ASCO 2022: Results From Cohorts 3, 4, 5 of the COSMIC-021 Study - Cabozantinib in Combination With Atezolizumab in Urothelial Carcinoma

( 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.


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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.

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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.

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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.

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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.

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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.

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Common adverse events related to treatment included diarrhea, transaminitis, decreased appetite and fatigue. No grade 5 treatment related adverse events were observed.

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Additional rates adverse events of interest were reported, including pancreatitis, though this may have included patients with asymptomatic elevations or amylase and lipase.

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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.