Nivolumab Shows Activity in Ipilimumab-Refractory or -Naive Melanoma in Phase I Trial
In a phase I trial reported in the Journal of Clinical Oncology, Jeffrey S. Weber, MD, of the H. Lee Moffitt Cancer Center and Research Institute, and colleagues assessed the effects of nivolumab—a human immunoglobulin G4-blocking antibody against the T-cell programmed death 1 checkpoint protein—with or without a peptide vaccine in patients with ipilimumab-refractory or -naive melanoma. They found that nivolumab with or without vaccine was safe and well tolerated and could induce enduring responses. They also observed that responses to ipilimumab could be achieved in nivolumab-refractory patients.
Study Details
The study involved 90 patients with unresectable stage III or IV melanoma who were ipilimumab-naive and had shown disease progression after at least one prior therapy (cohorts 1 to 3, n = 34) or experienced progression after prior ipilimumab (cohorts 4 to 6, n = 56).
The nivolumab dose was 1, 3, and 10 mg/kg in ipilimumab-naive cohorts 1 (n = 10), 2 (n = 13), and 3 (n = 11), respectively, with all patients in these cohorts receiving an HLA-A*0201-restricted multipeptide vaccine. The nivolumab dose was 3 mg/kg in ipilimumab-refractory cohorts 4 (n = 10), 5 (n =5), and 6 (n = 41), with only patients in cohort 6 not receiving peptide vaccine. Nivolumab was given every 2 weeks for 24 weeks and then every 12 weeks for up to 2 years.
Responses
The objective response rate in ipilimumab-naive patients was 24% (including two complete responses), with a disease control rate of 45%. At a median follow-up of 21.2 months, median response duration in responders had not been reached (range, 24 to 140+ weeks). In ipilimumab-refractory patients, the objective response rate was 26% and disease control rate was 47%. At median follow-up of 8.4 months, median response duration in responders had not been reached (range, 12+ to 60+ weeks). In cohort 6, the objective response rate was 26% and disease control rate was 44%.
Markers
PD-L1 tumor staining was significantly associated with response to nivolumab (P = .004), but negative staining did not predict absence of response. High baseline NY-ESO-1–specific (P < .001) and MART-1–specific CD8-positive T-cell levels (P = .003) were significantly associated with disease progression. Levels of MART-1–specific CD8-positive T cells increased in patients with response or stable disease at 12 weeks and decreased significantly in nonresponders, but this effect was not significant after adjustment for multiple comparisons. Levels of regulatory T cells decreased in patients with response or stable disease and significantly increased in nonresponders at 12 weeks (P = .009).
Ipilimumab Responses in Nivolumab-Refractory Patients
An unplanned analysis in 12 patients who received ipilimumab at 3 mg/kg for a planned four doses after progression in cohorts 1 to 3 showed partial response in two patients, mixed response in two, and progression in eight.
Toxicities
The most common adverse events were fatigue in all cohorts and injection site reactions from vaccine in cohorts 1 to 5. Most adverse events were mild to moderate and readily managed. One dose-limiting toxicity (grade 3 bilateral optic neuritis at 3 mg/kg in cohort 2) was observed in patients in cohorts 1 to 3.Two other patients in these cohorts discontinued study treatment due to toxicity (grade 3 fever and grade 3 pneumonitis) after the 12-week dose-limiting toxicity period. One dose-limiting toxicity (grade 3 rash) was observed in cohorts 4 to 6, and grade 3 pneumonitis was observed in another patient after the dose-limiting toxicity period. No dose-limiting colitis was observed during the study.
The investigators concluded, “In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.”
The study was supported by Bristol-Myers Squibb, a National Cancer Institute Grant, and the Donald A. Adam Comprehensive Melanoma Research Center.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
