Results of a phase 1/2 study that investigated 2 dosing regimens of 2 immunotherapies—the PD-1 inhibitor nivolumab (Opdivo) plus the CTLA-4 inhibitor ipilimumab (Yervoy)—in patients with previously treated metastatic urothelial carcinoma showed higher response rates and longer median overall survival with the regimen of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg than with the dosing of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.
This study is the first to assess combination immunotherapy in patients with metastatic urothelial carcinoma, said Padmanee Sharma, MD, University of Texas M.D. Anderson Cancer Center, Houston, at the 2016 Society for Immunotherapy of Cancer meeting.
In patients with previously treated metastatic urothelial cancer, chemotherapy is associated with poor efficacy and significant toxicity, Dr Sharma said. Monotherapy clinical trials with nivolumab have shown notable antitumor activity in patients with previously treated metastatic urothelial cancer, with an overall response rate of 19.6% and a median overall survival of 8.7 months.
A phase 2 study demonstrated efficacy for all subgroups of patients with metastatic urothelial cancer and PD-L1 expression. In other studies, clinical data with a combination regimen of nivolumab plus ipilimumab have shown improved antitumor activity in patients with advanced melanoma, non−small-cell lung cancer, or metastatic renal-cell carcinoma.
The CheckMate-032 Clinical Trial
In the CheckMate-032 clinical trial, 28 patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 104 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 cycles; both treatment groups received maintenance therapy with nivolumab 3 mg/kg every 2 weeks. The primary end point was investigator-assessed overall response rate that was confirmed by Response Evaluation Criteria in Solid Tumors version 1.1.
Overall, 50% of patients who received the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg regimen had a median age of ≥65 years versus 45.2% of patients who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. In both treatment groups, approximately 60% of patients received ≥2 previous regimens, and 88.5% of patients had visceral metastases. PD-L1 expression was ≥1% in 38.5% of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg compared with 28.8% of patients who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.
Overall, 46.2% of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg continued treatment compared with 14.4% of patients who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg; the discontinuation because of disease progression was 38.5% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg versus 64.4% with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Treatment-related adverse events led to treatment discontinuation in 7.7% of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg versus 13.5% of those who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.
Elevated ALT and AST levels were more common with the higher nivolumab dose (17.3% vs 0% and 11.5% vs 0%, respectively).
“Grade 3/4 adverse event rates were around 30% and very similar for both groups,” Dr Sharma added.
Response and Survival Rates
The confirmed overall response rate was 38.5% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (95% confidence interval [CI], 20.2-59.4) versus 26% with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (95% CI, 17.9-35.5).
“It’s very important to note the overall response rate compared to the 19% with nivolumab monotherapy reported in the Lancet Oncology, and the 15% rate previously reported for atezolizumab [Tecentriq]. Historical controls are 10% or less,” said Dr Sharma.
Although the cohort size is small, these findings are “very promising,” she emphasized, noting that the nivolumab monotherapy findings had previously been reported (Sharma P, et al. Lancet Oncol. 2016;17:1590-1598), she said.
The complete response rates in the CheckMate-032 trial were 3.8% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg versus 2.9% with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. In addition, partial response rates were 34.6% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg versus 23.1% with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, although progressive disease was higher with the lower ipilimumab-dose regimen (41.3%) than with the higher ipilimumab-dose regimen (26.9%).
The median tumor change was a reduction of 27.8% from baseline in the target lesion with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg versus no tumor change with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Although the median time to response was similar (ie, 1.4 months) in both groups, the ongoing response rates were higher with the higher ipilimumab-dose regimen (80%) versus the lower ipilimumab-dose regimen (70%), as were the median progression-free survival (4.3 months vs 2.6 months, respectively) and the median overall survival (10.2 months vs 7.3 months, respectively).
Practical Implications
“Efficacy with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg did not appear to differentiate with nivolumab monotherapy,” Dr Sharma said.
In response to a question regarding the possible benefit of using ipilimumab 10 mg/kg, Dr Sharma noted that “with ipilimumab 3 mg/kg, you get the same T-cell activation as with ipilimumab 10 mg/kg. Our monitoring showed, however, that ipilimumab 1 mg/kg does not give you the same level of T-cell activation as with 3 mg/kg, which would not give you the same level of antitumor response.”
“These results support further development of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for metastatic urothelial cancer,” Dr Sharma concluded. The cohort receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg is being expanded to 92 patients, she said.