In the COSMIC-021 study (NCT03170960), a multicenter, phase 1b, open-label study, the combination of cabozantinib (Cabometyx®; Exelixis) plus atezolizumab (Tecentriq®; Genentech/Roche) demonstrated encouraging clinical activity in patients with advanced renal cell carcinoma (RCC). Robust clinical activity was observed across dose levels and histologic subtypes. The safety profile with the combination was tolerable with dose modification and comparable to previous reports.
The findings of the study were published by Sumanta K. Pal, MD, Clinical Professor, Department of Medical Oncology & Therapeutics Research; Co-director, Kidney Cancer Program, City of Hope Comprehensive Cancer Center in Duarte, CA, USA, and colleagues on September 7, 2021, in the Journal of Clinical Oncology (JCO).
Renal Cell Carcinoma
Renal cell carcinoma or RCCs, which originate within the renal cortex, is responsible for 80 to 85% of all primary renal neoplasms. The next most common renal neoplasms are transitional cell carcinomas of the renal pelvis (approximately 8%), with other parenchymal epithelial tumors, including oncocytomas, collecting duct tumors, and renal sarcomas, occurring infrequently.
Nephroblastoma, also known as Wilms tumor, is common in children, making up between 5% and 6% of all primary renal tumors, while renal medullary carcinoma is considered a rare form of RCC seen in patients diagnosed with sickle cell disease.
The incidence of renal cell carcinoma varies from region to region. In the United States, there are approximately 76,000 new cases and almost 14,000 deaths from RCC each year.  Worldwide, there are over 400,000 new cases of RCC and over 170,000 deaths each year due to kidney cancer.
Advanced Solid Tumors
COSMIC-021 is evaluating the combination of cabozantinib plus atezolizumab in patients with various advanced solid tumors, including clear cell and non–clear cell RCC. Cabozantinib plus atezolizumab showed encouraging antitumor activity in patients with clear cell RCC in the dose-escalation stage of COSMIC-021 and in expansion cohorts of other solid tumors. In the latest article published in the JCO, the study team reports the results for all patients with advanced clear cell RCC and non-clear cell RCC enrolled in the study.
This phase Ib study enrolled adult patients with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for clear cell RCC, but it was allowed for non-clear cell RCC. Patients received oral cabozantinib 40 mg once a day (clear cell RCC and non-clear cell RCC) or 60 mg once a day (clear cell RCC only) plus 1,200 mg of atezolizumab intravenously, once every 3 weeks.
The study’s primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. The secondary endpoint was safety.
In total, 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40 mg clear cell RCC, 60 mg clear cell RCC, and non-clear cell RCC groups, respectively.
The ORR was 53% (80% confidence interval [CI] 41 to 65) in the 40 mg clear cell RCC group and 58% (80% CI 46 to 70) in the 60 mg clear cell RCC group, with a complete response of 3% and 11%, respectively. Median progression-free survival (mPFS) which was exploratory endpoint was 19.5 and 15.1 months. In non-clear cell RCC group, ORR was 31% (80% CI 20 to 44), all partial responses; mPFS was 9.5 months.
Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40 mg clear cell RCC group, 67% in the 60 mg clear cell RCC group, and 38% in the non-clear cell RCC group. TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs.
The study’s authors concluded that the combination of cabozantinib plus atezolizumab demonstrated encouraging antitumor activity across clear cell RCC and non-clear cell RCC histologies. They also noted that the combination showed a tolerable safety profile. Side effects were managed with dose modifications and supportive care measures.
Based on these results, the investigators believe that further evaluation of cabozantinib plus atezolizumab in RCC is ongoing in the phase III CONTACT-03 study (NCT04338269) is warranted. The CONTACT-03 study will evaluate cabozantinib plus atezolizumab compared with cabozantinib alone in patients with clear cell RCC and non-clear cell RCC who received prior immune checkpoint inhibitor as a first- or second-line treatment.
Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors- NCT03170960
A Study of Atezolizumab in Combination With Cabozantinib Compared to Cabozantinib Alone in Participants With Advanced Renal Cell Carcinoma After Immune Checkpoint Inhibitor Treatment (CONTACT-03) – NCT04338269
 Pal SK, McGregor B, Suárez C, Tsao CK, Kelly W, Vaishampayan U, Pagliaro L, Maughan BL, Loriot Y, Castellano D, Srinivas S, et al. Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study. J Clin Oncol. 2021 Sep 7:JCO2100939. doi: 10.1200/JCO.21.00939. Epub ahead of print. PMID: 34491815.
 Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010 May;7(5):245-57. doi: 10.1038/nrurol.2010.46. PMID: 20448658; PMCID: PMC3012455.
 Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. Erratum in: CA Cancer J Clin. 2021 Jul;71(4):359. PMID: 33433946.
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