(UroToday.com) Cabozantinib is a tyrosine kinase inhibitor against MET, AXL, and VEGFR that is hypothesized to enhance responses to immune checkpoint inhibitors and is approved in combination with the anti-PD-1 agent nivolumab as first line therapy for advanced renal cell carcinoma. COSMIC-021 (NCT03170960) is a multi-malignancy, multi-arm, and multicenter trial evaluating the efficacy of cabozantinib in combination with the anti-PD-L1 agent atezolizumab. Atezolizumab is a monotherapy treatment option in the first line for advanced urothelial cancers in patients felt to be ineligible for platinum-based chemotherapy. At ASCO 2020, Dr. Pal presented data from cohort 2 of this study, which tested the overall response rate of this combination in advanced urothelial cancers that had progressed on or after platinum-based first line therapy. Of the 30 patients in that cohort, there was a 27% overall response rate with two complete responses, and the median progression-free survival was 5.4 months.
In this presentation, Dr. Pal presented results from cohorts 3, 4 and 5 of COSMIC-021. In these cohorts, patients with locally advanced or metastatic transitional cell urothelial carcinoma who were ineligible for surgery were treated with cabozantinib and atezolizumab. Cohort 3 patients were ineligible for cisplatin therapy and had received no prior therapy, Cohort 4 patients were cisplatin eligible but had received no prior therapy, and Cohort 5 patients had received one prior immune checkpoint inhibitor but no prior tyrosine kinase inhibitor against the VEGFR protein. The primary endpoint in these cohorts was overall response rate.
The demographics of the patients enrolled in these arms of the study are shown below. Approximately 30% of patients in each arm had a urothelial cancer arising from outside the bladder.
Regarding the primary outcome, patients who had not received prior immune checkpoint blockade had higher rates of overall response - 20% and 30% in cohort 3 and 4, respectively. The disease control rates were greater than 60% in all three cohorts, including an 80% DCR of 80% in cohort 3.
Using spider and waterfall plots, Dr. Pal then illustrated a few patients in the immune checkpoint-blockade naïve cohorts had deep and so far sustained responses to combination therapy, especially in the cisplatin-eligible cohort 4.
The overall survival curves for these cohorts are shown below. Consistent with response rates, median overall survival was longer in cohorts 3 and 4 relative to cohort 5.
The median duration of exposure to combination therapy was longer in cohorts 3 and 4, and at least a third of patients required dose reduction in cabozantinib due to adverse events.
Common adverse events related to treatment included diarrhea, transaminitis, decreased appetite and fatigue. No grade 5 treatment related adverse events were observed.
Additional rates adverse events of interest were reported, including pancreatitis, though this may have included patients with asymptomatic elevations or amylase and lipase.
Dr. Pal concluded his presentation by stating that cabozantinib in combination with atezolizumab demonstrated clinical activity with expected and manageable toxicity in inoperable advanced urothelial carcinoma as either first-line therapy or in the second-line after prior immune checkpoint blockade.
Presented by: Sumanta K. Pal, FASCO, MD, City of Hope Comprehensive Cancer Center, Duarte, CA
Written by: Alok K. Tewari, MD, PhD, medical oncologist at the Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.