July 2015, Special ASCO Edition
Combination Immunotherapy Superior to Monotherapy in Patients with Melanoma
Combination treatment with the immunotherapies nivolumab and ipilimumab led to a doubling in progression-free survival (PFS) compared with ipilimumab alone in patients with advanced melanoma, investigators from the CheckMate 067 trial reported.
The study also suggested promise for programmed death-1 (PD-1) ligand 1 (PD-L1) as a biomarker of response that could help determine whether patients would benefit most from 1 or from 2 forms of immunotherapy, said Jedd D. Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, New York City.
â€śBased upon the available evidence, the combination represents a means to improve outcomes, versus nivolumab alone, particularly for patients whose tumors have <5% PD-L1 expression,â€ť Wolchok said.
Patients who expressed PD-L1 derived essentially as much benefit from single-agent nivolumab as from the combination of nivolumab and ipilimumab, he said.
The important findings were presented at a plenary session at ASCO 2015. Results of the phase 2 clinical trial were presented earlier this year.
The CheckMate 067 Phase 3 Trial
CheckMate 067 was the first phase 3 clinical trial to evaluate the combination of a PD-1 inhibitor and a cytotoxic T-lymphocyte antigen-4 inhibitor. The trial randomized 945 treatment-naive patients with advanced or metastatic melanoma in a 1:1:1 fashion to 1 of 3 arms: 1) nivolumab 1 mg/kg every 2 weeks plus ipilimumab 3 mg/kg every 3 week for 4 doses, followed by nivolumab 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 4 doses plus placebo, until disease progression or unacceptable toxicity.
The studyâ€™s coprimary end points were PFS with nivolumab alone and PFS with nivolumab plus ipilimumab versus ipilimumab alone.
â€śNivolumab alone and nivolumab plus ipilimumab significantly improved progression-free survival and objective response rates versus ipilimumab alone in patients with previously untreated melanoma,â€ť Wolchok said.
In the overall population, the median PFS was 11.5 months with the combination (hazard ratio [HR], 0.42 vs ipilimuÂmab; P <.001), 6.9 months with nivolumab alone (HR, 0.57 vs ipilimumab; P <.001), and 2.9 months with ipilimumab alone.
The combination also produced a higher response rate of 57.6% versus 43.7% with nivolumab alone and 19.0% for ipilimumab alone; both nivolumab-containing arms were statistically significant versus the ipilimumab monotherapy arm (P <.001).
The duration of response in all 3 arms was not yet reached at a minimum follow-up of 9 months. The median change in tumor burden was â€“51.9% with the combination, â€“34.5% with nivolumab alone, and +5.9% with ipilimumab alone.
The Importance of PD-L1 Expression
PD-L1 expression defined a group of patients with melanoma whose outcomes were different from the overall study population. In patients whose tumors had at least a 5% PD-L1 expression, nivolumab alone and nivolumab plus ipilimumab resulted in a similar prolongation in PFS, 14 months in each arm, versus 3.9 months with ipilimumab alone, Wolchok reported.
Steven Oâ€™Day, MD, a melanoma expert, commented, â€śRight now, in PD-L1â€“positive patients, we can be fairly reassured that their progression-free survival will be very similar,â€ť whether they receive a single-agent antiâ€“PD-1 agent or 2 immunotherapies together.
The dual immunotherapy regimen proved to be relatively well tolerated, although 55% of patients had grade 3/4 adverse events compared with 16.3% of patients receiving nivolumab and 27.3% receiving ipilimumab, Wolchok reported. These side effects were consistent with previous reports.
â€śWe had no drug-related deaths in the combination arm. This is a very important point, because the trial was conducted in 137 sites globally. Safety guidelines were put into place so that physicians in a variety of venues were able to handle the side effects,â€ť he said.
Michael B. Atkins, MD, Deputy Director, Georgetown-Lombardi Cancer Center, Washington, DC, discussed CheckMate 067 at the plenary session, commenting, â€śNivolumab and nivoluÂmab plus ipilimumab are superior to ipiÂlimumab. These treatments (along with pembrolizumab) are a new standard for advanced melanoma therapy.â€ť
However, Atkins objected to the concept of PD-L1 as a biomarker, at least at this point. â€śPD-L1 must be viewed as a weak biomarker,â€ť he maintained.
For a number of reasons, he said, PD-L1 and its assays need to be validated before PD-L1 can be used for clinical decision making.
Atkins added that based on available data on the 2 PD-1 inhibitors, nivoluÂmab and pembrolizumab have no â€śclear-cut distinction of therapeutic index.â€ť
In the absence of a clinical trial, he believes physicians will choose them based on factors such as dosing schedule, clinical experience, marketing, predictability of biomarkers, and cost.
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