Cabozantinib Plus Atezolizumab for Patients With Advanced Urothelial Carcinoma

According to results from the phase 1b COSMIC-021 trial, cabozantinib plus atezolizumab demonstrated promising clinical efficacy and safety among patients with inoperable, locally advanced or metastatic urothelial carcinoma. 

“Standard-of-care first-line therapy for advanced urothelial carcinoma is pembrolizumab plus enfortumab vedotin regardless of cisplatin eligibility,” stated Sumanta Pal, MD, City of Hope Comprehensive Cancer Center, Duarte, California, and coauthors. “Despite advances in treatment, clinical outcomes for metastatic disease remain poor, with a 5-year survival rate of 8%.” 

In this multicenter, open-label study, researchers enrolled 121 patients into 4 cohorts based on cisplatin eligibility (cisplatin-eligible, n = 30; cisplatin-ineligible, n = 30), prior lines of platinum-containing chemotherapy (n = 30), and prior lines of immune checkpoint inhibitor therapy (n = 31). Patients received 40 mg of once daily cabozantinib plus 1200 mg of atezolizumab once every 3 weeks. The primary end point was investigator-assessed objective response rate (ORR). Key secondary end points included progression-free survival (PFS) and safety. 

At analysis, the ORR was 30% in the cisplatin-eligible arm, 20% in the cisplatin-ineligible arm, 27% in the prior platinum-containing chemotherapy arm, and 10% in the prior immune checkpoint inhibitor arm. Median PFS was 5.5 months, 5.6 months, 5.4 months, and 3 months, respectively. Grade 3/4 treatment-related adverse events were reported in 43% of patients in the cisplatin-eligible arm, 67% of patients in the cisplatin-ineligible arm, 57% of patients in the prior platinum-containing chemotherapy arm, and 45% of patients in the prior immune checkpoint inhibitor arm. Treatment-related adverse events led to discontinuation in 17%, 13%, 3%, and 19% of patients, respectively. No grade 5 events were reported. 

As Dr Pal et al concluded, “Cabozantinib plus atezolizumab demonstrated clinical activity in patients with advanced [urothelial carcinoma] ... Safety with the combination was consistent with previous reports with no new safety signals detected.”

“The COSMIC-021 study supports the further development of [immune checkpoint inhibitor]-tyrosine kinase inhibitor trials in patients with advanced [urothelial carcinoma], especially among patients who are [immune checkpoint inhibitor]-naive,” added Journal of Clinical Oncology associate editor Gary Schwartz, MD, Columbia University Medical Center, New York, New York. 

Source: 

Pal SK, Loriot Y, Necchi A, et al. COSMIC-021 phase Ib study of cabozantinib plus atezolizumab: Results from the locally advanced or metastatic urothelial carcinoma cohorts. J Clin Oncol. Published online: February 18, 2025. doi: 10.1200/JCO-24-01675