COSMIC-021: Antitumor Activity with Cabozantinib plus Atezolizumab for Clear-Cell and Non–Clear-Cell Renal-Cell Carcinoma

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

References

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.
2. 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.