Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

Abstract

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances.

Patients and methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).

Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.

Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

Trial registration: ClinicalTrials.gov NCT02496208.

FIG 1.

Clinical activity of cabozantinib and nivolumab (CaboNivo) and cabozantinib, nivolumab, and ipilimumab (CaboNivoIpi). (A) Plot of confirmed tumor regression from baseline as measured by RECIST in all evaluable patients (n = 49). Upper dotted line represents progression at 20%; lower dotted line represents the RECIST boundary for complete response or partial response at 30%. (*) Patient with 40% increase in longest diameter of targeted lung lesion with cavitation. The protocol prespecified that patients with lung cavitary lesions who are experiencing clinical benefit may be allowed to stay on therapy until they experience disease progression based on noncavitary lung lesions. (B) Time to response, duration of treatment, and duration of response to CaboNivo and CaboNivoIpi (16 confirmed responses as of data cutoff). Numbers represent duration of response in months. IQR, interquartile range; PFS, progression-free survival.

FIG 2.

Kaplan-Meier estimates of (A) progression-free survival (PFS) and (B) overall survival (OS) for overall study population (N = 54). Kaplan-Meier estimates of (C) PFS and (D) OS for responding patients (complete or partial response; n = 15). Vertical lines show censored events.