ESMO Virtual Congress 2020: COSMIC-021, Cabozantinib in Combination with Atezolizumab as First-Line Therapy for Advanced Clear Cell Renal Cell Carcinoma

(UroToday.com) COSMIC-021 is a clinical trial platform testing the combination of the MET/VEGF/TAM kinase inhibitor cabozantinib in combination with the anti-PD-L1 drug atezolizumab. The rationale for this combination is based on data suggesting that cabozantinib promotes an immune-permissive environment that may enhance responses to immune checkpoint blockade, and clinical data showing promising combination activity in multiple tumor types. In this presentation, Dr. Pal shared data from a cohort of COSMIC-021 (NCT03170960) examining the efficacy (by objective response rate) and safety of this drug combination in previously untreated patients with advanced clear-cell renal cell carcinoma (ccRCC).

The study design is shown below. The initial dose of cabozantinib was 40 mg daily, but this was escalated to 60 mg in January 2019. In total, data was presented from 70 ccRCC patients enrolled as of July 21, 2020. Median follow-up was longer in the 40 mg dosing group (25.8 months) as compared to the 60 mg dosing group (15.3 months). 

Patient demographics and characteristics are shown below. The 40 mg cabozantinib group had fewer IMDC favorable risk patients relative to the 60 mg dosing group, and also had more patients with tumors that contained sarcomatoid features.

Tumor responses were determined by investigator. The objective response rates were similar in each cabozantinib dosing group, and each group had a disease control rate of over 90%. Responses appeared durable, with the median duration of response not reached in the 40 mg cabozantinib group.

Importantly, many patients with tumors that contained sarcomatoid features sustained decreases in tumor size on therapy, as shown by the patients denoted with a ‘+’ sign.

The median progression-free survival, and exploratory endpoint in this study, was 19.5 months in the 40 mg cabozantinib group and 15.1 months in the 60 mg cabozantinib group. At the data cut-off, over 40% of patients were still on treatment in each arm. Drug exposure characteristics and patient disposition is shown below.

Treatment related adverse events are noted below. More patients in the 60 mg cabozantinib treatment group had grade ¾ diarrhea. 35% of patients sustained an immune related adverse event. Three patients in the 40 mg group and 9 patients in the 60 mg group required high-dose steroids for management of IrAEs.

For correlative studies, PD-L1 status was assessed using the Ventana SP142 assay given its higher affinity for immune cell PD-L1 expression. The number of CD8 positive T cells was counted in tumor tissue. Tumors with PD-L1 expression and/or high numbers of CD8 T cells were more likely to respond to therapy.

Tumors enriched for T-cells in general were more likely to respond to therapy.

Dr. Pal concluded by suggesting that combination cabozantinib and atezolizumab demonstrated encouraging clinical efficacy with reasonable safety profiles. Correlative studies suggested that PD-L1+ tumors with high CD8+ T cell infiltrates were more likely to respond to therapy. A Phase 3 study (CONTACT-03) is now ongoing to confirm the activity of this combination, comparing cabozantinib +/- atezolizumab in mRCC previously treated with immune checkpoint blockade.

Presented by: Sumanta K. Pal, MD, Clinical Professor, Department of Medical Oncology and Therapeutics Research, and Co-Director of the Kidney Cancer Program, City of Hope, Duarte, California