TY - JOUR
T1 - Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients with Renal Cell Carcinoma
AU - Hirsch, Laure
AU - Martinez Chanza, Nieves
AU - Farah, Subrina
AU - Xie, Wanling
AU - Flippot, Ronan
AU - Braun, David A.
AU - Rathi, Nityam
AU - Thouvenin, Jonathan
AU - Collier, Katharine A.
AU - Seront, Emmanuel
AU - De Velasco, Guillermo
AU - Dzimitrowicz, Hannah
AU - Beuselinck, Benoit
AU - Xu, Wenxin
AU - Bowman, I. Alex
AU - Lam, Elaine T.
AU - Abuqayas, Bashar
AU - Bilen, Mehmet Asim
AU - Varkaris, Andreas
AU - Zakharia, Yousef
AU - Harrison, Michael R.
AU - Mortazavi, Amir
AU - Barthélémy, Philippe
AU - Agarwal, Neeraj
AU - McKay, Rana R.
AU - Brastianos, Priscilla K.
AU - Krajewski, Katherine M.
AU - Albigès, Laurence
AU - Harshman, Lauren C.
AU - Choueiri, Toni K.
N1 - Funding Information:
Chanza reports support for research travel from Pfizer and Ipsen, and consulting fees from Bristol Myers Squibb and Bayer. Ms Xie reports personal fees from Convergen Consulting. Dr Flippot reports personal fees from Pfizer, Ipsen, Bristol Myers Squibb, and Janssen. Dr Braun reports nonfinancial support from Bristol Myers Squibb; reports honoraria from LM Education and Exchange Services; reports personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnership, Charles River Associates, Trinity Group, Schlesinger Associates, MDedge, Adnovate Strategies, and Insight Strategy; and is on an advisory board for Exelixis outside of the submitted work. Dr Beuselinck reports personal fees from Bristol Myers Squibb, MSD, and Ipsen, as well as fees from Pfizer for speaking and travel accommodations. Dr de Velasco reports honoraria, consulting fees, and research funding from Pfizer, Novartis, Ipsen, Bristol Myers Squibb, Bayer, Roche, Astellas, EUSA Pharma, Merck, and MSD. Dr Lam reports grants from Exelixis for clinical trial support outside the submitted work. Dr Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, Bristol Myers Squibb, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, and Sanofi, and has received grants to his institution from Xencor, Bayer, Bristol Myers Squibb, Genentech/ Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed outside of the current study. Dr Zakharia reports consulting fees from Pfizer and Novartis; is on the advisory boards for Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Array, Bayer, Pfizer, Clovis, and EMD Serono; is on the data and safety monitoring committee of Janssen; and has received clinical trial support to his institution from NewLink Genetics, Pfizer, Exelixis, and Eisai. Dr Harrison reports research funding to his institution from Acerta Pharma, Astellas Pharma, Bristol Myers Squibb, Clovis Oncology, Exelixis, Genentech, Janssen, Merck, and Pfizer; personal fees from Bristol Myers Squibb and Pfizer; and consulting/speaking fees from AstraZeneca, Bayer, Exelixis, Fujifilm, Genentech, and Janssen. Dr Mortazavi reports working on advisory boards for Pfizer, Debiopharm Group, and Seattle Genetics, and research funding to his institution from Acerta Pharma, Astellas Pharma, Bristol Myers Squibb, Debiopharm Group, Genentech, Merck, Mirati Therapeutics, Novartis, Roche, and Seattle Genetics. Dr Barthélémy reports support from serving on the advisory boards of Ipsen, Bristol Myers Squibb, MSD, Pfizer, Merck, Janssen, Astellas, and Novartis, as well as consulting fees from Seattle Genetics. Dr Brastianos reports personal fees from Angiochem, Genentech/Roche, ElevateBio, Pfizer, Tesaro, Voyager Therapeutics, Eli Lilly, Pfizer, SK Life Science, and Dantari; consulting or advisory fees from Bristol Myers Squibb, Pfizer, MSD Oncology, Novartis, Ipsen, Roche, and Janssen Cilag; travel accommodations and expenses from Amgen; honoraria from Astellas Pharma, Merck, Genentech/Roche, and Eli Lilly; grants to her institution from Bristol Myers Squibb, Eli Lilly, Mirati Therapeutics, and Merck; and support from the Breast Cancer Research Foundation, Damon Runyon Cancer Research Foundation, Ben and Catherine Ivy Foundation, and the National Cancer Institute (5R01CA244975-02, 5R21CA220253-02, and 5R01CA227156-03). Dr Agarwal reports personal fees from Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics, as well as research funding to his institution from AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, Nektar, NewLink Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Dr McKay reports research funding from Bayer, Pfizer, and Tempus; reports personal fees from AstraZeneca, Calithera, Merck, and Caris; is on the advisory board of Bayer, Bristol Myers Squibb, Exelixis, Janssen, Novartis, Pfizer, Sanofi, and Tempus; and is a consultant for Dendreon and Vividion. Dr Albigès reports consulting fees from Pfizer, Novartis, Bristol Myers Squibb, Janssen, Ipsen, Roche, MSD, AstraZeneca, Merck, Amgen, Astellas, Eisai, and Exelixis, as well as other fees from Corvus Pharmaceuticals and Peloton Therapeutics. Dr Harshman reports previous employment at Dana-Farber Cancer Institute; grants to her institution from Bayer, SOTIO, Bristol Myers Squib, Merck, Takeda, Dendreon/Valeant, Janssen, Medivation/Astellas, Genentech, Pfizer, and Endocyte/Novartis; advisory or consulting services from Bayer, Genentech, Pfizer, Medivation/ Astellas, Corvus, Merck, Exelixis, Novartis, Advanced Accelerator Applications, Jounce, Bristol Myers Squibb, EMD Serono, Michael J Hennessy Associates, ASiM, and Ology Medical Education during the conduct of the study; current employment (including stock options) at Surface Oncology; and travel support from Bayer and Genentech outside the submitted work. Dr Choueiri reports personal fees from Merck, Bristol Myers Squibb, Roche, EMD Serono, AstraZeneca, Exelixis, Pfizer, and Eli Lilly during the conduct of the study; personal fees from the National Comprehensive Cancer Network, the Genitourinary Cancers Steering Committee of the National Cancer Institute, continuing medical education programs related to genitourinary oncology, and various national and international committees and programs outside of the submitted work; and support from the Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence (2P50CA101942-16) and program (5P30CA006516-56), the Kohlberg Chair at Harvard Medical School, the Michael Brigham Fund, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. No other disclosures were reported.
Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - Importance: Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear. Objective: To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. Design, Setting, and Participants: This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy. Exposures: Receipt of cabozantinib monotherapy at any line of treatment. Main Outcomes and Measures: Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. Results: Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. Conclusions and Relevance: In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.
AB - Importance: Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear. Objective: To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. Design, Setting, and Participants: This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy. Exposures: Receipt of cabozantinib monotherapy at any line of treatment. Main Outcomes and Measures: Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. Results: Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. Conclusions and Relevance: In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.
UR - http://www.scopus.com/inward/record.url?scp=85117842360&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117842360&partnerID=8YFLogxK
U2 - 10.1001/jamaoncol.2021.4544
DO - 10.1001/jamaoncol.2021.4544
M3 - Article
C2 - 34673916
AN - SCOPUS:85117842360
SN - 2374-2437
VL - 7
SP - 1815
EP - 1823
JO - JAMA Oncology
JF - JAMA Oncology
IS - 12
ER -