Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma

Results From the COSMIC-021 Study

Sumanta K. Pal, MD; Bradley McGregor, MD; Cristina Súarez, MD; Che-Kai Tsao, MD; William Kelly, DO; Ulka Vaishampayan, MD; Lance Pagliaro, MD; Benjamin L. Maughan, MD; Yohann Loriot, MD; Daniel Castellano, MD; Sandy Srinivas, MD; Rana R. McKay, MD; Robert Dreicer, MD; Thomas Hutson, DO; Sarita Dubey, MD; Scott Werneke, PhD; Ashok Panneerselvam, PhD; Dominic Curran, MBChB; Christian Scheffold, MD; Toni K. Choueiri, MD; Neeraj Agarwal, MD


J Clin Oncol. 2021;39(33):3725-3736. 

In This Article

Abstract and Introduction


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.


Clear cell (cc) renal cell carcinoma (RCC) accounts for approximately 75% of all RCC diagnoses, whereas non–clear cell (ncc) RCC, a heterogeneous group of histologies, accounts for approximately 25%.[1,2] Treatment of advanced ccRCC has evolved in recent years with the approval of new tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), as well as TKI-ICI combinations that have shown improved response and survival versus standard of care, sunitinib.[3–6] There are no approved standard systemic therapies for nccRCC, and prospective controlled trials have been limited. Recommended treatments include vascular endothelial growth factor receptor (VEGFR) TKIs.[1,2,7] Studies have identified potential targets for therapy, including MET alterations in papillary nccRCC.[2] Recently, cabozantinib monotherapy showed promising results in a phase II trial in advanced papillary RCC.[8] Trials with ICI monotherapies have also been reported, but prospective data of TKI-ICI combinations are lacking.[9–11]

Cabozantinib is a multitargeted TKI that inhibits receptor tyrosine kinases involved in tumor cell growth, angiogenesis, metastasis, and immune-cell function, including VEGFR, MET, and the TAM family of kinases (TYRO3, AXL, and MER).[12] Cabozantinib was approved for use as a single agent in patients with advanced RCC based on improved outcomes versus standard of care in the randomized CABOSUN (phase II) and METEOR (phase III) studies in the first-line and second-line settings, respectively.[13,14] In retrospective studies, cabozantinib also demonstrated clinically meaningful benefit across subtypes of nccRCC.[15,16] The recent randomized, phase II PAPMET study in patients with metastatic papillary RCC demonstrated improved progression-free survival (PFS) and objective response rate (ORR) with cabozantinib versus sunitinib.[8]

Cabozantinib may promote an immune-permissive environment that enhances response to ICIs.[17–20] In preclinical models, cabozantinib synergized with ICIs to inhibit tumor growth and mitigate immunosuppression;[18] and in clinical studies, cabozantinib increased the numbers of tumor-infiltrating cytotoxic T cells and reduced immunosuppressive cells.[17,20] These studies provided the rationale to combine cabozantinib with immunotherapy.[21] Recently, cabozantinib in combination with the programmed cell death protein-1 inhibitor nivolumab was approved as a first-line therapy for patients with advanced ccRCC based on outcomes from the phase III CheckMate 9ER study, which showed improved PFS, overall survival, and ORR with the combination therapy versus sunitinib.[6]

COSMIC-021 is a multinational phase Ib study evaluating cabozantinib in combination with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab in advanced solid tumors, including RCC. Atezolizumab has demonstrated single-agent activity in patients with advanced ccRCC,[22] and first-line atezolizumab plus bevacizumab, an anti-VEGF antibody, demonstrated improved PFS versus sunitinib.[23]

Cabozantinib plus atezolizumab showed encouraging antitumor activity in patients with ccRCC in the dose-escalation stage of COSMIC-021[24] and in expansion cohorts of other solid tumors.[25,26] Here, we report results for all patients with ccRCC and nccRCC enrolled in the study.