SAN FRANCISCO — Immunotherapy targeting the programmed cell death (PD) pathway was associated with better outcomes in patients with metastatic melanoma than any other therapy, a new meta-analysis concludes.
The meta-analysis was featured in a poster presentation here at the Society for Melanoma Research 2015 Congress.
Anti-PD-1 agents might be a better choice as a first-line therapeutic option, according to Seongseok Yun, MD, PhD, an internal medicine resident at the University of Arizona Medical Center in Tucson, and Nicole Vincelette, a PhD student from the Mayo Clinic in Rochester, Minnesota.
Progression-free survival, overall survival, and overall response rate were better in patients treated with anti-PD-1 agents than in those treated with chemotherapy or vaccination.
In subgroup analyses, outcomes were better with anti-PD-1 immunotherapies, such as nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co.), than with anti-CTLA-4 immunotherapies, such as ipilimumab (Yervoy, Bristol-Myers Squibb) and tremelimumab (under development by Pfizer), and outcomes were better with anti-PD-1 immunotherapies and anti-CTLA-4 immunotherapies than with control treatments.
Dr Yun noted that in the CheckMate 067 study, outcomes were significantly better with nivolumab plus ipilimumab than with ipilimumab alone, "which strongly supports our claim."
"At this point, we have very good evidence from randomized trials and meta-analyses that shows that anti-PD-1 therapy may have better efficacy than ipilimumab," he told Medscape Medical News. The next question will be whether nivolumab plus ipilimumab is better than nivolumab alone, he said.
"Apparently, combination treatment is associated with better efficacy — although this needs to be proved by randomized trials — but much higher treatment-related adverse events, which should be balanced with the efficacy," added Dr Yun.
Best Outcomes With Checkpoint Inhibitors
Metastatic cutaneous melanoma generally has a poor prognosis, with a 2-year survival rate of less than 20%, when treated with conventional chemotherapies, the investigators report. But in BRAF-mutant melanoma, targeted therapies, such as BRAF and MEK inhibitors, have demonstrated a significant survival advantage.
In addition, immunotherapy has risen to the forefront of cancer therapy with the blockade of the inhibitory receptors CTLA-4 and PD-1 and the PD ligand 1 (PD-L1); this approach in known as immune-checkpoint blockade.
Recent randomized trials of nivolumab and pembrolizumab have demonstrated a survival advantage in patients who progressed after ipilimumab treatment, the investigators point out. But the degree of clinical benefit from these agents appears to be variable, and seemingly dependent on target pathways and agents.
The pair conducted a systematic review and meta-analysis to compare the efficacy and safety of immune checkpoint inhibitors with conventional chemotherapy or vaccination.
Six phase 2 or 3 randomized controlled trials (three with anti-CTLA-4 immunotherapy and three with anti-PD-1 immunotherapy), with a total of 3196 patients, were selected for the meta-analysis. Of this cohort, 1960 were treated with immunotherapy — 790 with ipilimumab, 327 with tremelimumab, 482 with nivolumab, and 361 with pembrolizumab — and 1236 were treated with chemotherapy — 1100 with dacarbazine, carboplatin, temozolomide, or paclitaxel, and 136 with gp100.
The rate of progression-free survival was better with immune checkpoint inhibitors than with control treatments (28.5% vs 17.7%; relative risk [RR], 0.84; 95% conference interval [CI], 0.76 - 0.93; P = .0004), as was the rate of overall survival (51.2% vs 38.8%; RR, 0.72; 95% CI, 0.59 - 0.88; P = .001), and the overall response rate (23.2% vs 12.0%; RR, 0.86; 95% CI, 0.78 - 0.94; P = .001).
In the subgroup analysis, progression-free survival was better with anti-CTLA-4 therapy than with control treatments, and was better with anti-PD-1 inhibitors than with control treatments. However, there were significant differences in the subgroups; nivolumab or pembrolizumab were favored over ipilimumab or tremelimumab (RR, 0.92 vs 0.74; P < .00001).
For patients treated with nivolumab or pembrolizumab, the overall response rate was better in PD-L1-positive and ipilimumab-naïve patients than in PD-L1-negative patients (RR, 0.57 vs 0.84; P = .001) and ipilimumab-refractory patients (RR, 0.64 vs 0.80; P = .03). BRAF mutation status did not have any prognostic impact on the rate of overall response.
This work was supported by predoctoral fellowships to Ms Vincelette from the Mayo Foundation for Education and Research and a Bressler Alpert Society research grant from the University of Arizona to Dr Yun.
Society for Melanoma Research (SMR) 2015 Congress. Presented November 18, 2015.