Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results

Abstract

Purpose: CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.

Methods: Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.

Results: Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.

Conclusion: With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.

Trial registration: ClinicalTrials.gov NCT01928394.

FIG 1.

CONSORT diagram. AE, adverse event; NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks.

FIG 2.

Best tumor change from baseline in target lesion per investigator. NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks.

FIG 3.

Progression-free survival per investigator. NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; PFS, progression-free survival.

FIG 4.

Overall Survival. NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; OS, overall survival.

FIG A1.

Objective response rate by tumor programmed death ligand 1 (PD-L1) expression (A) per investigator and (B) per blinded independent central review. NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; ORR, objective response rate.

FIG A2.

Percent reduction from baseline in target lesions per investigator. Horizontal reference line indicates the 30% reduction consistent with a protocol-defined criteria response. Assessments are per investigator assessment using protocol-defined criteria. Crossover patients are truncated at the crossover date. NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks.

FIG A3.

Time to and duration of response per investigator. NIVO3, nivolumab 3 mg/kg monotherapy every 2 weeks; NIVO3+IPI1, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks; NIVO1+IPI3, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks.

FIG A4.

Progression-free survival (PFS) by tumor programmed death ligand 1 (PD-L1) expression per investigator. (A) NIVO3 (nivolumab 3 mg/kg monotherapy every 2 weeks). (B) NIVO3+IPI1 (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks). (C) NIVO1+IPI3 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks).

FIG A5.

Overall survival (OS) by tumor programmed death ligand 1 (PD-L1) expression. (A) NIVO3 (nivolumab 3 mg/kg monotherapy every 2 weeks). (B) NIVO3+IPI1 (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks). (C) NIVO1+IPI3 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks). NE, not estimable.