Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study

Abstract

Purpose: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC).

Methods: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety.

Results: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs.

Conclusion: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.

Conflict of interest statement

Sumanta K. PalConsulting or Advisory Role: F. Hoffmann LaRocheResearch Funding: Eisai, Genentech, Roche, Exelixis, PfizerTravel, Accommodations, Expenses: Genentech, Seattle Genetics Bradley McGregorConsulting or Advisory Role: Bayer, Seattle Genetics/Astellas, Exelixis, AstraZeneca, Astellas Pharma, Genentech/Roche, Nextar, Janssen Oncology, Pfizer, EMD Serono, Eisai, Dendreon, Bristol Myers SquibbResearch Funding: Bristol Myers Squibb, Exelixis, Calithera Biosciences, Seattle Genetics/Astellas Cristina SuárezConsulting or Advisory Role: Bristol Myers Squibb, Ipsen, Sanofi, Pfizer, EUSA Pharma, Astellas Pharma, Novartis, Merck Sharp & Dohme, EisaiSpeakers' Bureau: Bristol Myers Squibb, Ipsen, Pfizer, Roche/Genentech, AstraZeneca, Merck Sharp & DohmeResearch Funding: Astellas Pharma, Roche/Genentech, Exelixis, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Janssen Oncology, Calithera Biosciences, AB Science, Arog, AVEO, Bayer, SFJ Pharmaceuticals Group, Blueprint Medicines, Clovis Oncology, Boehringer Ingelheim, Cougar Biotechnology, Deciphera, GlaxoSmithKline, Incyte, Karyopharm Therapeutics, MedImmune, Nanobiotix, Millennium, Puma Biotechnology, TevaTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Ipsen Che-Kai TsaoConsulting or Advisory Role: Eisai, Clovis Oncology, MerckResearch Funding: Exelixis William KellyHonoraria: Janssen Oncology, BayerConsulting or Advisory Role: Merck Sharp & DohmeResearch Funding: Sanofi, Novartis, Janssen Oncology, Bayer, Exelixis, Seattle Genetics, Endocyte, Amgen, BioClin Therapeutics, Sarah Cannon Research Institute, RocheTravel, Accommodations, Expenses: Janssen Oncology, Merck Sharp & Dohme Ulka VaishampayanConsulting or Advisory Role: Pfizer, Exelixis, Bayer, Bristol Myers Squibb/Medarex, Merck Serono, Advanced Accelerator Applications, Alkermes, Helsinn TherapeuticsSpeakers' Bureau: Pfizer, Bayer, ExelixisResearch Funding: Astellas Pharma, Exelixis, Bristol Myers Squibb, Merck KGaA Lance PagliaroResearch Funding: Pfizer, Genentech/Roche, Exelixis, Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Benjamin L. MaughanConsulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Bristol Myers Squibb, Astellas Medivation, Bayer, AVEO, Clovis Oncology, Merck, Peloton TherapeuticsResearch Funding: Clovis Oncology, Bristol Myers Squibb, Bavarian Nordic, ExelixisTravel, Accommodations, Expenses: Exelixis Yohann LoriotHonoraria: Sanofi, PfizerConsulting or Advisory Role: Janssen, Astellas Pharma, Roche, AstraZeneca, MSD Oncology, Seattle Genetics, Bristol Myers Squibb, Immunomedics, Taiho PharmaceuticalResearch Funding: Sanofi, Janssen Oncology, MSD Oncology, AstraZeneca, Clovis Oncology, Exelixis, Boehringer Ingelheim, Incyte, Pfizer, Oncogenex, Medivation, CureVac, NektarTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, Seattle Genetics Daniel CastellanoConsulting or Advisory Role: Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, Bristol Myers Squibb, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Boehringer IngelheimResearch Funding: Janssen OncologyTravel, Accommodations, Expenses: Pfizer, Roche, Bristol Myers Squibb, AstraZeneca Spain Sandy SrinivasConsulting or Advisory Role: Eisai, Bayer, Bristol Myers Squibb, Merck, Exelixis, AstraZeneca, Seattle GeneticsResearch Funding: Bristol Myers Squibb, Genentech, Merck, Exelixis, Eisai, Bayer, AstraZeneca, Seattle Genetics/AstellasOther Relationship: Pfizer Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZenecaResearch Funding: Pfizer, Bayer, Tempus Robert DreicerConsulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/AstellasResearch Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis Thomas HutsonEmployment: Texas OncologyHonoraria: Pfizer, Astellas Pharma, Bristol Myers Squibb, Exelixis, Eisai, Novartis, Johnson & Johnson, Bayer/OnyxConsulting or Advisory Role: Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, Bristol Myers Squibb, Eisai, ExelixisSpeakers' Bureau: Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma, Bristol Myers SquibbResearch Funding: Pfizer, Johnson & Johnson, Exelixis, Eisai, Bristol Myers Squibb Sarita DubeyEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Scott WernekeEmployment: ExelixisStock and Other Ownership Interests: Exelixis Ashok PanneerselvamEmployment: ExelixisStock and Other Ownership Interests: Exelixis Dominic CurranEmployment: Exelixis, Syneos Health (I)Stock and Other Ownership Interests: ExelixisTravel, Accommodations, Expenses: Exelixis Christian ScheffoldEmployment: ExelixisStock and Other Ownership Interests: ExelixisPatents, Royalties, Other Intellectual Property: Patent Toni K. ChoueiriEmployment: Dana Farber Cancer HospitalLeadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCOStock and Other Ownership Interests: Pionyr, Tempest TherapeuticsHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, NCI GU Steering CommitteeConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, AraviveResearch Funding: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, Gateway for Cancer Research, Congressionally Directed Medical Research Programs (DOD)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint ResponseTravel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel Neeraj AgarwalConsulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Gilead SciencesResearch Funding: Bayer, Bristol Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, CRISPR Therapeutics, ArvinasNo other potential conflicts of interest were reported.

Figures

FIG 1.

Patient disposition. ccRCC, clear cell renal cell carcinoma; nccRCC, non–clear cell renal cell carcinoma.

FIG 2.

Best change from baseline in sum of tumor lesions in (A) patients with ccRCC receiving cabozantinib 40 mg plus atezolizumab (n = 34); (B) patients with ccRCC receiving cabozantinib 60 mg plus atezolizumab (n = 35); and (C) patients with nccRCC receiving cabozantinib 40 mg plus atezolizumab (n = 32). All complete and partial responses were confirmed. One patient in the 60-mg ccRCC group had no postbaseline tumor assessment. ccRCC, clear cell renal cell carcinoma; CPS, combined positive score; CR, complete response; IMDC, International Metastatic RCC Database Consortium; nccRCC, non–clear cell renal cell carcinoma; PD, progressive disease; PD-L1, programmed death-ligand 1; PR, partial response; RCC, renal cell carcinoma; SD, stable disease.

FIG 3.

Duration of treatment and responses in (A) patients with ccRCC receiving cabozantinib 40 mg plus atezolizumab (n = 34); (B) patients with ccRCC receiving cabozantinib 60 mg plus atezolizumab (n = 35); and (C) patients with nccRCC receiving cabozantinib 40 mg plus atezolizumab (n = 32). All complete and partial responses were confirmed. One patient in the 60-mg ccRCC group had no postbaseline tumor assessment. ccRCC, clear cell renal cell carcinoma; CR, complete response; nccRCC, non–clear cell renal cell carcinoma; PD, progressive disease; PR, partial response; RCC, renal cell carcinoma.

FIG 4.

PFS in patients with (A) clear-cell renal cell carcinoma and (B) patients with non–clear cell renal cell carcinoma. NE, not estimable; PFS, progression-free survival.