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Woods JJ, Rigby A, Wacker JN, Arino T, Alvarenga Vasquez JV, Cosby A, Martin KE, Abergel RJ. Synthesis and Evaluation of a Bifunctional Chelator for Thorium-227 Targeted Radiotherapy. J Med Chem 2025; 68:1682-1692. [PMID: 39752149 DOI: 10.1021/acs.jmedchem.4c02423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Thorium-227 (227Th) is an α-emitting radionuclide currently under investigation for targeted alpha therapy. Available chelators used for this isotope suffer from challenging multistep syntheses. Here, we present the synthesis and preclinical evaluation of a novel bifunctional chelator, p-SCN-Bn-DOTHOPO, which contains an isothiocyanate group that is suitable for conjugation to biological molecules. This bifunctional chelator was prepared with a 26% overall yield in four steps and conjugated to the human epidermal growth factor receptor 2 targeting antibody, trastuzumab. The resulting immunoconjugate was labeled with [227Th]ThIV (pH 5.5, room temperature, 60 min) with ≥95% radiochemical yield and purity. The conjugate was also labeled with zirconium-89 (89Zr), which can be used for positron emission tomography imaging. The radiometal complexes were subsequently investigated for their biological stability. The results described here provide insight into ligand design strategies and optimization of chelators for the development of the next generation of 89Zr and 227Th radiopharmaceuticals.
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Affiliation(s)
- Joshua J Woods
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Alex Rigby
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Jennifer N Wacker
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Trevor Arino
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
- Department of Nuclear Engineering, University of California Berkeley, Berkeley, California 94720, United States
| | | | - Alexia Cosby
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Kirsten E Martin
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Rebecca J Abergel
- Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
- Department of Nuclear Engineering, University of California Berkeley, Berkeley, California 94720, United States
- Department of Chemistry, University of California Berkeley, Berkeley, California 94720, United States
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Luo X, Wang N, Xing Y, Gao X, Yu Y, Liu T, Jiang S, Dong M. Pharmacokinetics of trastuzumab and its efficacy and safety in HER2-positive cancer patients. Cancer Chemother Pharmacol 2024; 94:721-732. [PMID: 39177768 DOI: 10.1007/s00280-024-04707-y] [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: 01/15/2024] [Accepted: 08/08/2024] [Indexed: 08/24/2024]
Abstract
Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients.
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Affiliation(s)
- Xinyu Luo
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Nan Wang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yue Xing
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Xinyue Gao
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yang Yu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Tong Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Shuai Jiang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
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Demetriou C, Abid N, Butterworth M, Lezina L, Sandhu P, Howells L, Powley IR, Pringle JH, Sidat Z, Qassid O, Purnell D, Kaushik M, Duckworth K, Hartshorn H, Thomas A, Shaw JA, MacFarlane M, Pritchard C, Miles GJ. An optimised patient-derived explant platform for breast cancer reflects clinical responses to chemotherapy and antibody-directed therapy. Sci Rep 2024; 14:12833. [PMID: 38834809 PMCID: PMC11150370 DOI: 10.1038/s41598-024-63170-0] [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: 05/15/2023] [Accepted: 05/27/2024] [Indexed: 06/06/2024] Open
Abstract
Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel approaches are required to improve patient outcomes. We have evaluated patient-derived explants (PDEs) as a novel preclinical platform for breast cancer (BC) and implemented cutting-edge digital pathology and multi-immunofluorescent approaches for investigating biomarker changes in both tumour and stromal areas at endpoint. Short-term culture of intact fragments of BCs as PDEs retained an intact immune microenvironment, and tumour architecture was augmented by the inclusion of autologous serum in the culture media. Cell death/proliferation responses to FET chemotherapy in BC-PDEs correlated significantly with BC patient progression-free survival (p = 0.012 and p = 0.0041, respectively) and cell death responses to the HER2 antibody therapy trastuzumab correlated significantly with HER2 status (p = 0.018). These studies show that the PDE platform combined with digital pathology is a robust preclinical approach for informing clinical responses to chemotherapy and antibody-directed therapies in breast cancer. Furthermore, since BC-PDEs retain an intact tumour architecture over the short-term, they facilitate the preclinical testing of anti-cancer agents targeting the tumour microenvironment.
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Affiliation(s)
- Constantinos Demetriou
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Naila Abid
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Michael Butterworth
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Larissa Lezina
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Pavandeep Sandhu
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Lynne Howells
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Ian R Powley
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - James H Pringle
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Zahirah Sidat
- HOPE Clinical Trials Facility, University Hospitals of Leicester NHS Trust, Sandringham Building, Leicester Royal Infirmary, Leicester, LE1 5WW, UK
| | - Omar Qassid
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
- Pathology Department, University Hospitals of Leicester NHS Trust, Leicester Glenfield General Hospital, Groby Road, Leicester, LE3 9QP, UK
| | - Dave Purnell
- Pathology Department, University Hospitals of Leicester NHS Trust, Leicester Glenfield General Hospital, Groby Road, Leicester, LE3 9QP, UK
| | - Monika Kaushik
- Breast Care Centre, University Hospitals of Leicester NHS Trust, Leicester Glenfield General Hospital, Groby Road, Leicester, LE3 9QP, UK
| | - Kaitlin Duckworth
- Breast Care Centre, University Hospitals of Leicester NHS Trust, Leicester Glenfield General Hospital, Groby Road, Leicester, LE3 9QP, UK
| | - Helen Hartshorn
- Breast Care Centre, University Hospitals of Leicester NHS Trust, Leicester Glenfield General Hospital, Groby Road, Leicester, LE3 9QP, UK
| | - Anne Thomas
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Jacqui A Shaw
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK
| | - Marion MacFarlane
- MRC Toxicology Unit, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK.
- Department of Molecular and Cell Biology, University of Leicester, Leicester, LE1 7HB, UK.
| | - Catrin Pritchard
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK.
| | - Gareth J Miles
- Leicester Cancer Research Centre, University of Leicester, Clinical Sciences Building, Leicester, LE2 7LX, UK.
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Kim M, Lee JL, Shin SJ, Bae WK, Lee HJ, Byun JH, Choi YJ, Youk J, Ock CY, Kim S, Song H, Park KH, Keam B. Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18. ESMO Open 2023; 8:101588. [PMID: 37385153 PMCID: PMC10485395 DOI: 10.1016/j.esmoop.2023.101588] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 05/11/2023] [Accepted: 05/21/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). PATIENTS AND METHODS We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. RESULTS Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). CONCLUSIONS Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.
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Affiliation(s)
- M Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; Cancer Research Institute, Seoul National University College of Medicine, Seoul
| | - J L Lee
- Department of Oncology and Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - S J Shin
- Division of Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul
| | - W K Bae
- Department of Hemato-Oncology, Chonnam National University Medical School & Hwasun Hospital, Hwasun
| | - H J Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon
| | - J H Byun
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon
| | - Y J Choi
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul
| | - J Youk
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; Cancer Research Institute, Seoul National University College of Medicine, Seoul
| | - C Y Ock
- Lunit, Seoul, Republic of Korea
| | - S Kim
- Lunit, Seoul, Republic of Korea
| | - H Song
- Lunit, Seoul, Republic of Korea
| | - K H Park
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul
| | - B Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; Cancer Research Institute, Seoul National University College of Medicine, Seoul.
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Zhou W, Wang M, Yu Y, Wang J, Wu Y, Yang G, Yu H, Li J, Zhou L, Zhang Q. Comparing the pharmacokinetics, safety, and immunogenicity of HLX02 to US- and EU-approved trastuzumab in healthy Chinese male subjects: A Phase I, randomized, double-blind, parallel-group study. Expert Opin Biol Ther 2023; 23:717-725. [PMID: 36843059 DOI: 10.1080/14712598.2023.2183117] [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: 10/10/2022] [Accepted: 02/17/2023] [Indexed: 02/28/2023]
Abstract
BACKGROUND HLX02, the first China-manufactured trastuzumab biosimilar, is approved in Europe (EU) and China. This study evaluated bioequivalence between HLX02 and US-approved trastuzumab (US-trastuzumab). METHOD In this double-blind, parallel-group, Phase I study, healthy Chinese men were randomized (1:1:1) to receive a single 6 mg/kg dose of HLX02, reference US-trastuzumab, or reference EU-approved trastuzumab (EU-trastuzumab). Equivalence in PK profiles was demonstrated if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for the difference between the least square means of the area under the curve (AUC) from time 0 to infinity (AUC∞) were 0.8-1.25. RESULTS Pharmacokinetic profiles of the three trastuzumab products were similar in 111 Chinese men. Equivalence was confirmed between HLX02 and US-trastuzumab (GMR for AUC∞ 1.009, 90% CI 0.950-1.072); HLX02 and EU-trastuzumab (GMR for AUC∞ 1.068, 90% CI 1.005-1.135); and EU- and US-trastuzumab (GMR for AUC∞ 0.945, 90% CI 0.889-1004). Exploratory analysis of all other PK parameters also demonstrated equivalence between any two of the three trastuzumab products. HLX02 had similar safety and immunogenicity profiles to US- and EU-trastuzumab. CONCLUSION HLX02 is bioequivalent to US-trastuzumab and EU-trastuzumab, with similar safety and immunogenicity profiles. US- and EU-trastuzumab were also bioequivalent to each other.
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Affiliation(s)
- Wenjia Zhou
- Phase 1 Clinical Trial Center, the Second Affiliated Hospital of Soochow University, Suzhou, Shanghai, China
| | - Meng Wang
- Phase 1 Clinical Trial Center, the Second Affiliated Hospital of Soochow University, Suzhou, Shanghai, China
| | - Yunli Yu
- Phase 1 Clinical Trial Center, the Second Affiliated Hospital of Soochow University, Suzhou, Shanghai, China
| | - Ji Wang
- Department of Medical Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, Shanghai, China
| | - Yanni Wu
- Department of Cardiology, the Second Affiliated Hospital of Soochow University, Suzhou, Shanghai, China
| | - Guiyu Yang
- Shanghai Henlius Biotech, Inc, Shanghai, Shanghai, China
| | - Haoyu Yu
- Shanghai Henlius Biotech, Inc, Shanghai, Shanghai, China
| | - Jing Li
- Shanghai Henlius Biotech, Inc, Shanghai, Shanghai, China
| | - Liang Zhou
- Shanghai Henlius Biotech, Inc, Shanghai, Shanghai, China
| | - Quanying Zhang
- Phase 1 Clinical Trial Center, the Second Affiliated Hospital of Soochow University, Suzhou, Shanghai, China
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Kumthekar PU, Avram MJ, Lassman AB, Lin NU, Lee E, Grimm SA, Schwartz M, Bell Burdett KL, Lukas RV, Dixit K, Perron I, Zhang H, Gradishar WJ, Pentsova EI, Jeyapalan S, Groves MD, Melisko M, Raizer JJ. A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics. Neuro Oncol 2023; 25:557-565. [PMID: 35948282 PMCID: PMC10013631 DOI: 10.1093/neuonc/noac195] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD). METHODS This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer. RESULTS Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. CONCLUSION This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.
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Affiliation(s)
- Priya U Kumthekar
- Department of Neurology at The Feinberg School of Medicine at Northwestern University and The Malnati Brain Tumor Institute at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Michael J Avram
- Department of Anesthesiology, Emeritus Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Andrew B Lassman
- Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, NewYork-Presbyterian Hospital, New York, New York, USA
| | - Nancy U Lin
- Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts, USA
| | - Eudocia Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts, USA
| | - Sean A Grimm
- Department of Neurology, Rush University Medical Center, Chicago, Illinois, USA
| | - Margaret Schwartz
- Department of Neurology at The Feinberg School of Medicine at Northwestern University and The Malnati Brain Tumor Institute at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
| | - Kirsten L Bell Burdett
- Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Rimas V Lukas
- Department of Neurology at The Feinberg School of Medicine at Northwestern University and The Malnati Brain Tumor Institute at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Karan Dixit
- Department of Neurology at The Feinberg School of Medicine at Northwestern University and The Malnati Brain Tumor Institute at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Isabella Perron
- Department of Neurosurgery at The Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA
| | - Hui Zhang
- Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - William J Gradishar
- Department of Medicine at The Feinberg School of Medicine at Northwestern University at The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
| | - Elena I Pentsova
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Suriya Jeyapalan
- Department of Neurology, Tufts Medical Center, Boston, Massachusetts, USA
| | - Morris D Groves
- Texas Oncology-Austin Brain Tumor Center, Austin, Texas, USA
| | - Michelle Melisko
- Department of Medicine at the University of California San Francisco, San Francisco, California, USA
| | - Jeffrey J Raizer
- Department of Neurology at The Feinberg School of Medicine at Northwestern University and The Malnati Brain Tumor Institute at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
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Bundred N, Porta N, Brunt AM, Cramer A, Hanby A, Shaaban AM, Rakha EA, Armstrong A, Cutress RI, Dodwell D, Emson MA, Evans A, Hartup SM, Horgan K, Miller SE, McIntosh SA, Morden JP, Naik J, Narayanan S, Ooi J, Skene AI, Cameron DA, Bliss JM. Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results. Clin Cancer Res 2022; 28:1323-1334. [PMID: 35165099 PMCID: PMC9610457 DOI: 10.1158/1078-0432.ccr-21-3177] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/11/2021] [Accepted: 01/20/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.
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Affiliation(s)
- Nigel Bundred
- Manchester University NHS Foundation Trust and University of Manchester, Manchester, United Kingdom
| | - Nuria Porta
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | | | - Angela Cramer
- The Christie Pathology Partnership, Manchester, United Kingdom
| | - Andrew Hanby
- Leeds Institute of Medical Research at St. James's, Leeds, United Kingdom
| | - Abeer M. Shaaban
- Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, United Kingdom
| | - Emad A. Rakha
- University of Nottingham, Nottingham, United Kingdom
| | - Anne Armstrong
- The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Ramsey I. Cutress
- University of Southampton and University Hospital Southampton, Southampton, United Kingdom
| | - David Dodwell
- Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Marie A. Emson
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | | | - Sue M. Hartup
- St James's University Hospital, Leeds, United Kingdom
| | - Kieran Horgan
- St James's University Hospital, Leeds, United Kingdom
| | - Sarah E. Miller
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | | | - James P. Morden
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
| | - Jay Naik
- Mid Yorkshire NHS Hospitals Trust, United Kingdom
| | | | - Jane Ooi
- Royal Bolton Hospital, Manchester, United Kingdom
| | | | - David A. Cameron
- University of Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, Western General Hospital, Edinburgh, United Kingdom
| | - Judith M. Bliss
- The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom
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8
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Zhang J, Ji D, Cai L, Yao H, Yan M, Wang X, Shen W, Du Y, Pang H, Lai X, Zeng H, Huang J, Sun Y, Peng X, Xu J, Yang J, Yang F, Xu T, Hu X. First-in-human HER2-targeted Bispecific Antibody KN026 for the Treatment of Patients with HER2-positive Metastatic Breast Cancer: Results from a Phase I Study. Clin Cancer Res 2021; 28:618-628. [PMID: 34844975 DOI: 10.1158/1078-0432.ccr-21-2827] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/12/2021] [Accepted: 11/19/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a "3+3" dose escalation rule followed by dose expansion. RESULTS Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. Results from exposure-response analysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2-8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). CONCLUSIONS KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.
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Affiliation(s)
- Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Dongmei Ji
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Li Cai
- Department of Medical Oncology, Tumor Hospital of Harbin Medical University, Harbin, P.R. China
| | - Herui Yao
- Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanghai, P.R. China
| | - Min Yan
- Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, P.R. China
| | - Xiaojia Wang
- Department of Medical Oncology, Zhejiang Cancer Hospital, Shanghai, P.R. China
| | - Weina Shen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Yiqun Du
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Hui Pang
- Department of Medical Oncology, Tumor Hospital of Harbin Medical University, Harbin, P.R. China
| | - Xiuping Lai
- Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanghai, P.R. China
| | - Huiai Zeng
- Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, P.R. China
| | - Jian Huang
- Department of Medical Oncology, Zhejiang Cancer Hospital, Shanghai, P.R. China
| | - Yan Sun
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
| | - Xinxin Peng
- Precision Scientific (Beijing) Co., Ltd, Beijing, P.R. China
| | - Junfang Xu
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, P.R. China
| | - Jing Yang
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, P.R. China
| | - Fei Yang
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, P.R. China
| | - Ting Xu
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, P.R. China
| | - Xichun Hu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China
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9
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Al Ojaimi Y, Blin T, Lamamy J, Gracia M, Pitiot A, Denevault-Sabourin C, Joubert N, Pouget JP, Gouilleux-Gruart V, Heuzé-Vourc'h N, Lanznaster D, Poty S, Sécher T. Therapeutic antibodies - natural and pathological barriers and strategies to overcome them. Pharmacol Ther 2021; 233:108022. [PMID: 34687769 PMCID: PMC8527648 DOI: 10.1016/j.pharmthera.2021.108022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
Antibody-based therapeutics have become a major class of therapeutics with over 120 recombinant antibodies approved or under review in the EU or US. This therapeutic class has experienced a remarkable expansion with an expected acceleration in 2021-2022 due to the extraordinary global response to SARS-CoV2 pandemic and the public disclosure of over a hundred anti-SARS-CoV2 antibodies. Mainly delivered intravenously, alternative delivery routes have emerged to improve antibody therapeutic index and patient comfort. A major hurdle for antibody delivery and efficacy as well as the development of alternative administration routes, is to understand the different natural and pathological barriers that antibodies face as soon as they enter the body up to the moment they bind to their target antigen. In this review, we discuss the well-known and more under-investigated extracellular and cellular barriers faced by antibodies. We also discuss some of the strategies developed in the recent years to overcome these barriers and increase antibody delivery to its site of action. A better understanding of the biological barriers that antibodies have to face will allow the optimization of antibody delivery near its target. This opens the way to the development of improved therapy with less systemic side effects and increased patients' adherence to the treatment.
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Affiliation(s)
- Yara Al Ojaimi
- UMR 1253, iBrain, Inserm, 37000 Tours, France; University of Tours, 37000 Tours, France
| | - Timothée Blin
- University of Tours, 37000 Tours, France; UMR 1100, CEPR, Inserm, 37000 Tours, France
| | - Juliette Lamamy
- University of Tours, 37000 Tours, France; GICC, EA7501, 37000 Tours, France
| | - Matthieu Gracia
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier F-34298, France
| | - Aubin Pitiot
- University of Tours, 37000 Tours, France; UMR 1100, CEPR, Inserm, 37000 Tours, France
| | | | - Nicolas Joubert
- University of Tours, 37000 Tours, France; GICC, EA7501, 37000 Tours, France
| | - Jean-Pierre Pouget
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier F-34298, France
| | | | | | - Débora Lanznaster
- UMR 1253, iBrain, Inserm, 37000 Tours, France; University of Tours, 37000 Tours, France
| | - Sophie Poty
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier F-34298, France
| | - Thomas Sécher
- University of Tours, 37000 Tours, France; UMR 1100, CEPR, Inserm, 37000 Tours, France
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10
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Esfandbod M, Naderi M, Sadatnaseri A, Ahmadi A, Noroozi M, Sadeghi Joni S. Evaluation of the Preventive Effects of Carvedilol on Trastuzumab-Induced Cardiotoxicity in Early-Stage and Locally Advanced HER2-Positive Breast Cancer Patients. Int J Hematol Oncol Stem Cell Res 2021; 15:206-212. [PMID: 35291664 PMCID: PMC8888356 DOI: 10.18502/ijhoscr.v15i4.7475] [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: 05/23/2020] [Accepted: 09/10/2020] [Indexed: 01/03/2023] Open
Abstract
Background: Trastuzumab is an efficient monoclonal antibody used in the treatment of Her2-positive breast cancer. Despite its prominent effect on Her2-positive patients' disease-free Survival. Trastuzumab-induced cardiotoxicity is still one of the main challenges. Angiotensin-converting enzyme inhibitors (ACE inhibitors) are one of the most potent agents used in heart failure, which also showed confirmed cardioprotective effects against anthracycline and doxorubicin. We aimed to assess the cardioprotective effects of Carvedilol in a randomized clinical trial study. Materials and Methods: sixty non-metastatic Her-2 positive patients (30 cases; 30 controls) were entered into the study via a simple randomization method.Carvedilol was administered for the patients with the starting dose of 3.125 mg twice a day and started 7 days before trastuzumab administration. The dose has been increased in a three-week period to reach 12.5 mg twice a day and continued until the end of therapy. All the patients underwent an echocardiography after receiving Adriamycin and Cyclophosphamide in order to measure basal Ejection Fraction (EF) and Pulmonary Artery Pressure (PAP). Each patient underwent a follow-up echocardiography in 3,6,9 and 12 months after initiation of the treatment. Finally, all the patients went through the last episode of echocardiography 1 month after the end of treatment. All the Measured PAP and EF has been recorded and analyzed Results: EF and PAP changes for both groups had no significant changes during the course of treatment with Trastuzmab (p-value = 0.628 and p-value = 0.723, respectively). Seven patients in the intervention group and 2 patients in the control group presented with EF decrease. Also, 8 patients in the intervention and 9 patients in the control groups showed PAP increase. Conclusion: According to our results, in patients with HER2-positive breast cancer treated with trastuzumab, Carvedilol showed no significant protective effect on trastuzumab-induced cardiotoxicity.
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Affiliation(s)
- Mohsen Esfandbod
- Department of Clinical Hematology and Bone Marrow Transplantation, Vali-e-Asr Hospital, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Naderi
- Department of Internal Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Sadatnaseri
- Department of Cardiology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ayat Ahmadi
- Knowledge Utilization Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadtaghi Noroozi
- Department of Internal Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeid Sadeghi Joni
- Department of Radiology, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
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11
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Abstract
Human epidermal growth factor receptor 2 (HER-2) is a checkpoint, controlling cell proliferation and differentiation. Trastuzumab, a humanized monoclonal antibody directed against HER-2, is nowadays standard treatment for breast cancer patients whose tumors express HER-2. It is generally well tolerated, with a small number of patients developing mild adverse reactions. Dermatomyositis is a rare adverse event of trastuzumab therapy not well described in the literature. We herein present a case of a patient treated for hormone-sensitive invasive ductal carcinoma, who presented with symptoms of proximal muscle weakness, arthralgias, skin rash, and generalized fatigue. The symptoms started after the sixth cycle of trastuzumab and progressively deteriorated. The patient's medical and family history was unremarkable. Disease progression as a possible cause of dermatomyositis had been ruled out, and laboratory evaluation revealed moderate elevation of serum muscle proteins and acute-phase reactants. Trastuzumab treatment was discontinued, and 3 months later, the patient was free of symptoms without any further intervention.
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Affiliation(s)
- Ioannis Panagiotis Trontzas
- 3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece
| | - Nikolaos Konstantinos Syrigos
- 3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece
| | - Elias Alexandros Kotteas
- 3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece
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12
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Tesch ME, Gelmon KA. Targeting HER2 in Breast Cancer: Latest Developments on Treatment Sequencing and the Introduction of Biosimilars. Drugs 2021; 80:1811-1830. [PMID: 33021725 DOI: 10.1007/s40265-020-01411-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Approximately 20% of all breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). Targeting breast cancer through this vital oncogenic protein has been a major step towards improved patient outcomes. Today, several anti-HER2 agents are in clinical use including: the monoclonal antibodies trastuzumab and pertuzumab; the small molecule inhibitors lapatinib, neratinib, and tucatinib; and the antibody-drug conjugates ado-trastuzumab emtansine and trastuzumab deruxtecan, in some jurisdictions. In addition, several trastuzumab biosimilars have recently been granted regulatory approval in North America and the EU, and are enhancing patient access to HER2-directed therapy. The various agents differ greatly in their side-effect profiles and approved indications, from neoadjuvant and adjuvant use in early disease, to first- and later-line use in metastatic disease. This review discusses the current treatment recommendations for the use of anti-HER2 agents alone and in combination, examines the latest advances in HER2-targeted drugs and how they may be best applied in clinical practice, and provides guidance on optimal sequencing of the growing array of therapeutic options for HER2-positive breast cancer.
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Affiliation(s)
- Megan E Tesch
- Department of Medical Oncology, British Columbia Cancer, 600 W. 10th Avenue, Vancouver, BC, V5Z 4E6, Canada
| | - Karen A Gelmon
- Department of Medical Oncology, British Columbia Cancer, 600 W. 10th Avenue, Vancouver, BC, V5Z 4E6, Canada.
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13
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Vazdar L, Gabrić ID, Kruljac I, Pintarić H, Šeparović R, Kirigin Biloš LS, Pavlović M, Tečić Vuger A, Štefanović M. Influence of Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in early-stage HER2 positive breast cancer. Sci Rep 2021; 11:14395. [PMID: 34257352 PMCID: PMC8277791 DOI: 10.1038/s41598-021-93634-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 06/14/2021] [Indexed: 11/08/2022] Open
Abstract
Trastuzumab has improved the prognosis of HER2 positive breast cancer, but cardiotoxicity remains a concern. We aimed to identify risk factors for trastuzumab-induced cardiotoxicity, with an emphasis on the HER2 Ile655Val single nucleotide polymorphism. This single-center case-control study included 1056 patients with early-stage HER2 positive breast cancer that received adjuvant trastuzumab. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) > 15% in patients without previous cardiomyopathy, or > 10% in patients with baseline LVEF of < 50%. Patient characteristics and cardiac parameters were compared in 78 (7.38%) cases and 99 randomly assigned controls, and the polymorphism was genotyped using real-time polymerase chain reaction. Cardiotoxicity was independently associated with advanced age (P = 0.024), lower body mass index (P = 0.023), left breast involvement (P = 0.001), N3 status (P = 0.004), diabetes (P = 0.016), and a family history of coronary artery disease (P = 0.019). Genotype distribution was as follows: A/A (Ile/Ile) was found in 111 (62.7%) patients, A/G (Ile/Val) in 60 (33.9%) patients, and G/G (Val/Val) in 6 (3.4%) patients. The genotype was not associated with cardiotoxicity or the severity of heart failure, reversibility, and recovery time. We found no association between the HER2 Ile655Val polymorphism and trastuzumab-induced cardiotoxicity; therefore, we do not recommend routine cardiotoxicity-risk stratification using this polymorphism.
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Affiliation(s)
- Ljubica Vazdar
- Department of Radiotherapy and Medical Oncology, Clinic for Tumors, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Ivo Darko Gabrić
- Department of Cardiovascular Diseases, Institute for Cardiomyopathies, Heart Failure and Valvular Diseases, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Ivan Kruljac
- Department of Internal Medicine, University Hospital Center "Sestre Milosrdnice", Vinogradska cesta 29, Zagreb, Croatia
| | - Hrvoje Pintarić
- Cardiac Catheterization Laboratory, Department of Cardiovascular Diseases, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
- School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Robert Šeparović
- Department of Radiotherapy and Medical Oncology, Clinic for Tumors, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Lora Stanka Kirigin Biloš
- Department of Internal Medicine, University Hospital Center "Sestre Milosrdnice", Vinogradska cesta 29, Zagreb, Croatia.
| | - Mirjana Pavlović
- Department of Radiotherapy and Medical Oncology, Clinic for Tumors, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Ana Tečić Vuger
- Department of Radiotherapy and Medical Oncology, Clinic for Tumors, University Hospital Center "Sestre Milosrdnice", Zagreb, Croatia
| | - Mario Štefanović
- Faculty of Pharmacy and Biochemistry, Clinical Institute of Chemistry, University Hospital Center "Sestre Milosrdnice", University of Zagreb, Zagreb, Croatia
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14
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Characterization of ultrasound-mediated delivery of trastuzumab to normal and pathologic spinal cord tissue. Sci Rep 2021; 11:4412. [PMID: 33627726 PMCID: PMC7904756 DOI: 10.1038/s41598-021-83874-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 02/08/2021] [Indexed: 01/31/2023] Open
Abstract
Extensive studies on focused ultrasound (FUS)-mediated drug delivery through the blood-brain barrier have been published, yet little work has been published on FUS-mediated drug delivery through the blood-spinal cord barrier (BSCB). This work aims to quantify the delivery of the monoclonal antibody trastuzumab to rat spinal cord tissue and characterize its distribution within a model of leptomeningeal metastases. 10 healthy Sprague-Dawley rats were treated with FUS + trastuzumab and sacrificed at 2-h or 24-h post-FUS. A human IgG ELISA (Abcam) was used to measure trastuzumab concentration and a 12 ± fivefold increase was seen in treated tissue over control tissue at 2 h versus no increase at 24 h. Three athymic nude rats were inoculated with MDA-MB-231-H2N HER2 + breast cancer cells between the meninges in the thoracic region of the spinal cord and treated with FUS + trastuzumab. Immunohistochemistry was performed to visualize trastuzumab delivery, and semi-quantitative analysis revealed similar or more intense staining in tumor tissue compared to healthy tissue suggesting a comparable or greater concentration of trastuzumab was achieved. FUS can increase the permeability of the BSCB, improving drug delivery to specifically targeted regions of healthy and pathologic tissue in the spinal cord. The achieved concentrations within the healthy tissue are comparable to those reported in the brain.
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15
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Zhu X, Ding Y, Yu Y, Wang M, Zhou W, Wang J, Zhu X, Zhang H, Wang M, Chai K, Zhang X, Luk A, Jiang W, Liu S, Zhang Q. A Phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX02 to reference CN- and EU-sourced trastuzumab in healthy subjects. Cancer Chemother Pharmacol 2020; 87:349-359. [PMID: 33169186 DOI: 10.1007/s00280-020-04196-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/26/2020] [Indexed: 01/01/2023]
Abstract
PURPOSE This study evaluated the bioequivalence of China-manufactured biosimilar, HLX02, to reference China (CN)- and European Union (EU)-sourced trastuzumab. METHODS This was a two-part Phase 1 study conducted in healthy Chinese males. Part 1 evaluated the safety of different doses of HLX02 (2, 4, 6 or 8 mg/kg; intravenous infusion over 90 min, n = 3 per group). Part 2, a randomized, double-blind study, investigated the pharmacokinetics (PK), safety and immunogenicity of study drugs (HLX02 [n = 37], CN-trastuzumab [n = 35] or EU-trastuzumab [n = 37] at the dose suggested by Part 1 results). The primary PK endpoint was the area under the serum concentration-time curve from time 0 to infinity (AUCinf). Equivalence was concluded if the 90% confidence interval (CI) for the geometric least squares mean ratio (GLSMR) fell in the equivalence criteria of 0.80-1.25. RESULTS In Part 1, all doses of HLX02 were well tolerated and 6 mg/kg was suggested for Part 2. The GLSMRs and 90% CIs for AUCinf were: 0.950 (0.891-1.013), 0.914 (0.858-0.973) and 0.962 (0.902-1.025) for HLX02 versus CN-trastuzumab, HLX02 versus EU-trastuzumab and CN-trastuzumab versus EU-trastuzumab, respectively. Secondary endpoints comparisons also fell in the equivalence criteria. Treatment-emergent adverse events were reported in 75.7, 86.5 and 70.3% of the subjects in HLX02, CN-trastuzumab, and EU-trastuzumab groups, respectively. No serious adverse events or deaths occurred. No treatment-related anti-drug antibodies were detected. CONCLUSION This study demonstrated comparable safety profiles and PK bioequivalence among HLX02, CN-trastuzumab and EU-trastuzumab in healthy Chinese male subjects. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02581748, registered at October 19, 2015.
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Affiliation(s)
- X Zhu
- Phase 1 Clinical Trial Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Y Ding
- Phase 1 Clinical Trial Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Y Yu
- Phase 1 Clinical Trial Laboratory, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Gusu District, Suzhou, 215004, China
| | - M Wang
- Phase 1 Clinical Trial Laboratory, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Gusu District, Suzhou, 215004, China
| | - W Zhou
- Phase 1 Clinical Trial Laboratory, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Gusu District, Suzhou, 215004, China
| | - J Wang
- Internal Medicine Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - X Zhu
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - H Zhang
- Phase 1 Clinical Trial Laboratory, The First Hospital of Jilin University, Changchun, China
| | - M Wang
- Phase 1 Clinical Trial Laboratory, The First Hospital of Jilin University, Changchun, China
| | - K Chai
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - X Zhang
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - A Luk
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - W Jiang
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - S Liu
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - Q Zhang
- Phase 1 Clinical Trial Laboratory, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Gusu District, Suzhou, 215004, China.
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16
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Barfield RM, Kim YC, Chuprakov S, Zhang F, Bauzon M, Ogunkoya AO, Yeo D, Hickle C, Pegram MD, Rabuka D, Drake PM. A Novel HER2-targeted Antibody-drug Conjugate Offers the Possibility of Clinical Dosing at Trastuzumab-equivalent Exposure Levels. Mol Cancer Ther 2020; 19:1866-1874. [PMID: 32651200 DOI: 10.1158/1535-7163.mct-20-0190] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/24/2020] [Accepted: 07/02/2020] [Indexed: 11/16/2022]
Abstract
Trastuzumab and the related ADC, ado-trastuzumab emtansine (T-DM1), both target HER2-overexpressing cells. Together, these drugs have treatment indications in both early-stage and metastatic settings for HER2+ breast cancer. T-DM1 retains the antibody functionalities of trastuzumab and adds the potency of a cytotoxic maytansine payload. Interestingly, in the clinic, T-DM1 cannot always replace the use of trastuzumab plus chemotherapy administered together as single agents. We hypothesize that this failure may be due, in part, to the limited systemic exposure achieved by T-DM1 relative to trastuzumab because of toxicity-related dosing constraints on the ADC. We have developed a trastuzumab-based ADC site specifically conjugated to maytansine through a noncleavable linker. This construct, termed CAT-01-106, has a drug-to-antibody ratio (DAR) of 1.8, approximately half the average DAR of T-DM1, which comprises a mixture of antibodies variously conjugated with DARs ranging from 0 to 8. The high DAR species present in T-DM1 contribute to its toxicity and limit its clinical dose. CAT-01-106 showed superior in vivo efficacy compared with T-DM1 at equal payload dosing and was equally or better tolerated compared with T-DM1 at equal payload dosing up to 120 mg/kg in Sprague-Dawley rats and 60 mg/kg in cynomolgus monkeys. CAT-01-106 also showed improved pharmacokinetics in rats relative to T-DM1, with 40% higher ADC exposure levels. Together, the data suggest that CAT-01-106 may be sufficiently tolerable to enable clinical dosing at trastuzumab-equivalent exposure levels, combining the functions of both the antibody and the payload in one drug and potentially improving patient outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Mark D Pegram
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California
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17
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A physiologically based pharmacokinetic - pharmacodynamic modelling approach to predict incidence of neutropenia as a result of drug-drug interactions of paclitaxel in cancer patients. Eur J Pharm Sci 2020; 150:105355. [PMID: 32438273 DOI: 10.1016/j.ejps.2020.105355] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/21/2020] [Accepted: 04/17/2020] [Indexed: 12/24/2022]
Abstract
Paclitaxel is the backbone of standard chemotherapeutic regimens used in a number of malignancies and is frequently given with concomitant medications. Newly developed oncolytic agents, including tyrosine kinase inhibitors are often shown to be CYP3A4 and P-gp inhibitors. The aim of this study was to develop a PBPK model for intravenously administered paclitaxel in order to predict the incidence of neutropenia and to estimate the DDI potential as a victim drug. The dose-dependent effects on paclitaxel plasma protein binding, volume of distribution and drug clearance were considered for dose levels of 80 mg/m2, 135 mg/m2 and 175 mg/m2. A pharmacodynamics model that incorporate the impact of paclitaxel on the neutrophil was developed. The relative metabolic clearance via CYP3A4 and CYP2C8, the renal clearance as well as P-gp mediated biliary clearance were incorporated in the model in order to assess the neutropenia in the presence of DDI. The developed PBPK-PD model was able to recover the drop in neutrophils observed after the administration of 175mg/m2 of paclitaxel over a 3-h duration. The mean nadir observed was 1.9 × 109 neutrophils/L and was attained after 10 days of treatment, and a fraction of 47% of the population was predicted to have at some point a neutropenia including 12% with severe neutropenia. In the case of concomitant administration of ketoconazole, 39% of the population was predicted to suffer from severe neutropenia. In summary, PBPK-PD modeling allows a priori prediction of DDIs and safety events involving complex combination therapies which are often utilized in an oncology setting.
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18
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Pivot X, Goupille P. [Biosimilars antibodies: positioning compared to originators - the experience in rheumatology and the biosimilars of trastuzumab in oncology]. Med Sci (Paris) 2020; 35:1137-1145. [PMID: 31903928 DOI: 10.1051/medsci/2019214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Biosimilars have demonstrated their equivalence with biologic originators, according to rigorous specifications imposed by the regulatory agencies, the FDA and the EMA. Their development is justified by the very high cost of biopharmaceuticals, and strong incentives for their prescription lead us to hope substantial savings, allowing to finance other innovative molecules. Trastuzumab marked history of the treatment of breast cancer. Four biosimilars of trastuzumab are available for routine use and we will detail the key points of their development.
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Affiliation(s)
- Xavier Pivot
- Centre Paul Strauss, Institut de Cancérologie de Strasbourg, Strasbourg France
| | - Philippe Goupille
- EA 7501, GICC, Université de Tours; Service de Rhumatologie, CHRU de Tours, France
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19
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Matsumoto T, Oda T, Yoshida Y, Kimura S, Himei H, Tsuduki T, Takagi S, Takatani M, Morishita H. Takotsubo cardiomyopathy caused by infusion reaction to trastuzumab. Int Cancer Conf J 2019; 9:28-31. [PMID: 31950014 DOI: 10.1007/s13691-019-00396-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 11/26/2019] [Indexed: 12/25/2022] Open
Abstract
Takotsubo cardiomyopathy (TCM) is also known as stress-induced cardiomyopathy. The occurrence of TCM due to infusion reaction is extremely rare. A 65-year-old man began receiving trastuzumab monotherapy for gastric cancer. However, he developed an infusion reaction after administration. Electrocardiography revealed negative T waves, ST segment elevation, and apical akinesis and hypokinesis of the left ventricle with apical ballooning in the systole and diastole. Furthermore, troponin I and creatinine kinase (CK) levels and CK-myocardial band were elevated. Based on these findings, he was diagnosed with TCM. This is the first report of TCM due to an infusion reaction.
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Affiliation(s)
- Toshihiko Matsumoto
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Takashi Oda
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Yu Yoshida
- 2Department of Cardiology, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Shogo Kimura
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Hitomi Himei
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Takao Tsuduki
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Shinjiro Takagi
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Masahiro Takatani
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
| | - Hirofumi Morishita
- 1Department of Internal Medicine, Himeji Red Cross Hospital, 1-12-1, Shimoteno, Himeji, Hyogo 6708540 Japan
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Pegram MD, Miles D, Tsui CK, Zong Y. HER2-Overexpressing/Amplified Breast Cancer as a Testing Ground for Antibody-Drug Conjugate Drug Development in Solid Tumors. Clin Cancer Res 2019; 26:775-786. [PMID: 31582515 DOI: 10.1158/1078-0432.ccr-18-1976] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/17/2019] [Accepted: 09/30/2019] [Indexed: 11/16/2022]
Abstract
Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) C max limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1-based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.
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Affiliation(s)
- Mark D Pegram
- Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, California.
| | - David Miles
- Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, London, United Kingdom
| | - C Kimberly Tsui
- Department of Genetics, Stanford University School of Medicine, Stanford, California
| | - Yu Zong
- Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, California
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21
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22
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Quartino AL, Li H, Kirschbrown WP, Mangat R, Wada DR, Garg A, Jin JY, Lum B. Population pharmacokinetic and covariate analyses of intravenous trastuzumab (Herceptin ®), a HER2-targeted monoclonal antibody, in patients with a variety of solid tumors. Cancer Chemother Pharmacol 2018; 83:329-340. [PMID: 30467591 PMCID: PMC6394489 DOI: 10.1007/s00280-018-3728-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 11/08/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations. METHODS Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling. RESULTS A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range. CONCLUSIONS Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.
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Affiliation(s)
- Angelica L Quartino
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA.
| | - Hanbin Li
- Certara, L.P., 845 Oak Grove Ave, Menlo Park, CA, 94025, USA
| | | | - Ranvir Mangat
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA.,Insight Rx, 233 Stanyan Street, San Francisco, CA, 94118, USA
| | - D Russell Wada
- Certara, L.P., 845 Oak Grove Ave, Menlo Park, CA, 94025, USA
| | - Amit Garg
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA
| | - Jin Y Jin
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA
| | - Bert Lum
- Genentech, Inc., 1 DNA Way, Mail Stop 463A, South San Francisco, CA, 94080, USA
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23
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Reijers JAA, Dane MJC, van Zonneveld AJ, Burggraaf J, Moerland M. Potential Influence of Endothelial Adsorption on the Delayed Time to Maximum Concentration of Biopharmaceuticals. Eur J Drug Metab Pharmacokinet 2018; 43:103-113. [PMID: 28795390 PMCID: PMC5794845 DOI: 10.1007/s13318-017-0430-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Background and objectives Maximum plasma concentration of biopharmaceuticals sometimes occurs long after completion of intravenous infusion. The objective of this research was to study the hypothetical adsorption of biopharmaceuticals to endothelium and infusion material, which may theoretically explain this phenomenon. Methods Infusion procedures were mimicked in an artificial vessel covered with a confluent monolayer of endothelial cells. Three monoclonal antibodies (MAbs) and C1 inhibitor were studied. Results Adsorption of MAbs to endothelium was observed followed by release when the vessel was subsequently perfused with buffer. Adsorption to infusion material also occurred to various degrees and in a seemingly random fashion, with a loss of up to 15% during a single flush of the line, but release from the line was not seen. Conclusions Our results indicate that adsorption of biopharmaceuticals to endothelium can occur. This observation can explain the increase in plasma concentration after completion of intravenous administration.
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Affiliation(s)
- Joannes A A Reijers
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands. .,Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Martijn J C Dane
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jacobus Burggraaf
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands
| | - Matthijs Moerland
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL, Leiden, The Netherlands
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24
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Can we establish a hierarchy among trastuzumab biosimilar candidates? Br J Cancer 2018; 119:263-265. [PMID: 30002436 PMCID: PMC6068097 DOI: 10.1038/s41416-018-0171-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/13/2018] [Accepted: 06/13/2018] [Indexed: 02/06/2023] Open
Abstract
The European patent for intravenous trastuzumab lapsed in 2017, and this stimulated research into a number of trastuzumab biosimilars. Quality assessment of their development and clinical results might enable establishment of a clinical hierarchy of these agents. This editorial will underline the key points for consideration when determining such an evaluation.
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25
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Fiedler W, Stoeger H, Perotti A, Gastl G, Weidmann J, Dietrich B, Baumeister H, Danielczyk A, Goletz S, Salzberg M, De Dosso S. Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours. ESMO Open 2018; 3:e000381. [PMID: 30018811 PMCID: PMC6045773 DOI: 10.1136/esmoopen-2018-000381] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 05/21/2018] [Accepted: 05/23/2018] [Indexed: 01/21/2023] Open
Abstract
Purpose TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab’s antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX. Patients and methods A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12–720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose. Results No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7–26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively. Conclusion TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2–3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).
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Affiliation(s)
- Walter Fiedler
- Department of Medicine II, Hubertus-Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Herbert Stoeger
- Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Guenther Gastl
- Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University (IMU), Innsbruck, Austria
| | - Jens Weidmann
- Department of Medicine II, Hubertus-Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | | | | | - Sara De Dosso
- Oncology Institute of Southern Switzerland, Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland
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26
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Johnson TA, Singla DK. Breast cancer drug trastuzumab induces cardiac toxicity: evaluation of human epidermal growth factor receptor 2 as a potential diagnostic and prognostic marker. Can J Physiol Pharmacol 2018; 96:647-654. [PMID: 29842793 DOI: 10.1139/cjpp-2018-0005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Breast cancer is one of the most prevalent forms of cancer in the United States and worldwide. Cancer occurs through the uncontrolled development of new abnormal cell growth. Clinicians and researchers strive to improve diagnostics and treatments in pursuit of remedying breast cancer, while limiting or removing any potential side effects that may arise. Unfortunately, traditional treatments, such as anthracyclines (i.e., doxorubicin), can damage the cardiovascular system. Recent strategies have utilized antibody-based compounds as singular treatments, or in conjunction with other treatments, with the aim to minimize side effects. The human epidermal growth factor receptor 2 (HER2) protein has been the target of numerous antibody-based breast cancer therapies, such as trastuzumab (TZM) and trastuzumab emtansine (T-DM1). This review will discuss the HER2 receptor as a diagnostic marker in targeting breast cancer using the therapeutic agents TZM and T-DM1, as well as discuss the induced cardiac toxicity following TZM and T-DM1 treatments.
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Affiliation(s)
- Taylor A Johnson
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.,Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
| | - Dinender K Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.,Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
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27
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Bonneau C, Paintaud G, Trédan O, Dubot C, Desvignes C, Dieras V, Taillibert S, Tresca P, Turbiez I, Li J, Passot C, Mefti F, Mouret-Fourme E, Le Rhun E, Gutierrez M. Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis. Eur J Cancer 2018; 95:75-84. [PMID: 29635147 DOI: 10.1016/j.ejca.2018.02.032] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 02/25/2018] [Indexed: 11/20/2022]
Abstract
PURPOSE Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT). METHODS The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics. RESULTS We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease. CONCLUSIONS The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing. REGISTRATION IDENTIFICATION ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1).
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Affiliation(s)
- Claire Bonneau
- Department of Surgery, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France
| | - Gilles Paintaud
- Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Service de Pharmacologie-Toxicologie, Tours, France
| | - Olivier Trédan
- Department of Oncology, Centre Leon Berard, 28 Prom. Léa et Napoléon Bullukian, 69008, Lyon, France
| | - Coraline Dubot
- Department of Oncology, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France
| | - Céline Desvignes
- Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Service de Pharmacologie-Toxicologie, Tours, France
| | - Véronique Dieras
- Department of Oncology, Institut Curie, Hôpital Claudius Regaud, 26 Rue d'Ulm, 75005, Paris, France
| | - Sophie Taillibert
- Department of Neurology Mazarin, Groupe Hospitalier Pitié Salpétrière, 47 bd del'hôpital, 75013, Paris, France; Assistance Publique des Hôpitaux de Paris, Paris, France; Université Pierre et Marie Curie, Paris VI, Paris, France
| | - Patricia Tresca
- Department of Clinical Research, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France
| | - Isabelle Turbiez
- Department of Clinical Research, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France
| | - Jacques Li
- Department of Epidemiology, Institut Curie, 26 Rue d'Ulm, 75005, Paris, France
| | - Christophe Passot
- Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Service de Pharmacologie-Toxicologie, Tours, France
| | - Fawzia Mefti
- Department of Oncology, Clinique de La Porte Verte, 6 Avenue Maréchal Franchet D'Esperey, 78004, Versailles, France
| | | | - Emilie Le Rhun
- Lille University, Inserm U1192 PRISM, Villeneuve d'Ascq, France; Breast unit, Department of Medical Oncology, Oscar Lambret Center, 3 Rue Frédéric Combemale, 59000, Lille, France; Neuro-oncology, Department of Neurosurgery, University Hospital, Lille, France
| | - Maya Gutierrez
- Department of Oncology, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France.
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28
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A novel way to manage trastuzumab cardiotoxicity. Cancer Chemother Pharmacol 2018; 81:791-796. [PMID: 29497813 DOI: 10.1007/s00280-018-3555-2] [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: 11/18/2017] [Accepted: 02/27/2018] [Indexed: 10/17/2022]
Abstract
PURPOSE Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab-induced cardiotoxicity by modifying the drug administration schedule. METHODS In this paper, we report the case of a patient with metastatic breast cancer responding to trastuzumab, who developed severe cardiac toxicity twice using a 3-weekly regimen. Considering preclinical pharmacological data on trastuzumab cardiotoxicity, we hypothesized that a weekly schedule of trastuzumab with lower peaks of serum concentration could be safe while remaining efficient. With the patient's consent, we started a weekly combination of carboplatin (AUC2) and trastuzumab (2 mg/kg) with close monitoring of trastuzumab concentrations. RESULTS We successfully controlled the disease for an additional 6 months with relevant trough concentrations of trastuzumab of around 50 mg/L. Another important aspect is that, with this weekly schedule, we observed no cardiac toxicity, and the left ventricular ejection fraction remained stabilized, at over 50%. CONCLUSIONS Trastuzumab is the most widely prescribed anti-HER2 monoclonal antibody for the treatment of HER2 metastatic breast cancer, and it is the only drug that has been approved for the treatment of localized HER2 breast cancer, 1-year treatment being required after surgery. In case of cardiac toxicity, particularly in women over 60 years of age, a weekly regimen with lower peaks of concentration could be an alternative to the standard 3-weekly regimen.
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29
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Pivot X, Deslypere JP, Park LS, Kim MJ, Lee W, Lee J. A Randomized Phase I Study Comparing the Pharmacokinetics of HD201, a Trastuzumab Biosimilar, With European Union–sourced Herceptin. Clin Ther 2018; 40:396-405.e4. [DOI: 10.1016/j.clinthera.2018.01.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 01/13/2018] [Accepted: 01/16/2018] [Indexed: 11/29/2022]
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30
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van Rosmalen M, Ni Y, Vervoort DFM, Arts R, Ludwig SKJ, Merkx M. Dual-Color Bioluminescent Sensor Proteins for Therapeutic Drug Monitoring of Antitumor Antibodies. Anal Chem 2018; 90:3592-3599. [PMID: 29443503 PMCID: PMC5843950 DOI: 10.1021/acs.analchem.8b00041] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Monitoring the levels of therapeutic antibodies in individual patients would allow patient-specific dose optimization, with the potential for major therapeutic and financial benefits. Our group recently developed a new platform of bioluminescent sensor proteins (LUMABS; LUMinescent AntiBody Sensor) that allow antibody detection directly in blood plasma. In this study, we targeted four clinically important therapeutic antibodies, the Her2-receptor targeting trastuzumab, the anti-CD20 antibodies rituximab and obinutuzumab, and the EGFR-blocking cetuximab. A strong correlation was found between the affinity of the antibody binding peptide and sensor performance. LUMABS sensors with physiologically relevant affinities and decent sensor responses were obtained for trastuzumab and cetuximab using mimotope and meditope peptides, respectively, with affinities in the 10-7 M range. The lower affinity of the CD20-derived cyclic peptide employed in the anti-CD20 LUMABS sensor ( Kd = 10-5 M), translated in a LUMABS sensor with a strongly attenuated sensor response. The trastuzumab and cetuximab sensors were further characterized with respect to binding kinetics and their performance in undiluted blood plasma. For both antibodies, LUMABS-based detection directly in plasma compared well to the analytical performance of commercial ELISA kits. Besides identifying important design parameters for the development of new LUMABS sensors, this work demonstrates the potential of the LUMABS platform for point-of-care detection of therapeutic antibodies.
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Affiliation(s)
- Martijn van Rosmalen
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems (ICMS), Department of Biomedical Engineering , Eindhoven University of Technology , P.O. Box 513, 5600 MB Eindhoven , The Netherlands
| | - Yan Ni
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems (ICMS), Department of Biomedical Engineering , Eindhoven University of Technology , P.O. Box 513, 5600 MB Eindhoven , The Netherlands
| | - Daan F M Vervoort
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems (ICMS), Department of Biomedical Engineering , Eindhoven University of Technology , P.O. Box 513, 5600 MB Eindhoven , The Netherlands
| | - Remco Arts
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems (ICMS), Department of Biomedical Engineering , Eindhoven University of Technology , P.O. Box 513, 5600 MB Eindhoven , The Netherlands
| | - Susann K J Ludwig
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems (ICMS), Department of Biomedical Engineering , Eindhoven University of Technology , P.O. Box 513, 5600 MB Eindhoven , The Netherlands
| | - Maarten Merkx
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems (ICMS), Department of Biomedical Engineering , Eindhoven University of Technology , P.O. Box 513, 5600 MB Eindhoven , The Netherlands
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Lucas AT, Price LSL, Schorzman AN, Storrie M, Piscitelli JA, Razo J, Zamboni WC. Factors Affecting the Pharmacology of Antibody-Drug Conjugates. Antibodies (Basel) 2018; 7:E10. [PMID: 31544862 PMCID: PMC6698819 DOI: 10.3390/antib7010010] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 01/30/2018] [Accepted: 02/01/2018] [Indexed: 12/12/2022] Open
Abstract
Major advances in therapeutic proteins, including antibody-drug conjugates (ADCs), have created revolutionary drug delivery systems in cancer over the past decade. While these immunoconjugate agents provide several advantages compared to their small-molecule counterparts, their clinical use is still in its infancy. The considerations in their development and clinical use are complex, and consist of multiple components and variables that can affect the pharmacologic characteristics. It is critical to understand the mechanisms employed by ADCs in navigating biological barriers and how these factors affect their biodistribution, delivery to tumors, efficacy, and toxicity. Thus, future studies are warranted to better understand the complex pharmacology and interaction between ADC carriers and biological systems, such as the mononuclear phagocyte system (MPS) and tumor microenvironment. This review provides an overview of factors that affect the pharmacologic profiles of ADC therapies that are currently in clinical use and development.
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Affiliation(s)
- Andrew T Lucas
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Lauren S L Price
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Allison N Schorzman
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Mallory Storrie
- UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
| | | | - Juan Razo
- UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
| | - William C Zamboni
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
- UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Xiong H, Ni J, Jiang Z, Tian F, Zhou J, Yao J. Intracellular self-disassemble polysaccharide nanoassembly for multi-factors tumor drug resistance modulation of doxorubicin. Biomater Sci 2018; 6:2527-2540. [DOI: 10.1039/c8bm00570b] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Drug efflux induced by multidrug resistance (MDR) overexpression, as well as secondary drug resistance caused by subtoxic drug microenvironments as a result of inefficient drug release of nanoscopic drug carriers in tumor cells, are major bottlenecks for chemotherapy.
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Affiliation(s)
- Hui Xiong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals
- Department of Pharmaceutics
- China Pharmaceutical University
- Nanjing 210009
- China
| | - Jiang Ni
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals
- Department of Pharmaceutics
- China Pharmaceutical University
- Nanjing 210009
- China
| | - Zhijie Jiang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals
- Department of Pharmaceutics
- China Pharmaceutical University
- Nanjing 210009
- China
| | - Fengchun Tian
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals
- Department of Pharmaceutics
- China Pharmaceutical University
- Nanjing 210009
- China
| | - Jianping Zhou
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals
- Department of Pharmaceutics
- China Pharmaceutical University
- Nanjing 210009
- China
| | - Jing Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals
- Department of Pharmaceutics
- China Pharmaceutical University
- Nanjing 210009
- China
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Hurvitz SA, Gelmon KA, Tolaney SM. Optimal Management of Early and Advanced HER2 Breast Cancer. Am Soc Clin Oncol Educ Book 2017; 37:76-92. [PMID: 28561711 DOI: 10.1200/edbk_175630] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Approximately 15%-20% of breast cancer is HER2 positive, and patients with this subtype of disease historically had worse outcomes than patients with HER2-negative disease. However, the introduction of HER2-directed therapies has dramatically altered outcomes for these patients, especially for persons with early disease. However, despite these achievements, metastatic disease is still not curable. This review summarizes the current treatment approach for patients in the preoperative and adjuvant setting, including data regarding selecting the optimal chemotherapy partner as well as determining the duration and type of anti-HER-directed therapy. This article also reviews how to approach patients with advanced HER2-positive disease and discusses promising new therapies that are in development.
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Affiliation(s)
- Sara A Hurvitz
- From the David Geffen School of Medicine, University of California, Los Angeles, CA; BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; Dana-Farber Cancer Institute, Boston, MA
| | - Karen A Gelmon
- From the David Geffen School of Medicine, University of California, Los Angeles, CA; BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; Dana-Farber Cancer Institute, Boston, MA
| | - Sara M Tolaney
- From the David Geffen School of Medicine, University of California, Los Angeles, CA; BC Cancer Agency, University of British Columbia, Vancouver, BC, Canada; Dana-Farber Cancer Institute, Boston, MA
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Shammas RL, Cho EH, Glener AD, Poveromo LP, Mundy LR, Greenup RA, Blackwell KL, Hollenbeck ST. Association Between Targeted HER-2 Therapy and Breast Reconstruction Outcomes: A Propensity Score-Matched Analysis. J Am Coll Surg 2017; 225:731-739.e1. [DOI: 10.1016/j.jamcollsurg.2017.08.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 08/22/2017] [Accepted: 08/22/2017] [Indexed: 10/18/2022]
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Nemeth BT, Varga ZV, Wu WJ, Pacher P. Trastuzumab cardiotoxicity: from clinical trials to experimental studies. Br J Pharmacol 2017; 174:3727-3748. [PMID: 27714776 PMCID: PMC5647179 DOI: 10.1111/bph.13643] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/21/2016] [Accepted: 09/24/2016] [Indexed: 01/03/2023] Open
Abstract
UNLABELLED Epidermal growth factor receptor-2 (HER-2) is overexpressed in 20 to 25% of human breast cancers, which is associated with aggressive tumour growth and poor prognosis. Trastuzumab (Herceptin®) is a humanized monoclonal antibody directed against HER-2, the first highly selective form of therapy targeting HER-2 overexpressing tumours. Although initial trials indicated high efficacy and a favourable safety profile of the drug, the first large, randomized trial prompted a retrospective analysis of cardiac dysfunction in earlier trials utilizing trastuzumab. There has been ongoing debate on the cardiac safety of trastuzumab ever since, initiating numerous clinical and preclinical investigations to better understand the background of trastuzumab cardiotoxicity and evaluate its effects on patient morbidity. Here, we have given a comprehensive overview of our current knowledge on the cardiotoxicity of trastuzumab, primarily focusing on data from clinical trials and highlighting the main molecular mechanisms proposed. LINKED ARTICLES This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.
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Affiliation(s)
- Balazs T Nemeth
- Laboratory of Cardiovascular Physiology and Tissue InjuryNational Institute on Alcohol Abuse and AlcoholismRockvilleMDUSA
| | - Zoltan V Varga
- Laboratory of Cardiovascular Physiology and Tissue InjuryNational Institute on Alcohol Abuse and AlcoholismRockvilleMDUSA
| | - Wen Jin Wu
- Division of Biotechnology Research and Review 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBethesdaMDUSA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue InjuryNational Institute on Alcohol Abuse and AlcoholismRockvilleMDUSA
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Thiele NA, Brown V, Kelly JM, Amor‐Coarasa A, Jermilova U, MacMillan SN, Nikolopoulou A, Ponnala S, Ramogida CF, Robertson AKH, Rodríguez‐Rodríguez C, Schaffer P, Williams C, Babich JW, Radchenko V, Wilson JJ. An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy. Angew Chem Int Ed Engl 2017; 56:14712-14717. [DOI: 10.1002/anie.201709532] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Indexed: 01/19/2023]
Affiliation(s)
- Nikki A. Thiele
- Chemistry and Chemical Biology Cornell University Ithaca NY 14853 USA
| | - Victoria Brown
- Life Science Division, TRIUMF Vancouver BC V6T 2A3 Canada
| | | | | | - Una Jermilova
- Life Science Division, TRIUMF Vancouver BC V6T 2A3 Canada
| | | | | | | | | | | | - Cristina Rodríguez‐Rodríguez
- Fac. of Pharmaceutical Sciences, Dept. of Physics and Astronomy and Centre for Comparative Medicine University of British Columbia Vancouver BC V6T 1W5 Canada
| | - Paul Schaffer
- Life Science Division, TRIUMF Vancouver BC V6T 2A3 Canada
| | | | | | | | - Justin J. Wilson
- Chemistry and Chemical Biology Cornell University Ithaca NY 14853 USA
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Thiele NA, Brown V, Kelly JM, Amor‐Coarasa A, Jermilova U, MacMillan SN, Nikolopoulou A, Ponnala S, Ramogida CF, Robertson AKH, Rodríguez‐Rodríguez C, Schaffer P, Williams C, Babich JW, Radchenko V, Wilson JJ. An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy. Angew Chem Int Ed Engl 2017. [DOI: 10.1002/ange.201709532] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Nikki A. Thiele
- Chemistry and Chemical Biology Cornell University Ithaca NY 14853 USA
| | - Victoria Brown
- Life Science Division, TRIUMF Vancouver BC V6T 2A3 Canada
| | | | | | - Una Jermilova
- Life Science Division, TRIUMF Vancouver BC V6T 2A3 Canada
| | | | | | | | | | | | - Cristina Rodríguez‐Rodríguez
- Fac. of Pharmaceutical Sciences, Dept. of Physics and Astronomy and Centre for Comparative Medicine University of British Columbia Vancouver BC V6T 1W5 Canada
| | - Paul Schaffer
- Life Science Division, TRIUMF Vancouver BC V6T 2A3 Canada
| | | | | | | | - Justin J. Wilson
- Chemistry and Chemical Biology Cornell University Ithaca NY 14853 USA
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Cavaco M, Goncalves J. Interactions Between Therapeutic Proteins and Small Molecules: The Shared Role of Perpetrators and Victims. Clin Pharmacol Ther 2017; 102:649-661. [PMID: 28002637 DOI: 10.1002/cpt.605] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 11/21/2016] [Accepted: 12/12/2016] [Indexed: 12/19/2022]
Abstract
Therapeutic proteins (TPs) are becoming increasingly important as therapeutic agents. A consequence of expanding their clinical indications is coadministration with well-established small-molecule drugs (sMDs), which could lead to unpredictable effects. According to the existing regulatory guidance, the development of an sMD includes the evaluation of potential drug-drug interactions (DDIs). For TPs, only a few drug interaction studies have been published. Limited clinically relevant models, long half-lives, and complex elimination pathways are among the associated difficulties.
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Affiliation(s)
- M Cavaco
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - J Goncalves
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Stage TB, Bergmann TK, Kroetz DL. Clinical Pharmacokinetics of Paclitaxel Monotherapy: An Updated Literature Review. Clin Pharmacokinet 2017; 57:7-19. [DOI: 10.1007/s40262-017-0563-z] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Guglin M, Munster P, Fink A, Krischer J. Lisinopril or Coreg CR in reducing cardiotoxicity in women with breast cancer receiving trastuzumab: A rationale and design of a randomized clinical trial. Am Heart J 2017; 188:87-92. [PMID: 28577685 DOI: 10.1016/j.ahj.2017.03.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 03/20/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Trastuzumab (TZB) is an established therapy for HER2-positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin-converting enzyme (ACE) inhibitors and β-blockers (BBs) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a BB during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo. METHODS AND RESULTS We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to evaluate the effects of an ACE inhibitor (lisinopril) and a BB (carvedilol phosphate-extended release) on cardiotoxicity in patients with breast cancer who are receiving adjuvant or neoadjuvant TZB therapy. The primary objectives include (1) comparison of incidence of cardiotoxicity and (2) comparison of LVEF as a continuous variable in between the arms. Cardiotoxicity was defined as an absolute decrease in LVEF from baseline of ≥10% at follow-up or an absolute decrease of ≥5% in LVEF from baseline for individuals with <50% LVEF at follow-up. The target accrual is 468 participants, representing patients both with and without anthracycline exposure. The enrollment is completed. The trial is co-sponsored by University of South Florida and National Cancer Institute. The LVEF is being evaluated by echocardiography or multigated acquisition scan. CONCLUSIONS If we can demonstrate that the use of an ACE inhibitor or a BB can reduce the degree of TZB-induced cardiotoxicity, it is hoped that patients will receive complete and uninterrupted TZB therapy for breast cancer without compromising cardiac function.
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Yavas G, Celik E, Yavas C, Elsurer C, Afsar RE. Spironolactone ameliorates the cardiovascular toxicity induced by concomitant trastuzumab and thoracic radiotherapy. Rep Pract Oncol Radiother 2017; 22:295-302. [PMID: 28507459 DOI: 10.1016/j.rpor.2017.01.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 01/28/2017] [Indexed: 02/08/2023] Open
Abstract
AIM We aimed to evaluate impact of spironolactone (S) on cardiovascular toxicity of concomitant use of radiotherapy (RT) and trastuzumab (T). BACKGROUND S, an aldosterone receptor antagonist, is known to ameliorate the cardiac damage. S ameliorates anthracycline -induced cardiotoxicity, there is no data regarding to effect of S on both T and radiation-induced cardiotoxicity. MATERIALS/METHODS Eighty rats were divided into eight groups: group (G) 1 was defined as control group. G2, G3 and G4 were RT, S and T groups respectively. G5, G6, G7 and G8 were RT + T, T + S, RT + S and RT + T + S groups respectively. Rats were sacrificed at 6th hour; 21st and 100th days after RT. Heart and thoracic aorta samples were taken for microscopical examination. RESULTS Cardiac inflammation and fibrosis scores and; TGF-β expression were not significantly different within study groups at 6th hour and 21st days of RT. By 100th days of RT fibrosis scores and TGF-β expression in cardiac samples were significantly different between study groups (p values were 0.004 and 0.002 respectively). Pair-wise comparisons revealed that both cardiac fibrosis scores and TGF-β expression levels were higher in G5 when compared to G8 (p values were 0.046 and 0.028 respectively). Moreover the TGF-β expression was higher in G5 when compared to G2 (p = 0.046). We could not demonstrate any significant differences with respect to inflammation, fibrosis and TGF-β expression in thoracic aorta samples between study groups. CONCLUSIONS Although S had a protective effect on cardiac tissue it had no protective effect on thoracic aorta when administered with RT + T.
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Affiliation(s)
- Guler Yavas
- Selcuk University, Department of Radiation Oncology, Konya, Turkey
| | - Esin Celik
- Selcuk University, Department of Pathology, Konya, Turkey
| | - Cagdas Yavas
- Selcuk University, Department of Radiation Oncology, Konya, Turkey
| | - Cagdas Elsurer
- Selcuk University, Department of Ear, Nose and Throat, Konya, Turkey
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Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, Nordstrom JL, Li H, Chichili GR, Moore PA, Hong S, Stewart SJ, Baughman JE, Lechleider RJ, Burris HA. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol 2017; 28:855-861. [PMID: 28119295 PMCID: PMC6246722 DOI: 10.1093/annonc/mdx002] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas. PATIENTS AND METHODS Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1-6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10-18 mg/kg) (Regimen B). RESULTS Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders. Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab. CONCLUSIONS Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing. TRIAL REGISTRATION ID NCT01148849.
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Affiliation(s)
- Y. J. Bang
- Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - G. Giaccone
- Department of Medical Oncology, National Cancer Institute, Bethesda
| | - S. A. Im
- Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D. Y. Oh
- Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - T. M. Bauer
- Department of Drug Development, Sarah Cannon Research Institute and Tennessee Oncology, Nashville
| | | | - H. Li
- MacroGenics, Inc, Rockville, and South San Francisco, USA
| | - G. R. Chichili
- MacroGenics, Inc, Rockville, and South San Francisco, USA
| | - P. A. Moore
- MacroGenics, Inc, Rockville, and South San Francisco, USA
| | - S. Hong
- MacroGenics, Inc, Rockville, and South San Francisco, USA
| | - S. J. Stewart
- MacroGenics, Inc, Rockville, and South San Francisco, USA
| | - J. E. Baughman
- MacroGenics, Inc, Rockville, and South San Francisco, USA
| | | | - H. A. Burris
- Department of Drug Development, Sarah Cannon Research Institute and Tennessee Oncology, Nashville
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Malik PRV, Hamadeh A, Phipps C, Edginton AN. Population PBPK modelling of trastuzumab: a framework for quantifying and predicting inter-individual variability. J Pharmacokinet Pharmacodyn 2017; 44:277-290. [PMID: 28260166 DOI: 10.1007/s10928-017-9515-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 03/01/2017] [Indexed: 12/11/2022]
Abstract
In this work we proposed a population physiologically-based pharmacokinetic (popPBPK) framework for quantifying and predicting inter-individual pharmacokinetic variability using the anti-HER2 monoclonal antibody (mAb) trastuzumab as an example. First, a PBPK model was developed to account for the possible mechanistic sources of variability. Within the model, five key factors that contribute to variability were identified and the nature of their contribution was quantified with local and global sensitivity analyses. The five key factors were the concentration of membrane-bound HER2 ([Formula: see text]), the convective flow rate of mAb through vascular pores ([Formula: see text]), the endocytic transport rate of mAb through vascular endothelium ([Formula: see text]), the degradation rate of mAb-HER2 complexes ([Formula: see text]) and the concentration of shed HER2 extracellular domain in circulation ([Formula: see text]). [Formula: see text] was the most important parameter governing trastuzumab distribution into tissues and primarily affected variability in the first 500 h post-administration. [Formula: see text] was the most significant contributor to variability in clearance. These findings were used together with population generation methods to accurately predict the observed variability in four experimental trials with trastuzumab. To explore anthropometric sources of variability, virtual populations were created to represent participants in the four experimental trials. Using populations with only their expected anthropometric diversity resulted in under-prediction of the observed inter-individual variability. Adapting the populations to include literature-based variability around the five key parameters enabled accurate predictions of the variability in the four trials. The successful application of this framework demonstrates the utility of popPBPK methods to understand the mechanistic underpinnings of pharmacokinetic variability.
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Affiliation(s)
- Paul R V Malik
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener, ON, N2G 1C5, Canada
| | - Abdullah Hamadeh
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener, ON, N2G 1C5, Canada
| | - Colin Phipps
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener, ON, N2G 1C5, Canada
| | - Andrea N Edginton
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener, ON, N2G 1C5, Canada.
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Charge variant analysis of proposed biosimilar to Trastuzumab. Biologicals 2017; 46:46-56. [DOI: 10.1016/j.biologicals.2016.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 11/04/2016] [Accepted: 12/20/2016] [Indexed: 12/21/2022] Open
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Jawa Z, Perez RM, Garlie L, Singh M, Qamar R, Khandheria BK, Jahangir A, Shi Y. Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: A meta-analysis. Medicine (Baltimore) 2016; 95:e5195. [PMID: 27858859 PMCID: PMC5591107 DOI: 10.1097/md.0000000000005195] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Trastuzumab targets the human epidermal growth factor receptor 2 oncogene and in combination with first-line therapy results in significantly improved survival outcomes and has thus become standard of care in both adjuvant and metastatic settings. While it is estimated that 1% to 4% of patients treated with trastuzumab will develop heart failure and ∼10% will experience a reduction in left ventricular ejection fraction (LVEF), the patient risk factors associated with trastuzumab-induced cardiotoxicity (TIC) are unclear. This meta-analysis aims to consolidate previously published data to identify the risk factors most likely leading to TIC. METHODS A search of the MEDLINE literature database using the keywords trastuzumab/Herceptin, risk factors, outcomes, cardiac, cardiotoxicity, cardiomyopathy, LVEF, and chemotherapy was performed. Only prospective/retrospective human studies were included, with additional studies excluded if they reported baseline LVEF > 68%, a cohort of <50 patients, or results that were not stratified based on cardiotoxic events. Pooled odds ratio (OR) and 95% confidence interval (CI) for each potential risk factor were calculated, with heterogeneity of data and samples explored using random-effects modeling. RESULTS Data were collected from 17 articles, capturing 6527 patients. Hypertension (OR 1.61, 95% CI 1.14-2.26; P < 0.01), diabetes (OR 1.62; 95% CI 1.10-2.38; P < 0.02), previous anthracycline use (OR 2.14; 95% CI 1.17-3.92; P < 0.02), and older age (P = 0.013) were all shown to be associated with TIC. CONCLUSION Cardiac performance should be closely monitored in women treated with trastuzumab. Recognizing potential risk factors along with careful attention to symptoms/LVEF measurements could minimize the occurrence of TIC in this population.
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Affiliation(s)
- Zeeshan Jawa
- Department of Internal Medicine, Medical College of Wisconsin
| | | | | | | | - Rubina Qamar
- Department of Medical Oncology, Aurora Health Care
| | | | - Arshad Jahangir
- Aurora Cardiovascular Services, Aurora Health Care
- Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Health Care, Milwaukee, WI
| | - Yang Shi
- Aurora Research Institute, Aurora Health Care
- Sheikh Khalifa bin Hamad Al Thani Center for Integrative Research on Cardiovascular Aging, Aurora Health Care, Milwaukee, WI
- Correspondence: Yang Shi, Aurora Research Institute, 960 N. 12th Street, Suite 4155, Milwaukee, WI 53233 (e-mail: )
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Gulia S, Gupta S, Singh A. Intrathecal trastuzumab for leptomeningeal carcinomatosis in patients with human epidermal growth factor receptor 2 positive breast cancer. Indian J Med Paediatr Oncol 2016; 37:196-8. [PMID: 27688614 PMCID: PMC5027793 DOI: 10.4103/0971-5851.190354] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
There has been recent increase in incidence of leptomeningeal carcinomatosis, possibly due to widespread use of adjuvant trastuzumab and its known poor CNS penetration. Currently there are limited therapeutic options for these patients and outcome is poor. We report two cases of women with HER2 positive breast cancer who developed leptomeningeal carcinomatosis for which they were treated with intrathecal trastuzumab in combination with systemic therapy. Both patients had rapid symptomatic benefit and radiological response and remained progression free for at least seven months. Intrathecal trastuzumab can be considered a reasonable therapeutic option for these difficult to treat patients.
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Affiliation(s)
- Seema Gulia
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Ashish Singh
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India
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Demonty G. Docetaxel Plus Trastuzumab as Treatment for Her-2 Positive Metastatic Breast Cancer: Review of the Existing Evidence. WOMENS HEALTH 2016; 3:523-8. [DOI: 10.2217/17455057.3.5.523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The aim of this review is to examine the evidence available supporting the use of the docetaxel plus trastuzumab combination for patients with HER-2-positive metastatic breast cancer. The results of trials involving this combination are summarized, with an emphasis on efficacy and cardiotoxicity data. Finally, this article attempts to identify areas of uncertainty where new trials are warranted to improve our knowledge regarding optimal care for patients with HER-2-positive metastatic breast cancer.
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Affiliation(s)
- Gaston Demonty
- European Organisation for Research and Treatment of Cancer Data Center, Avenue Mounier 83 (1200), Brussels, Belgium, Tel.: +32 2774 1005; Fax: +32 2771 3810
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Pharmacokinetics interactions of monoclonal antibodies. Pharmacol Res 2016; 111:592-599. [DOI: 10.1016/j.phrs.2016.07.015] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/12/2016] [Accepted: 07/13/2016] [Indexed: 12/27/2022]
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Chow LQM, Smith DC, Tan AR, Denlinger CS, Wang D, Shepard DR, Chaudhary A, Lin Y, Gao L. Lack of pharmacokinetic drug-drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors. Cancer Chemother Pharmacol 2016; 78:433-41. [PMID: 27379498 PMCID: PMC4965482 DOI: 10.1007/s00280-016-3098-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 06/22/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE The objective of this phase II study was to evaluate pharmacokinetic interaction potential between ramucirumab and paclitaxel in patients with advanced cancer. METHODS This study was designed to assess 2-way pharmacokinetic drug-drug interactions between ramucirumab and paclitaxel. Twenty-four patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m(2) was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15). Patients could continue to receive combination therapy with ramucirumab and paclitaxel. In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle. Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel. RESULTS Concomitant administration of ramucirumab had no effect on pharmacokinetics of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab vs. alone) of 1.09 (90 % confidence interval [CI] 0.93, 1.29) for AUC(0-∞) and 0.97 (90 % CI 0.83, 1.13) for C max. In addition, similar ramucirumab pharmacokinetic characteristics were observed with or without paclitaxel administration. The ratios of geometric LS means of AUC(0-∞) and C max of ramucirumab (with paclitaxel vs. alone) were 1.00 (90 % CI 0.84, 1.19) for AUC(0-∞) and 1.07 (90 % CI 0.93, 1.24) for C max, respectively. CONCLUSIONS Concomitant paclitaxel administration is unlikely to affect the pharmacokinetics of ramucirumab, and vice versa. The incidence and severity of adverse events were consistent with the known safety profiles of paclitaxel and ramucirumab.
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Affiliation(s)
- Laura Q M Chow
- University of Washington, Seattle Cancer Care Alliance, MSG4-940, 825 Eastlake Ave E, Box 358081, Seattle, WA, 98109, USA.
| | | | | | | | - Ding Wang
- Henry Ford Hospital, Detroit, MI, USA
| | | | | | - Yong Lin
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Ling Gao
- Eli Lilly and Company, Bridgewater, NJ, USA
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Pivot X, Curtit E, Lee YJ, Golor G, Gauliard A, Shin D, Kim Y, Kim H, Fuhr R. A Randomized Phase I Pharmacokinetic Study Comparing Biosimilar Candidate SB3 and Trastuzumab in Healthy Male Subjects. Clin Ther 2016; 38:1665-1673.e3. [DOI: 10.1016/j.clinthera.2016.06.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/31/2016] [Accepted: 06/06/2016] [Indexed: 10/21/2022]
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