Although non–clear-cell renal-cell carcinoma (RCC) makes up approximately 25% of all RCC cases, there are no approved systemic therapies for advanced non–clear-cell RCC.1 In a recent phase 2 trial, the tyrosine kinase inhibitor cabozantinib improved antitumor activity compared with sunitinib in advanced papillary RCC.2 It has been suggested that cabozantinib treatment may increase the immunogenicity of the RCC microenvironment, improving response to immune checkpoint inhibitors.1
In the COSMIC-021 study, once-daily cabozantinib was combined with the checkpoint inhibitor atezolizumab in advanced solid tumors, including clear-cell RCC and non–clear-cell RCC. Cabozantinib was dosed at 40 mg (non–clear-cell RCC and clear-cell RCC) or 60 mg (clear-cell RCC only), whereas atezolizumab 1200 mg was administered once every 3 weeks. Previous systemic therapy was not permitted for clear-cell RCC but was permitted for non–clear-cell RCC. Investigator-assessed objective response rate was the primary end point, and safety was the secondary end point.1
The trial enrolled 70 patients with clear-cell RCC (40 mg, N = 34; 60 mg, N = 36) and 32 patients with non–clear-cell RCC. In the non–clear-cell RCC cohort, 22% of patients had received previous treatment with a tyrosine kinase inhibitor. Median follow-up was 25.8 months for 40-mg clear-cell RCC, 15.3 months for 60-mg clear-cell RCC, and 13.3 months for non–clear-cell RCC.1
Confirmed objective response rate was 53% in the 40-mg clear-cell RCC group (3% complete responses), 58% in the 60-mg clear-cell RCC group (11% complete responses), and 31% in the non–clear-cell RCC group (0 complete responses). Across the various subtypes of non–clear-cell RCC, the highest objective response rate was for those with papillary RCC (47%), and the lowest was for chromophobe RCC (11%). Disease control rates were high across treatment groups: 94% for 40-mg non–clear-cell RCC, 92% for 60-mg clear-cell RCC, and 94% for non–clear-cell RCC.1
Median progression-free survival was 19.5 months for 40-mg clear-cell RCC, 15.1 months for 60-mg clear-cell RCC, and 9.5 months for non–clear-cell RCC. However, the researchers noted that the differences in follow-up times prevent comparisons across groups.1
Grade 3 or 4 treatment-related adverse events were reported in 71% of the 40-mg clear-cell RCC cohort, 67% of the 60-mg clear-cell RCC cohort, and 38% in the non–clear-cell RCC cohort. The most common grade 3 or 4 treatment-related adverse events included hypertension (3%-24%), diarrhea (0%-19%), hypophosphatemia (3%-15%), and increased levels of alanine aminotransferase (3%-14%).1
The researchers concluded that cabozantinib combined with atezolizumab appeared to have antitumor activity in advanced clear-cell RCC and non–clear-cell RCC with good tolerability.1
- Pal SK, McGregor B, Suárez C, et al. Cabozantinib in combination with atezolizumab for advanced renal cell carcinoma: results from the COSMIC-021 study. J Clin Oncol. 2021;39:3725-3736.
- Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomized, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703.