Padmanee Sharma, MD, PhD
The combination of nivolumab and ipilimumab led to a high response rate and improved overall survival (OS) versus historical controls for patients with pretreated metastatic urothelial carcinoma, according to findings from the phase I/II CheckMate-032 study presented at the Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting and Associated Programs.1
In the open-label study, the objective response rate (ORR) for patients receiving nivolumab at 1 mg/kg with ipilimumab at 3 mg/kg (N1/I3; n = 26) was 38.5% (95% CI, 20.2-59.4), with a complete response (CR) rate of 3.8%. In patients receiving nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg (N3/I1; n = 104), the ORR was 26% (95% CI, 17.9-35.5) and the CR rate was 2.9%.
The median progression-free survival (PFS) in the N1/I3 group was 4.3 months (95% CI, 1.6-8.2) and the median OS was 10.2 months (95% CI, 4.5-NR). The median PFS in the N3/I1 arm was 2.6 months (95% CI, 1.4-3.9) and the median OS was 7.3 months (5.6-11.4).
"Nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg led to higher rates of response and median OS than nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg, nivolumab monotherapy, and historical control," said lead investigator Padmanee Sharma, MD, PhD, professor at The University of Texas MD Anderson Cancer Center. "The safety profile was consistent between both combination therapy arms."
The 3-arm CheckMate-032 study enrolled pretreated patients with locally advanced or metastatic urothelial carcinoma who had progressed on ≥1 prior lines of chemotherapy, including a platinum-containing regimen. In each combination arm, treatment was administered every 3 weeks. After 4 cycles of combination therapy, all patients received nivolumab monotherapy at 3 mg/kg every 2 weeks. A third arm, not reported at SITC, explored nivolumab monotherapy at 3 mg/kg every 2 weeks (n = 86).
The median follow-up in the N1/I3 arm was 7.8 months. In the N3/I1 arm, the median follow-up was 16.7 months. Treatment beyond progression was permitted in the study, if a clinical benefit was noted.
In the N1/I3 arm, the median age of patients was 64 years, with 50% ≥65 years of age. The majority of patients had received 1 to 3 prior therapies (84.6%) and the most common ECOG performance status (PS) was 1 (73.1%). In the N3/I1 group, the median age was 63 and 45.2% were ≥65 years old. Overall, 78.8% of patients had received 1 to 3 prior therapies and 61.5% had an ECOG PS of 1. The most common site of metastasis was the viscera in both arms (88.5%).
In addition to responses, 19.2% of patients in the N1/I3 arm had stable disease. The overall disease control rate (DCR) was 57.7%. Across all patients in this group, the median reduction in target lesion size was 27.8%. The median time to response was 1.4 months and 80% of patients had an ongoing response at the time of the analysis.
In the N3/I1 arm, 25% of patients had stable disease, for a DCR of 51%. When looking at all patients in this arm, the median reduction in target lesion size was 0%. The median time to response was 1.4 months and 70% of patients had an ongoing response.
In previously reported findings from the monotherapy arm,2
the ORR was 24.4% (95% CI, 15.3-35.4) and the DCR was 52.4%. The median OS was 9.7 months (95% CI, 7.3-16.2) and the median PFS was 2.8 months (95% CI, 1.5-5.9).
In both combination arms, the most common cause of treatment discontinuation was disease progression (38.5% in the N1/I3 arm and 64.4% in the N3/I1 group). Toxicity led to discontinuation for 7.7% of those in the N1/I3 arm and for 13.5% of those in the N3/I1 group. After the study, 22.1% of patients in the N3/I1 arm received subsequent therapy compared with 7.7% of those in the N1/I3 group.
All-grade treatment-related adverse events (AEs) were experienced by 76.9% of those in the N1/I3 arm compared with 84.6% of those in the N3/I1 arm. The rates of grade 3/4 AEs were similar in each group, at 30.8% and 31.7%, for the N1/I3 and N3/N1 arms, respectively.
The most common all-grade AEs in the N1/I3 and N3/I1 groups, respectively, were pruritus (42.3% and 28.8%), rash (26.9% and 16.3%), diarrhea (26.9% and 23.1%), hypothyroidism (15.4% and 13.5%), hyperthyroidism (0% and 12.5%), pneumonitis (7.7% and 4.8%), colitis (3.8% and 5.8%), elevated ALT (0% and 17.3%), and elevated AST (0% and 11.5%).
The most common grade 3/4 AEs in the N1/I3 arm were diarrhea (7.7%) and pneumonitis (3.8%). In most common grade 3/4 AEs in the N3/I1 arm were elevated ALT (5.8%), diarrhea (4.8%), colitis (3.8%), and elevated AST (3.8%). There was 1 treatment-related death in the N3/I1 arm that was related to pneumonitis.
“Earlier this year, we presented encouraging results from this trial for nivolumab monotherapy, and now we are seeing the promise of a combination regimen with nivolumab and ipilimumab for previously treated patients with this common type of advanced bladder cancer," said Sharma. "These findings support the need for further study of combination therapy to assess outcomes and potential survival in patients with metastatic urothelial carcinoma.”
In the phase II CheckMate-275 trial, single-agent nivolumab demonstrated an ORR of 19.6% for patients with previously treated metastatic urothelial carcinoma. The median OS with nivolumab monotherapy was 8.74 months and the median PFS was 2 months (95% CI, 1.87-2.63).3
Based on these data, which were presented at the 2016 ESMO meeting, the FDA granted nivolumab a priority review for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-based regimen. The agency is expected to make a decision on the application by March 2, 2017.
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- Sharma P, Callahan MK, Calvo E, et al. Efficacy and safety of nivolumab plus ipilimumab in previously treated metastatic urothelial carcinoma: First results from the phase I/II CheckMate 032 study. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD.
- Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 2016;17(11):1590-1598.
- Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.