Cabozantinib plus atezolizumab shows potential in advanced urothelial carcinoma
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CHICAGO — Cabozantinib plus atezolizumab showed encouraging clinical activity in patients with inoperable locally advanced or metastatic urothelial carcinoma, according to data from the COSMIC-021 study.
“COSMIC-021 is a study including multiple cohorts and multiple histologies. At this meeting a couple of years ago, we presented data for the combination in patients with advanced urothelial carcinoma previously treated with platinum-containing chemotherapy. Today, we focus on three distinct cohorts,” Sumanta K. Pal, MD, FASCO, from City of Hope Comprehensive Cancer Center, said during a presentation at ASCO Annual Meeting.
In this analysis, Pal and colleagues focused on results from cohorts 3, 4 and 5. Cohort 3 included patients with no prior systemic therapy who were cisplatin-ineligible; cohort 4 included patients with no prior systemic therapy who were cisplatin-eligible; and cohort 5 included patients who had received one prior immune checkpoint inhibitor therapy, had no prior treatment with a VEGF tyrosine kinase inhibitor and had no more than two prior lines of therapy.
To qualify for study inclusion, patients had to have inoperable locally advanced or metastatic urothelial carcinoma with transitional cell histology and an ECOG performance status of 0 or 1. All patients received oral cabozantinib (Cabometyx/Cometrique, Exelixis) 40 mg daily in combination with IV atezolizumab (Tecentriq, Genentech) 1,200 mg every 3 weeks. Patients were followed every 6 weeks during the first year and every 12 weeks thereafter.
Cohorts 3 and 4 included 30 patients and cohort 5 included 31 patients, with the median age ranging from 66 to 74 years. Consistent with this histology, most patients were men. The majority of patients also had an ECOG performance status of 1, and the bladder was the most common site of the primary tumor. Notably, in cohort 5, 32% of patients had received one prior treatment with an immune checkpoint inhibitor and 68% had received two or more prior lines of therapy.
As of Nov. 30, 2021, the median follow-up was 27.9 months in cohort 3, 19.1 months in cohort 4 and 32.9 months in cohort 5.
In cohort 3, the investigator-defined objective response rate — the study’s primary endpoint — was 20%, with one patient (3%) achieving a complete response, and the disease control rate was 80%. In cohort 4, the objective response rate was 30%, with two patients (7%) experiencing a complete response, and the disease control rate was 63%. In cohort 5, the objective response rate was 10%, with no patients achieving a complete response, and the disease control rate was 61%.
The median duration of response was 7.1 months in cohort 3 and 4.1 months in cohort 5. The median duration of response, however, had not yet been achieved in cohort 4, suggesting “some protracted and deep responses in this cohort,” Pal noted.
Reductions in tumor size were also observed in 74% of patients in cohort 3, 62% in cohort 4 and 63% in cohort 5.
The median PFS was 5.6 months in cohort 3, 7.8 months in cohort 4 and 3 months in cohort 5. The median OS was 14.3 months in cohort 3, 13.5 months in cohort 4 and 8.2 months in cohort 5.
The median duration of exposure to cabozantinib plus atezolizumab ranged from 2.8 to 5.3 months. Pal noted that a modest proportion of patients required dose reductions in cabozantinib, and discontinuation due to treatment-related adverse events, for both agents, ranged from 13% to 19% across the three cohorts. The most common treatment-related adverse events included diarrhea, increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, decreased appetite and fatigue.
“Although, I would comment that the rate of grade 3/4 toxicities among these was relatively low, by and large, and notably, there were no grade 5 treatment-related adverse events,” Pal said.
Adverse events of special interest, which occurred in at least 10% of the study population, included AST and ALT increases (hepatitis), pancreatitis, rash and colitis, Pal noted.
Overall, these results appear promising, according to Pal.
“Cabozantinib with atezolizumab demonstrated clinical activity with manageable toxicity in the context of patients with inoperable locally advanced or metastatic urothelial cancer as either first-line systemic therapy in cisplatin-based chemotherapy-eligible or ineligible patients and second- or later-line therapy in patients who received prior immune checkpoint inhibitors,” Pal said.
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Pal SK, et al. Abstract 4504. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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