Safety guidelines were put into place so that physicians in a variety of venues were able to handle the side effects,” he said. This is a very important point, because the trial was conducted in 137 sites globally. “We had no drug-related deaths in the combination arm. Most adverse events were “managed and resolved with established safety guidelines,” he noted. Grade 3/4 treatment-related adverse events, which were consistent with previous reports, occurred in 55% of the combination arm, 16.3% of the nivolumab arm, and 27.3% of the ipilimumab arm. Wolchok emphasized that the combination proved to be relatively well tolerated, as physicians were able to manage the common immune-related toxicities. The median change in tumor burden was −51.9% with the combination, −34.5% with nivolumab alone, and +5.9% with ipilimumab alone.ĭr. “Characteristic of any immunotherapy,” he said, the duration of response in all three arms was not yet reached at a minimum follow-up of 9 months. Complete responses were observed in 11.5%, 8.9%, and 2.2%, respectively. Objective response rates in the intent-to-treat population were 57.6% for the combination, 43.7% with nivolumab alone, and 19.0% for ipilimumab alone for both nivolumab-containing arms, these differences were statistically significant vs ipilimumab ( P <. Steven O’Day, MD, speaking at a press briefing as an ASCO expert in melanoma, commented, “Right now, in PD-L1–positive patients, we can be fairly reassured that their progression-free survival will be very similar” whether they receive a single-agent anti–PD-1 agent or a combined immunotherapy.ĭeaths were reduced by 43% to 58% with the PD-1 inhibitor on board, and in a descriptive analysis, the combination reduced deaths by 26% over nivolumab monotherapy. “Nivolumab plus ipilimumab resulted in numerically longer progression-free survival and a higher response rate, but in patients whose tumors had at least 5% PD-L1 expression, both nivolumab alone and nivolumab/ipilimumab resulted in a similar prolongation in progression-free survival ,” he reported. “Nivolumab alone and nivolumab plus ipilimumab significantly improved progression-free survival and objective response rates vs ipilimumab alone in patients with previously untreated melanoma,” Dr. Results for overall survival will not be reported until after 22 months of follow-up. The study’s coprimary endpoint was progression-free survival for nivolumab alone, and for nivolumab/ipilimumab, vs ipilimumab. Patients were stratified by PD-L1 status (≥ 5% expression was considered positive), BRAF mutation status, and M stage. “Even with a high threshold for positivity, which greatly enriched the biomarker-positive group in this trial, the utility of PD-L1 expression for selecting patients for nivolumab monotherapy, to me, is still unconvincing,” he said.ĬheckMate 067 randomly assigned 945 treatment-naive patients with advanced or metastatic melanoma 1:1:1 to (1) nivolumab (1 mg/kg every 2 weeks) plus ipilimumab (3 mg/kg every 3 weeks for four doses), followed by nivolumumab (3 mg/kg every 2 weeks), (2) nivolumab (3 mg/kg every 2 weeks) plus placebo, or (3) ipilimumab (3 mg/kg every 3 weeks for four doses) plus placebo, until disease progression or unacceptable toxicity. Atkins, MD, Deputy Director of the Lombardi Cancer Center at Georgetown University, a key figure in the PD-1 research story, said much more work is needed before involving PD-L1 expression in patient selection. Some experts, however, were more tempered in their impression of PD-L1 as a potential biomarker. In this study, we see it’s a way to initiate meaningful conversations between patients and clinicians about whether a combination is the right thing for them, vs nivolumab alone,” he told The ASCO Post. “PD-L1 expression is not a binary discriminator of absolute benefit, but this trial is a first effort to try to introduce a precision aspect to immunotherapy. The findings from CheckMate 067, the first phase III trial to evaluate the combination of anti–PD-1 and anti–CTLA-4 agents, were presented at the Plenary Session of the 2015 ASCO Annual Meeting by Jedd Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, New York. That said, single-agent nivolumab proved almost as powerful in patients expressing the programmed cell death ligand 1 (PD-L1). In advanced melanoma, combination treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) more than doubled the median progression-free survival time over ipilimumab alone in the CheckMate 067 trial. PD-L1 expression is not a binary discriminator of absolute benefit, but this trial is a first effort to try to introduce a precision aspect to immunotherapy.
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