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Dual checkpoint blockade with nivolumab (Opdivo) plus ipilimumab (Yervoy) failed to improve outcomes as adjuvant therapy for resected melanoma over nivolumab alone, the CheckMate 915 trial found.

In the intent-to-treat (ITT) population of more than 1,800 patients with stage IIIB-D/IV melanoma, relapse-free survival (RFS) at 2 years was nearly identical with the combination versus single-agent PD-1 blockade with nivolumab, at 64.6% and 63.2%, respectively (HR 0.92, 95% CI 0.77-1.09), reported Georgina Long, MBBS, PhD, of the University of Sydney.

In the subset with low PD-L1 expression (<1%), RFS at 2 years was 53.6% with nivolumab plus the CTLA-4 checkpoint inhibitor ipilimumab compared to 52.4% with nivolumab alone (HR 0.91, 95% CI 0.73-1.14).

"These results reaffirm nivolumab as an adjuvant standard of care," said Long during her presentation at the American Association for Cancer Research (AACR) virtual meeting.

Prior in advanced melanoma showed that nivolumab-ipilimumab was associated with a numerical advantage in 5-year overall survival compared with nivolumab alone, and suggested that patients with low PD-L1 expression may benefit most from the combination.

But in the current study, both the median treatment duration and cumulative nivolumab dose was far lower in the combination arm (7.6 months and 3,840 mg) compared with the monotherapy arm (11.1 months and 6,240 mg), owing to more than triple the discontinuation rates due to toxicity with nivolumab-ipilimumab (32% vs 10% with nivolumab alone).

Less than half of patients on the combination stayed on therapy for beyond 9 months, compared with two-thirds of those in the nivolumab-alone arm, said Long. Post-hoc analysis showed that patients able to stay on the combination for beyond 6 months fared better than those who stopped before that timepoint (2-year RFS: 79.6% and 74.9%).

AACR discussant Alexander Eggermont, MD, PhD, of Princess Maxima Center for Pediatric Oncology in the Netherlands, pointed out that the dosing for ipilimumab (1 mg/kg every 6 weeks) was six times lower in the current study compared with previous investigations (3 mg/kg every 3 weeks) showing benefit with the combination in the adjuvant setting, such as in resected stage IV melanoma. And this lower maintenance-style dosing has never been established.

"I really think this is the problem," he said. "We should have learned from the that it was enough to just give three to four doses of ipilimumab, that does the trick. Ipi is a remarkable drug and doesn't need maintenance therapy."

Eggermont argued that neoadjuvant therapy with two courses of nivolumab plus ipilimumab in resectable melanoma will move the field forward, and likely improve outcomes as well as reduce surgical morbidity. Various smaller trials -- including and -- have already started to demonstrate impressive results with such an approach, he said.

"That is the future and what will dominate the next 5 years -- more cures, less surgery," he said. "Is there a future for Ipi-nivo? For anti-CTLA-4 plus anti-PD-1? You bet. It's within the new paradigm, and it's going to be the biggest revolution we've seen in many years."

Study Details

CheckMate 915 was a phase III trial that randomized 1,844 patients with completely resected stage IIIB-D/IV melanoma to 1 year of treatment with either nivolumab (240 mg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) or nivolumab alone (480 mg every 4 weeks). The trial was conducted at 122 sites across 19 countries, and patients were stratified by tumor PD-L1 expression and disease stage.

Median age was 55, 57% were men, 38% had low PD-L1 expression (<1%), and about a third had BRAF mutations. Most patients (53%) had stage IIIC tumors, followed by stage IIIB in 31%, stage IIID in 3%, and stage IV tumors in 13%.

Subgroup analyses failed to show any group that significantly benefited with the combination versus monotherapy, including by stage. The 2-year RFS rates were 64.7% and 63.6%, respectively, for patients with stage III disease (HR 0.94, 95% CI 0.80-1.11) and 63.6% versus 61.1% for those with stage IV disease (HR 0.88, 95% CI 0.58-1.32).

An exploratory analysis of distant metastasis-free survival among the stage III group also showed no difference between the combination and monotherapy arms, with 2-year rates of 75.4% versus 77.4% in the ITT population (HR 1.01, 95% CI 0.83-1.23) and 68.4% versus 67.9% in low PD-L1 expressors (HR 0.94, 95% CI 0.70-1.25).

Grade 3/4 treatment-related adverse events (AEs) were far more frequent with the combination (33% vs 13% with monotherapy), and consistent with the past experience with the individual agents. There were four treatment-related deaths with the combination (0.4%) versus none in the monotherapy arm.

Compared with baseline, no clinically meaningful changes in quality of life (either deterioration or improvement) occurred in either treatment arm.

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