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.

Case Report: TFE3 Positive Xp11.2 Translocation Renal Cell Carcinoma (TRCC) – A Case Study and Review of the Literature

“…However, the study exclusively involved patients with papillary RCC, so the results cannot be extrapolated to other subtypes ( 32 ). Treatment with cabozantinib (40 mg QD orally) in combination with atezolizumab (1200 mg iv Q3W) assessed in the COSMIC-021 study ( 33 ) was associated with an ORR of 27% (95% CI 19%–36%) across all non-clear RCC histologies (of 112 patients, 66 (59%) had papillary RCC, 17 (15%) had TRCC, 15 (13%) were unclassified, ten (9%) had the chromophobe subtype, and four (4%) had collecting duct histology). Among the 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (22%) and MET (20%), and responses were seen irrespective of mutational status.…”

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

“…Recently, their study reported that cabozantinib combined with atezolizumab showed encouraging efficacy and acceptable tolerability in advanced clear cell and nonclear cell renal cell carcinoma. 499…”

From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma

“…Anti-angiogenesis TKIs have a clear role in the treatment of RCC and display multifaceted immunomodulatory properties. Current clinical combination approaches in development include: TKI with a single ICI in multiple disease settings [31,[173][174][175][176][177], triple therapy with TKI plus dual ICI/ICI [176,178], adding cabozantinib to nivolumab as maintenance in patients who had clinical benefit to first-line ipilimumab plus nivolumab [179], and using ICI/TKI as a second-line treatment for patients who previously received ICI [180]. In addition, TKI combination approaches are also in development for those with non-ccRCC, including combining the MET-TKI savolitinib with durvalumab [181].…”