COSMIC-021 Phase Ib Study of Cabozantinib Plus Atezolizumab: Results from the Locally Advanced or Metastatic Urothelial Carcinoma Cohorts

Abstract

Purpose: The COSMIC-021 study assessed the safety and efficacy of cabozantinib plus atezolizumab in advanced solid tumors. Presented here are results from the expansion cohorts with advanced urothelial carcinoma (UC).

Methods: This phase Ib study (ClinicalTrials.gov identifier: NCT03170960) enrolled patients with inoperable locally advanced/metastatic UC into four tumor cohorts: first-line cisplatin-eligible (cis-eligible), first-line cisplatin-ineligible (cis-ineligible), previous platinum-containing chemotherapy (previous chemotherapy-treated), and previous immune checkpoint inhibitor (ICI)-treated. Patients received oral cabozantinib 40 mg once daily and intravenous atezolizumab 1,200 mg once every 3 weeks. The primary end point was objective response rate (ORR), as assessed by the investigator per RECIST v1.1 every 6 weeks for 12 months and every 12 weeks thereafter; the secondary end point was safety.

Results: A total of 121 patients (previous ICI-treated cohort, n = 31, and each of the other cohorts, n = 30) received study treatment from March 2018 to November 2021. The ORR (95% CI) was 30% (15 to 49) for cis-eligible, 20% (8 to 39) for cis-ineligible, 27% (12 to 46) for previous chemotherapy-treated, and 10% (2 to 26) for previous ICI-treated cohorts. The median progression-free survival (95% CI) was 5.5 (1.6 to 11.6), 5.6 (3.1 to 11.1), 5.4 (1.6 to 7.6), and 3.0 (1.8 to 5.5) months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) were experienced by 43%, 67%, 57%, and 45% of patients, respectively. TRAEs led to discontinuation of all treatment components in 17%, 13%, 3%, and 19%, respectively. No grade 5 TRAEs were reported in any cohort.

Conclusion: The novel combination of cabozantinib plus atezolizumab exhibited clinical activity in advanced UC that is cis-eligible, cis-ineligible, or previously treated with platinum-containing chemotherapy; clinical activity in previous ICI-treated UC was modest. The toxicity profile was consistent with that previously reported for the combination.

FIG 1.

Flow diagram. AE, adverse event; ICI, immune checkpoint inhibitor.

FIG 2.

Best change from baseline in the sum of diameters of tumor lesions in patients with UC receiving cabozantinib plus atezolizumab who (A) are cis-eligible, (B) are cis-ineligible, (C) received previous chemotherapy, and (D) received previous ICI. Only patients with at least one measurable baseline and postbaseline assessment are shown; the percentages of patients with any reduction are based on the overall safety population. Confirmed CR and PR are shown. cis, cisplatin; CR, complete response; ICI, immune checkpoint inhibitor; PD, progressive disease; PR, partial response; SD, stable disease; UC, urothelial carcinoma.

FIG 3.

PFS and OS for patients with UC receiving cabozantinib plus atezolizumab who (A) are cis-eligible, (B) are cis-ineligible, (C) received previous chemotherapy, and (D) received previous ICI. cis, cisplatin; ICI, immune checkpoint inhibitor; OS, overall survival; PFS, progression-free survival; UC, urothelial carcinoma.

FIG 4.

Association of TMB and PD-L1 scores with clinical outcomes in previous chemotherapy-treated, cis-ineligible, and cis-eligible cohorts of patients with UC receiving cabozantinib plus atezolizumab. Association of median TMB score with (A) response, (B) PFS, and (C) OS. Association of (D) median PD-L1 TPS and (E) median PD-L1 CPS with response. Correlation between TMB score and (F) PD-L1 TPS and (G) PD-L1 CPS. In (A), (D), and (E), the line inside the box represents the median, and lower and upper boundaries of the boxes represent the first and third quartiles, respectively; the whiskers extend from the first or third quartile to the most extreme values within 1.5 times the IQR of the quartiles. In (A), the significance of the difference between the medians of the groups was assessed using a Welch t-test. In (B) and (C), the association between survival and TMB grouping on the basis of the median was assessed using Cox proportional hazards regression. In (D) and (E), the significance of the difference between the medians of the groups was assessed using a Wilcoxon rank-sum test. (F) and (G) evaluate the relationship between TMB and PD-L1 expression on the basis of TPS and CPS scores, respectively. cis, cisplatin; CPS, combined positive score; CR, complete response; HR, hazard ratio; NA, not available; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TMB, tumor mutational burden; TPS, tumor proportion score; UC, urothelial carcinoma.