Dual checkpoint-inhibitor therapy showed greater activity against advanced or metastatic urothelial cancer but imposed more toxicity than a single agent, a preliminary clinical evaluation showed.
Pairing a lower dose of anti-PD-1 agent nivolumab (Opdivo) with a higher dose of the CTLA-4 inhibitor ipilimumab (Yervoy) led to an overall response rate of 38%, as compared with 26-27% with nivolumab alone or a combination that reversed the higher and lower doses of the two checkpoint inhibitors.
“Responses were observed regardless of PD-L1 expression level in all treatment arms,” Padmanee Sharma, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues reported in the Journal of Clinical Oncology.
They said it was “promising” that median overall survival was 15.3 months in this study, with 56.9% of patients surviving to 1 year. This is in contrast with studies of other immune checkpoint inhibitor monotherapies, which have shown survival ranging from 6.5 to 10.5 months and 1-year overall survival rates from 39% to 55%.
Immunotherapies, particularly PD-1-targeted agents, have become the standard of care for previously treated advanced or metastatic urothelial cancer. Now, the benefits observed with single-agent immune checkpoint inhibitors “demand investigations of how outcomes might be improved with combination therapies,” Sharma and coauthors said.
Their results provided support for potentially greater therapeutic benefits with immunotherapy combinations, particularly low-dose nivolumab plus high-dose ipilimumab in the first-line setting for metastatic urothelial carcinoma, the authors concluded.
However, this combination led to grade 3/4 toxicity in 39.1% of patients versus 27% with nivolumab alone and 31% with the lower dose of ipilimumab in the study.
“Any benefits that might be observed with combination therapy have to be carefully balanced against the additional toxicity,” said Sumanta Pal, MD, of the City of Hope in Duarte, California, who was not involved with the study.
The “marginal” benefit seen with the addition of ipilimumab also has to be considered within the context of the considerably higher cost of combination therapy, said Alexander Kutikov, MD, of Fox Chase Cancer Center in Philadelphia. Additionally, the combination will face competition from multiple agents targeting the PD-1 pathway, most notably pembrolizumab (Keytruda), which has the backing of the National Comprehensive Cancer Network guidelines.
“It’s too early to say whether this combination will be the ‘go-to’ regimen or just another option,” Kutikov told MedPage Today. “Time will tell.”
Immunotherapy for Bladder Cancer
The international group of investigators conducted an open-label, multicohort study involving patients with platinum resistant or refractory metastatic urothelial carcinoma.
The primary endpoint was investigator-assessed objective response by RECIST criteria. Three checkpoint inhibitor regimens were evaluated:
- NIVO3+IPI1 (n=104): Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy every 2 weeks
- NIVO1+IPI3 (n=92): Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy every 2 weeks
- NIVO3 (n=78): Single-agent nivolumab 3 mg/kg every 2 weeks
Patients had been randomized to the NIVO3 and NIVO3+IPI1 arms, whereas 86 of 92 patients in the NIVO1+IPI3 cohort were enrolled after the randomized arms had completed enrollment, resulting in different durations of follow-up (median 38-39 months for NIVO3 and NIVO3+IPI1 vs 8 months for NIVO1+IPI3).
Treatment in all three groups continued until disease progression or development of unacceptable toxicity.
Ultimately, patients treated with single-agent nivolumab had a median treatment exposure of 8.5 doses. Nivolumab exposure in both combination arms was four doses, and median exposure to ipilimumab was four doses in the NIVO3+IPI1 arm and three doses in the NIVO1+IPI3 arm.
More than 60% of the patients in each arm had received two or more prior regimens at baseline. Two patients in the NIVO3+IPI1 arm and three in the NIVO1+IPI3 arm had received no prior chemotherapy.
PD-L1 expression status was <1 in 55% of the single-agent nivolumab group, 53.8% in the NIVO3+IPI1 group, and 45.7% in the NIVO1+IPI3 group. The proportion of patients with PD-L1 expression ≥1 ranged from 30-34% across the three groups.
Investigator-reported objective response rates were 25.6% with NIVO3, 26.9% with NIVO3+IPI1, and 38.0% with NIVO1+IPI3. Median response duration exceeded 22 months in all three groups. The median change in tumor size from baseline was +1.9% with NIVO3, 0% with NIVO3+IPI1, and -30% with NIVO1+IPI3.
Median progression-free survival and overall survival favored the NIVO1+IPI3 arm.
- NIVO3: 2.8 months, 9.9 months
- NIVO3+IPI1: 2.6 months, 7.4 months
- NIVO1+IPI3: 4.9 months, 15.3 months
The 12-month overall survival was 47.3% with NIVO3, 38.3% with NIVO3+IPI1, and 56.9% with NIVO1+IPI3.
The most common grade 3/4 adverse events were elevated lipase (6.4%), elevated amylase (5.1%), and maculopapular rash (3.8%) with NIVO3; elevated liver function tests (4-6%), elevated lipase (5.8%) and diarrhea with NIVO3+IPI1; and diarrhea (9.8%), elevated liver function tests (ALT, 6.5%), and elevated lipase (4.3%) with NIVO1+IPI3. One fatal case of pneumonitis occurred in the single-agent nivolumab and NIVO3+IPI3 groups.
Larger randomized trials will provide more information to define the potential role of combination therapies, and this study helps set up phase III randomized comparisons of nivolumab-ipilimumab combination therapy against various single agents that have demonstrated activity in pretreated metastatic bladder cancer, Pal said.
The study was supported by Bristol-Myers Squibb.
Sharma disclosed relationships with Bristol-Myers Squibb, Jounce Therapeutics, Neon Therapeutics, Constellation Pharmaceuticals, Oncolytics, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak Biosciences, ImaginAb, Tvardi Therapeutics, Hummingbird, Optera, Dragonfly Therapeutics, Pieris Pharmaceuticals, and Merck, as well as patent/royalty/intellectual property interests.