26Subgroup analysis of the efficacy and safety of cabozantinib ± atezolizumab in patients from CONTACT-03 who received first-line treatment with immuno-oncology–based combinations

Abstract Background Cabozantinib, a tyrosine kinase inhibitor (TKI) that targets multiple kinases, including vascular endothelial growth factor receptor, is a preferred treatment option for patients with previously treated advanced renal cell carcinoma (RCC); however, its effectiveness after treatment with first-line immuno-oncology (IO)-based combinations is not fully understood. The efficacy and safety of second-line cabozantinib, with or without atezolizumab, were evaluated in the multicenter, randomized, phase 3 CONTACT-03 study (Pal et al., Lancet 2023; ClinicalTrials.gov: NCT04338269). Here, we report the results of a post hoc analysis of patients from CONTACT-03 who received contemporary IO–IO or IO–TKI combination regimens in the first-line setting. Methods In CONTACT-03, adults with metastatic RCC and disease progression on or after IO-based regimens were randomized to oral cabozantinib 60 mg once daily alone or with atezolizumab 1200 mg intravenously every 3 weeks. The current analysis evaluated progression-free survival (PFS) by blinded independent central review (BICR), overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety in the subgroup of patients who received first-line standard-of-care IO–IO (ipilimumab–nivolumab) or IO–TKI (avelumab–axitinib, pembrolizumab–axitinib, or pembrolizumab–lenvatinib) combinations prior to enrolling in CONTACT-03. Results Of 522 patients enrolled in CONTACT-03, 107 and 129 in the cabozantinib and cabozantinib plus atezolizumab arms, respectively, received prior treatment with first-line IO–IO or IO–TKI combinations. Efficacy outcomes were comparable between treatments. For cabozantinib and cabozantinib plus atezolizumab, respectively, median PFS by BICR was 10.4 months (95% confidence interval [CI], 7.95–12.45) and 10.2 months (95% CI, 8.34–10.64), and median OS was not estimable (NE; 95% CI, 18.30–NE) and 24.3 months (95% CI, 20.24–NE). The ORR was 36% with cabozantinib and 37% with cabozantinib plus atezolizumab (all partial responses); 50% and 52% of patients had a best response of stable disease, and 10% and 5% had progressive disease, respectively. The median DOR was 15.1 months (95% CI, 10.28–NE) with cabozantinib and 10.5 months (95% CI, 7.95–NE) with cabozantinib plus atezolizumab. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 48% of patients treated with cabozantinib and in 58% of those treated with cabozantinib plus atezolizumab; serious TRAEs were reported in 13% and 25% of patients, respectively. Dose modifications due to adverse events were reported in 87% of patients treated with cabozantinib and in 92% of those treated with cabozantinib plus atezolizumab; discontinuation of treatment due to adverse events occurred in 5% and 17% of patients, respectively. Conclusions From this post hoc subgroup analysis of CONTACT-03 can help inform treatment decisions for patients with disease progression on first-line IO-containing combinations. The data suggest that second-line cabozantinib is effective in patients with advanced RCC previously treated with contemporary first-line IO–IO or IO–TKI regimens. Safety outcomes were consistent with the overall study population.