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CHICAGO -- An immunotherapy combination for untreated melanoma reduced the risk of death or progression by more than half as compared with a drug currently used as a standard of care, a large randomized trial showed.

Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months -- more than four times greater than the PFS of patients who received only ipilimumab -- among patients whose tumors tested positive for programmed death receptor ligand 1 (PD-L1), the target of nivolumab.

The PFS improvement came at a price of increased toxicity, as grade 3/4 adverse events occurred twice as often with the combination as with ipilimumab monotherapy, but even patients who discontinued treatment because of side effects did better with the combination, as reported here at the American Society of Clinical Oncology meeting.

"The majority of adverse events were managed and resolved with established algorithms, so based upon the available evidence, the combination represents a means to improve outcomes, particularly for patients whose tumors have less than 5% PD-L1 expression," , of Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing.

The findings were reported simultaneously online in the New England Journal of Medicine. The outcome of the phase III trial corroborates and extends results from a phase II study reported in April, also showing a significant PFS advantage for the combination over ipilimumab alone.

The rationale for combining the two drugs comes from recognition that cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 represent distinct but complementary pathways involved in the negative regulation of anti-tumor immunity. Ipilimumab targets CTLA-4 and nivolumab targets PD-L1. Preclinical and phase I and II clinical studies have consistently shown greater activity (including response, complete response, and survival) with the combination than with ipilimumab alone.

Wolchok reported findings from the first phase III trial to compare nivolumab alone or in combination with ipilimumab versus ipilimumab alone. Investigators in the multicenter trial enrolled almost 1,000 patients with untreated, unresectable, or metastatic melanoma. Patients were randomized to ipilimumab, nivolumab, or the combination. Treatment continued until disease progression or development of unacceptable toxicity.

Data were stratified by PD-L1 expression, BRAF expression, and melanoma stage (by criteria). The trial had co-primary endpoints of PFS and overall survival, and Wolchok reported data for PFS. Secondary endpoints included objective response rate, correlation between PD-L1 expression and efficacy, and safety.

The primary comparison was nivolumab monotherapy and the combination versus ipilimumab alone, which is a current standard of care for the patient population enrolled in the study. The results showed that the combination reduced the hazard for death or progression by 58% versus ipilimumab alone (P<0.00001). Nivolumab alone reduced the hazard by 43% versus ipilimumab (P<0.00001).

An exploratory analysis showed that the combination significantly reduced the hazard for death or progression by 26% versus nivolumab monotherapy (HR 0.74, 95% CI 0.60-0.98).

The level of PD-L1 expression had a major influence on efficacy. Patients whose tumors had expression levels of at least 5% had median PFS of 14.0 months with the combination or nivolumab alone versus 3.9 months with ipilimumab. For tumors with PD-L1 expression <5%, the combination was the clear winner with a median PFS of 11.2 months compared with 5.3 months with nivolumab alone and 2.8 months with ipilimumab monotherapy.

Secondary analyses favored the combination and nivolumab over ipilimumab, including overall response rate (57.6% with the combination, 43.7% with nivolumab alone, and 19.0% with ipilimumab, P<0.001), complete response, and partial response. Median duration of response had yet to be reached in any of the treatment groups but favored the combination (13.1 months) and nivolumab (11.7) over ipilimumab (6.9).

Median reduction in tumor size was 51.9% with the combination, 34.5% with nivolumab, and 5.9% with ipilimumab.

On the basis of the efficacy analysis, the results appeared to be a slam-dunk for the combination. The safety data added a new consideration to the evaluation process.

In the combination arm, 55% of patients had grade 3/4 adverse events, most often diarrhea, elevated liver enzymes, colitis, rash, and fatigue. However, Wolchok emphasized that the rate was in line with earlier studies of the combination. Grade 3/4 adverse events occurred in 16.3% in the nivolumab arm and 27.3% of those treated with ipilimumab alone.

A similar difference existed across treatment groups with respect to the proportion of patients who discontinued because of grade 3/4 adverse events: 29.4% with the combination, 5.1% with nivolumab alone, and 13.2% with ipilimumab alone. However, patients who discontinued the combination had an overall response rate of 68%, and half of the responses occurred after patients stopped treatment, Wolchok said.

The trial had established guidelines for managing adverse effects and stopping treatment, and "clearly, they worked." Overall survival data, which continue to mature, should help inform discussions with patients about choosing between the combination and monotherapy, he added.

"This study highlights just how much progress we've made in the treatment of melanoma," said press briefing moderator , of Northwestern University's Feinberg School of Medicine in Chicago. "Certainly, this is a powerful combination, and it comes with some toxicity, but it is clearly manageable in a global setting.

"The most important thing this study shows is that we are beginning to define which patients may benefit from one drug and those that may benefit from both drugs. That will only inform conversations about toxicity for patients and physicians as they decide the treatment course."

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