patients classified as intermediate and poor risk. However, in the favorable risk group, the available data remains less compelling. This study aims to assess and compare the effectiveness of IO-based combination therapies versus tyrosine kinase inhibitor (TKI) monotherapy in patients with favorable risk group according to the International mRCC Database Consortium (IMDC). METHODS Recent update data from phase-III RCTs of IO-based combinations approved by the Food and Drug Administration were used. Studies that provided data on progression free survival (PFS) and overall survival (OS) of IMDC favorable risk were included in the analysis. RESULTS A cohort of 1,088 patients categorized within the IMDC favorable risk group was enrolled for analysis. In comparison to sunitinib, the combination of immunotherapy (IO) and tyrosine kinase inhibitor (TKI) exhibited a reduction in the risk of disease progression (HR = 0.67, 95 % CI: 0.55-0.82; p < 0.001). Conversely, the combination of IO and IO displayed an elevated risk of disease progression (HR = 1.60, 95 % CI: 1.13-2.26; p = 0.008). However, neither the IO plus TKI (HR = 0.99, 95 % CI: 0.79-1.24; p = 0.92) nor IO plus IO (HR = 0.94, 95 % CI: 0.64-1.37; p = 0.75) combinations demonstrated a noteworthy improvement in overall survival (OS). Notably, within the IO plus TKI subgroup, combination therapy yielded a higher objective response rate (ORR) (OR = 0.40, 95 % CI: 0.28-0.57; p < 0.001). On the other hand, the IO plus IO combination displayed a lower ORR than sunitinib (OR = 2.54, 95 % CI: 1.51-4.27; p < 0.001). CONCLUSIONS In the first-line treatment of IMDC favorable-risk mRCC, IO and TKI combinations show enhanced progression-free survival and response rate without improving overall survival. This emphasizes the demand for further exploration of combination therapies in this patient group.
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Affiliation(s)
- Hatice Bolek
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Türkiye; Ankara University Cancer Research Institute, Ankara, Türkiye
| | - Emre Yekedüz
- Ankara Etlik City Hospital, Medical Oncology Clinic, Ankara, Türkiye
| | - Yüksel Ürün
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Türkiye; Ankara University Cancer Research Institute, Ankara, Türkiye.
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Meng L, Collier KA, Wang P, Li Z, Monk P, Mortazavi A, Hu Z, Spakowicz D, Zheng L, Yang Y. Emerging Immunotherapy Approaches for Advanced Clear Cell Renal Cell Carcinoma. Cells 2023; 13:34. [PMID: 38201238 PMCID: PMC10777977 DOI: 10.3390/cells13010034] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/16/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). While localized ccRCC can be cured with surgery, metastatic disease has a poor prognosis. Recently, immunotherapy has emerged as a promising approach for advanced ccRCC. This review provides a comprehensive overview of the evolving immunotherapeutic landscape for metastatic ccRCC. Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated clinical efficacy as monotherapies and in combination regimens. Combination immunotherapies pairing ICIs with antiangiogenic agents, other immunomodulators, or novel therapeutic platforms such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy are areas of active research. Beyond the checkpoint blockade, additional modalities including therapeutic vaccines, cytokines, and oncolytic viruses are also being explored for ccRCC. This review discusses the mechanisms, major clinical trials, challenges, and future directions for these emerging immunotherapies. While current strategies have shown promise in improving patient outcomes, continued research is critical for expanding and optimizing immunotherapy approaches for advanced ccRCC. Realizing the full potential of immunotherapy will require elucidating mechanisms of response and resistance, developing predictive biomarkers, and rationally designing combination therapeutic regimens tailored to individual patients. Advances in immunotherapy carry immense promise for transforming the management of metastatic ccRCC.
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Affiliation(s)
- Lingbin Meng
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
| | - Katharine A. Collier
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
| | - Peng Wang
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
| | - Zihai Li
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Paul Monk
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
| | - Amir Mortazavi
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
| | - Zhiwei Hu
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
| | - Daniel Spakowicz
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Linghua Zheng
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Yuanquan Yang
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA; (K.A.C.); (P.W.); (Z.L.); (P.M.); (A.M.); (D.S.); (L.Z.)
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30
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Tomita Y, Motzer RJ, Choueiri TK, Rini BI, Miyake H, Oya M, Albiges L, Aizawa M, Umeyama Y, Wang J, di Pietro A, Schmidinger M. Efficacy of avelumab plus axitinib versus sunitinib by numbers of IMDC risk factors and target tumor sites at baseline in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101. ESMO Open 2023; 8:102034. [PMID: 37866029 PMCID: PMC10774904 DOI: 10.1016/j.esmoop.2023.102034] [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: 06/02/2023] [Revised: 09/01/2023] [Accepted: 09/16/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline. METHODS Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed. RESULTS In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage. CONCLUSIONS In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites.
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Affiliation(s)
- Y Tomita
- Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medicine, Niigata, Japan.
| | - R J Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T K Choueiri
- The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - B I Rini
- Hematology Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - H Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - M Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - L Albiges
- Department of Oncology, Institut Gustave Roussy, Villejuif, France
| | | | | | - J Wang
- Pfizer, Cambridge, MA, USA
| | | | - M Schmidinger
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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Bolek H, Ürün Y. Adjuvant therapy for renal cell carcinoma: A systematic review of current landscape and future directions. Crit Rev Oncol Hematol 2023; 192:104144. [PMID: 37748694 DOI: 10.1016/j.critrevonc.2023.104144] [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: 06/17/2023] [Revised: 09/11/2023] [Accepted: 09/21/2023] [Indexed: 09/27/2023] Open
Abstract
The advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has been transformative for the treatment of advanced renal cell carcinoma (RCC). Their efficacy post-surgical resection remains a contentious point. Various phase 3 RCTs have assessed their potency. Amongst evaluated agents, sunitinib and pembrolizumab have demonstrated notable disease-free survival benefits. Sunitinib's potential is diminished due to absence of clear overall survival (OS) benefits and side-effect profile. Pembrolizumab shows better tolerance, conclusive OS data are forthcoming. This scenario underscores the pressing need for advanced risk stratification methods and discovery of novel biomarkers. Existing strategies, largely pre-dating TKI and ICI therapeutic era, lack sufficient accuracy in predicting relapse-risk. Our review offers a comprehensive analysis of key phase 3 RCTs, focusing on TKIs, mTOR-inhibitors, and ICIs for adjuvant RCC treatment. The intent is to shed light on the intricate landscape of RCC treatment, guiding future research directions for optimizing patient outcomes.
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Affiliation(s)
- Hatice Bolek
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey; Ankara University Cancer Research Institute, Ankara, Turkey.
| | - Yüksel Ürün
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey; Ankara University Cancer Research Institute, Ankara, Turkey.
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Sazuka T, Matsushita Y, Sato H, Osawa T, Hinata N, Hatakeyama S, Numakura K, Ueda K, Kimura T, Takahashi M, Tanaka H, Kawasaki Y, Kurahashi T, Kato T, Fujita K, Miyake M, Kojima T, Kitamura H, Miyake H, Ichikawa T. Efficacy and safety of second-line cabozantinib after immuno-oncology combination therapy for advanced renal cell carcinoma: Japanese multicenter retrospective study. Sci Rep 2023; 13:20629. [PMID: 37996622 PMCID: PMC10667220 DOI: 10.1038/s41598-023-48087-4] [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: 08/26/2023] [Accepted: 11/22/2023] [Indexed: 11/25/2023] Open
Abstract
Immuno-oncology (IO) combination therapy is utilized as a first-line systemic treatment for advanced renal cell carcinoma. However, evidence supporting the use of cabozantinib after IO combination therapy is lacking. We retrospectively analyzed patients who received second-line cabozantinib after IO combination therapy using the Japanese Urological Oncology Group (JUOG) database. In total, 254 patients were enrolled in the JUOG global study, and 118 patients who received second-line cabozantinib comprised the study cohort. The objective response rate, disease control rate, second-line cabozantinib progression-free survival (PFS), and overall survival from second-line for overall were 32%, 75%, 10.5 months, and not reached, respectively, for first-line IO-IO therapy were 37%, 77%, 11.1 months, and not reached, respectively, versus 24%, 71%, 8.3 months, and not reached, respectively, for first-line IO-tyrosine kinase inhibitor therapy. In univariate and multivariate analyses, discontinuation of first-line treatment because of progressive disease and liver metastasis were independent risk factors for PFS. All-grade adverse events occurred in 72% of patients, and grade 3 or higher adverse events occurred in 28% of patients. Second line-cabozantinib after first-line IO combination therapy for advanced renal cell carcinoma was expected to be effective after either IO-IO or IO-TKI treatment and feasible in real-world practice.
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Affiliation(s)
- Tomokazu Sazuka
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Yuto Matsushita
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Sato
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takahiro Osawa
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Nobuyuki Hinata
- Department of Urology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
| | - Shingo Hatakeyama
- Department of Advanced Blood Purification Therapy, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kazuyuki Numakura
- Department of Urology, Akita University Graduate School of Medicine, Akita, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Masayuki Takahashi
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hajime Tanaka
- Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshihide Kawasaki
- Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | - Takuma Kato
- Department of Urology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Kazutoshi Fujita
- Department of Urology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Makito Miyake
- Department of Urology, Nara Medical University, Kashihara, Japan
| | | | | | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomohiko Ichikawa
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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Martin SD, Bhuiyan I, Soleimani M, Wang G. Biomarkers for Immune Checkpoint Inhibitors in Renal Cell Carcinoma. J Clin Med 2023; 12:4987. [PMID: 37568390 PMCID: PMC10419620 DOI: 10.3390/jcm12154987] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized renal cell carcinoma treatment. Patients previously thought to be palliative now occasionally achieve complete cures from ICI. However, since immunotherapies stimulate the immune system to induce anti-tumor immunity, they often lead to adverse autoimmunity. Furthermore, some patients receive no benefit from ICI, thereby unnecessarily risking adverse events. In many tumor types, PD-L1 expression levels, immune infiltration, and tumor mutation burden predict the response to ICI and help inform clinical decision making to better target ICI to patients most likely to experience benefits. Unfortunately, renal cell carcinoma is an outlier, as these biomarkers fail to discriminate between positive and negative responses to ICI therapy. Emerging biomarkers such as gene expression profiles and the loss of pro-angiogenic proteins VHL and PBRM-1 show promise for identifying renal cell carcinoma cases likely to respond to ICI. This review provides an overview of the mechanistic underpinnings of different biomarkers and describes the theoretical rationale for their use. We discuss the effectiveness of each biomarker in renal cell carcinoma and other cancer types, and we introduce novel biomarkers that have demonstrated some promise in clinical trials.
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Affiliation(s)
- Spencer D. Martin
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
| | - Ishmam Bhuiyan
- Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada;
| | - Maryam Soleimani
- Division of Medical Oncology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada;
- British Columbia Cancer Vancouver Centre, Vancouver, BC V5Z 4E6, Canada
| | - Gang Wang
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
- British Columbia Cancer Vancouver Centre, Vancouver, BC V5Z 4E6, Canada
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