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Frontline treatment of unresectable melanoma with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to an unprecedented median overall survival (OS) of 6 years, an updated analysis of a randomized trial showed.

After a minimum follow-up of 6.5 years, patients randomized to nivolumab plus ipilimumab had a median OS of 72.1 months, twice the survival length associated with nivolumab alone (36.9 months) and more than three times longer than the survival associated with ipilimumab alone (19.9 months). Median melanoma-specific survival (MSS) had yet to be reached in the combination arm of the trial as compared with 58.7 and 21.9 months, respectively, for the single-agent nivolumab and ipilimumab arms.

The updated analysis also showed substantially better survival with the combination for patients with or without BRAF-mutant melanoma and for those who discontinued treatment, reported Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and coauthors, in the .

The findings expanded and extended results of previous analyses dating back to the in 2015.

"For the first time, we can estimate a median overall survival for the subset of patients who were randomized to the combination of ipilimumab and nivolumab. Before, the median had not been reached," Wolchok told 名媛直播. "With this six and a half-year follow-up, the median survival for that group is estimated at 72 months."

"The other thing we learned was that we could estimate a melanoma-specific survival," he continued. "We had sort of a unique opportunity because of the long-term follow-up data. The median melanoma-specific survival for that combination group still had not been reached."

The findings came from the landmark CheckMate-067 trial, which showed almost a 50% improvement in progression-free survival (PFS) in the initial report. The trial involved 945 patients with previously untreated unresectable melanoma. They were randomized to the combination, nivolumab alone, or ipilimumab alone. Co-primary endpoints were PFS and OS.

An analysis after continued to show a large survival advantage for the combination over single-agent therapy, but median OS had yet to be reached for the combination arm. A landmark analysis yielded 5-year OS rates of 52% for the combination arm, 44% for nivolumab alone, and 26% for ipilimumab monotherapy.

With the latest analysis, CheckMate-067 claimed the distinction of the longest follow-up for a phase III trial of anti-PD-1/L1 therapy for melanoma. The extended duration of follow-up afforded an opportunity to assess MSS, "which is increasingly valuable in removing non-disease-related deaths that become an increasingly important consideration with long-term follow-up," the authors noted.

After a 77-month minimum follow-up for all patients, key takeaways from the data analysis included:

• Median PFS: 11.5 months with the combination, 6.9 months with nivolumab alone, 2.9 months with single-agent ipilimumab
• PFS rate at 6.5 years: 34%, 29%, and 7%, respectively
• Median OS: 72.1 months, 36.9 months, and 19.9 months
• OS rate at 6.5 years: 49%, 42%, and 23%
• Median MSS: Not reached, 58.7 months, and 21.9 months
• MSS rate at 6.5 years: 56%, 48%, and 27%

Despite the long follow-up and unprecedented survival for unresectable melanoma, the trial did not answer a key question: Which patients need both drugs and who do just as well with single-agent nivolumab?

"We still don't know exactly how to make that decision," said Wolchok. "It's a subject for thoughtful conversations between the care team and the patient and their family. Patients who we are more likely to use the combination with are those who have disease in the bone, liver, or brain, which are traditionally the more challenging sites to treat. Also, those with a high LDH (lactate dehydrogenase)."

"Those patients for whom we are more likely to use single-agent nivolumab are those who have the disease restricted to the lung," he added. "But it is a complex discussion because we don't have a firm binary biomarker."

As for ipilimumab monotherapy, Wolchok said the only patients he would consider for that therapeutic strategy are those who previously progressed after treatment with single-agent anti-PD-1/L1 therapy.

Providing context for the latest published results from CheckMate-067, the authors noted that median survival for unresectable melanoma was 8 months a decade ago.

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