Immunotherapy Combination Shows Promise in Bladder Cancer

A high response rate was seen with the immunotherapy combination of Opdivo (nivolumab) and Yervoy (ipilimumab) when compared to historical controls in patients with pretreated metastatic urothelial carcinoma, according to the findings from CheckMate-032, a phase 1/2 study that was presented at Society for Immunotherapy of Cancer (SITC) 31st Annual Meeting and Associated Programs.

In the open-label study, the objective response rate (ORR) for patients receiving Opdivo at 1 mg/kg with Yervoy at 3 mg/kg (26 patients) was 38.5 percent. with a complete response (CR) rate of 3.8 percent. In patients receiving Opdivo at 3 mg/kg and Yervoy at 1 mg/kg (104 patients), the ORR was 26 percent and the CR rate was 2.9 percent.

The median progression-free survival (PFS) in the N1/I3 group was 4.3 months and the median OS was 10.2 months. The median PFS in the N3/I1 arm was 2.6 months 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, M.D., Ph.D., professor at The University of Texas MD Anderson Cancer Center. "The safety profile was consistent between both combination therapy arms."

The three-arm CheckMate-032 study enrolled pretreated patients with locally advanced or metastatic urothelial carcinoma who had progressed on at least one prior lines of chemotherapy, including a platinum-containing regimen. In each combination arm, treatment was administered every three weeks. After four cycles of combination therapy, all patients received Opdivo monotherapy at 3 mg/kg every two weeks. A third arm, not reported at SITC, explored Opdivo monotherapy at 3 mg/kg every two weeks (86 patients).

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 percent at least 65 years of age. The majority of patients had received one to three prior therapies (84.6 percent) and the most common ECOG performance status (PS) was 1 (73.1 percent). In the N3/I1 group, the median age was 63 and 45.2 percent were at least 65 years old. Overall, 78.8 percent of patients had received one to three prior therapies and 61.5 percent had an ECOG PS of 1. The most common site of metastasis was the viscera in both arms (88.5 percent).

In addition to responses, 19.2 percent of patients in the N1/I3 arm had stable disease. The overall disease control rate (DCR) was 57.7 percent. Across all patients in this group, the median reduction in target lesion size was 27.8 percent. The median time to response was 1.4 months and 80 percent of patients had an ongoing response at the time of the analysis.

In the N3/I1 arm, 25 percent of patients had stable disease, for a DCR of 51 percent. When looking at all patients in this arm, the median reduction in target lesion size was 0 percent. The median time to response was 1.4 months and 70 percent of patients had an ongoing response.

In previously reported findings from the monotherapy arm, the ORR was 24.4 percent and the DCR was 52.4 percent. The median OS was 9.7 months and the median PFS was 2.8 months.

In both combination arms, the most common cause of treatment discontinuation was disease progression (38.5 percent in the N1/I3 arm and 64.4 percent in the N3/I1 group). Toxicity led to discontinuation for 7.7 percent of those in the N1/I3 arm and for 13.5 percent of those in the N3/I1 group. After the study, 22.1 percent of patients in the N3/I1 arm received subsequent therapy compared with 7.7 percent of those in the N1/I3 group.

All-grade treatment-related adverse events (AEs) were experienced by 76.9 percent of those in the N1/I3 arm compared with 84.6 percent of those in the N3/I1 arm. The rates of grade 3/4 AEs were similar in each group, at 30.8 percent and 31.7 percent, 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 percent and 28.8 percent), rash (26.9 percent and 16.3 percent), diarrhea (26.9 percent and 23.1 percent), hypothyroidism (15.4 percent and 13.5 percent), hyperthyroidism (0 percent and 12.5 percent), pneumonitis (7.7 percent and 4.8 percent), colitis (3.8 percent and 5.8 percent), elevated ALT (0 percent and 17.3 percent) and elevated AST (0 percent and 11.5 percent).

The most common grade 3/4 AEs in the N1/I3 arm were diarrhea (7.7 percent) and pneumonitis (3.8 percent). In most common grade 3/4 AEs in the N3/I1 arm were elevated ALT (5.8 percent), diarrhea (4.8 percent), colitis (3.8 percent), and elevated AST (3.8 percent). There was one 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 2 CheckMate-275 trial, single-agent Opdivo demonstrated an ORR of 19.6 percent for patients with previously treated metastatic urothelial carcinoma. The median OS with Opdivo monotherapy was 8.74 months and the median PFS was two months.

Based on these data, which were presented at the 2016 ESMO meeting, the FDA granted Opdivo 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.