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NEW ORLEANS -- Nivolumab (Opdivo) plus ipilimumab (Yervoy) improved outcomes compared with ipilimumab alone for patients with advanced melanoma who have primary resistance to PD-1 inhibitors, a randomized study found.

While median progression-free survival (PFS) was similar between the two arms of the trial, at 3 months and 2.7 months, respectively, the 6-month PFS rate was 34% with the combination compared with 13% with ipilimumab alone (HR 0.63, 90% CI 0.41-0.97, P=0.04), reported Ari M. VanderWalde, MD, MPH, of the West Cancer Center and Research Institute in Germantown, Tennessee.

These data "support the use of nivolumab plus ipilimumab as next-line treatment in patients whose tumors have not responded to anti-PD-1 therapy alone," he said during a plenary session at the American Association for Cancer Research annual meeting.

The PFS benefit was consistent across different subgroups, with patients who had stage IV disease, no prior adjuvant therapy, or less than 6 months of anti-PD-1 therapy prior to enrollment "doing particularly well," VanderWalde noted:

• Stage IV disease: HR 0.48 (90% CI 0.29-0.79)
• No prior adjuvant therapy: HR 0.53 (90% CI 0.32-0.86)
• Less than 6 months of anti-PD-1: HR 0.48 (90% CI 0.28-0.82)

However, while the 6-month PFS results "look very nice, the durable PFS difference declines to less than 10% by 18 to 24 months. So, an impressive result, but not as we would have liked," said discussant Mario Sznol, MD, of Yale Cancer Center in New Haven, Connecticut.

Of the 69 patients in the combination arm, 13 had a partial response and six had a complete response, for an objective response rate (ORR) of 28%. Two of the 23 patients in the ipilimumab-alone arm had partial responses, for an ORR of 9%. Both responders in the ipilimumab arm had continuing responses as of data cutoff compared with eight of the 19 responders in the combination arm (median duration of response 18.9 months).

The 12-month overall survival (OS) rate was numerically greater in the nivolumab/ipilimumab arm (63% vs 57%), though at a median follow-up of 27.3 months, median OS was numerically longer in the ipilimumab-alone arm (25.7 months) versus the combination arm (21.7 months).

"Given that the study was not powered to detect a difference in overall survival, it is not surprising that no difference in overall survival was seen," VanderWalde pointed out.

Regarding how the trial impacts the standard of care for melanoma, "I think the investigators came to the right conclusion," Sznol said. "But, it does leave unanswered whether these treatments actually do improve survival in this setting."

He pointed out that there are other treatments that can be given in this setting, such as nivolumab combined with the anti-LAG-3 antibody relatlimab (known as Opdualag), which was recently approved by the FDA. "The problem here is that moving forward, much of anti-PD-1 therapy alone in the frontline setting may be replaced by nivolumab/relatlimab," Sznol noted. "We really don't know the activity of ipilimumab alone or ipilimumab plus nivolumab in that setting."

This enrolled 92 patients who were randomized 3:1 to receive ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks up to 2 years (69 patients, median age 64, 67% men), or ipilimumab 3 mg/kg every 3 weeks for four cycles (23 patients, median age 69, 65% men). Median follow-up for the primary endpoint of PFS was 28.3 months.

All patients had stage IV or unresectable stage III melanoma, documented disease progression on treatment or after stopping therapy with anti-PD-1 or anti-PD-L1 agents, no confirmed partial or complete response to these therapies prior to progression, and no prior anti-CTLA-4 therapy such as ipilimumab.

Treatment-related adverse events (TRAEs) of any grade occurred in 93% of patients in the nivolumab/ipilimumab arm and 87% in the ipilimumab-alone arm. More patients in the combination arm experienced grade 3 or higher TRAEs (57% vs 35%, respectively). The most common adverse events in both arms were diarrhea, alanine aminotransferase and aspartate aminotransferase increases, rash, fatigue, anemia, hypotension, and hyponatremia.

The rates of high-grade adverse events seen with these agents are "consistent with what has been previously published," VanderWalde noted.

Regimens of ipilimumab plus nivolumab that incorporate lower doses of ipilimumab "might get the same effect with less toxicity," Sznol suggested. "However, you have to keep in mind there are populations where the dose of ipilimumab may matter more. For example, patients with acral-lentiginous melanoma, mucosal melanomas, where a higher dose of ipilimumab may be more important."

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