Hitting metastatic melanoma with two immunotherapies, each targeted to a different metabolic pathway, has shown some preliminary success in an early study.
Ipilimumab (Yervoy) used in combination with the investigational drug nivolumab shrank stage-III and -IV melanomas in approximately half of 37 evaluable patients in a phase-I study. Tumor reductions of at least 80% were seen at 12 weeks in 11 of 37 (30%) of patients and 90% of all patients who have responded continue to respond to therapy, Dr. Jedd D. Wolchok said at a press briefing sponsored by the American Society of Clinical Oncology highlighting research to be presented at its annual meeting.
Dr. Jedd Wolchok
Phase-I trials are conducted to examine drug safety and give indications of dose ranges; they do not allow conclusions about efficacy. A randomized phase-III trial of the nivolumab/ipilimumab combination as first-line therapy for patients with advanced melanoma is scheduled to begin in June.
Ipilimumab is a CTLA-4 inhibitor approved for the treatment of metastatic melanoma. Nivolumab is an investigational PD-1 inhibitor that has shown activity when used alone against melanoma and other cancers.
"The rapidity and magnitude of the responses are what’s so striking," Dr. Wolchok said. "We were particularly impressed that the drugs work together so well" and show that two immunotherapies offer a promising strategy for advanced melanoma.
For the trial, patients who had inoperable stage-III and stage-IV melanoma and had undergone up to three prior therapies were assigned to one of six treatment arms. Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York, presented results on 37 evaluable patients in three completed treatment arms, in which patients received concurrent treatment with the two drugs.
In the phase-I study, nivolumab and ipilimumab were given every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses. At week 24, patients began to receive one concurrent combination treatment every 3 months.
The first arm of 14 patients received 3 mg/kg of ipilimumab plus 0.3 mg/kg of nivolumab, the second arm of 17 patients received 3 mg/kg of ipilimumab plus 1 mg/kg of nivolumab, and the third arm of 6 patients received 3 mg/kg of ipilimumab plus 3 mg/kg of nivolumab. In those three arms, tumor shrinkage rates were 21%, 47%, and 50%, respectively. Tumor reductions of at least 80% were seen in 29%, 41%, and 0%, respectively.
The responses to therapy were rapid for an immunotherapy – three out of four patients who responded to the concurrent treatment experienced tumor reduction within the first 3 months, which is faster than with single-agent ipilimumab, according to Dr. Wolchok.
Two of the remaining three arms of the study enrolled patients who had undergone prior ipilimumab treatment. Those patients received only nivolumab every 2 weeks for up to 48 treatments. Although the data are still preliminary, 4 of 16 evaluable patients in the study arm given nivolumab at 1 mg/kg had at least 80% tumor shrinkage after 8 weeks, even though they initially had little benefit from ipilimumab.
In the concurrently treated patients, grade 3-4 side effects – primarily due to asymptomatic lipase, AST, and ALT abnormalities – occurred in 28 of 53 patients (53%).
With sequenced treatment, grade 3-4 side effects occurred in 6 of 33 patients (18%).
Side effects were managed using standard protocols and no treatment-related deaths were reported.
The nivolumab/ipilimumab combination also is being investigated in non–small cell lung cancer and renal cell carcinoma.
The research was supported by Bristol-Myers Squibb. Dr. Wolchok serves in consultant or advisory roles with, and receives research funding from, Bristol-Meyers Squibb.