Experts Welcome Adjuvant Nivolumab for Melanoma

Liam Davenport

January 19, 2018

Now that it has been approved for adjuvant use in the treatment of melanoma, nivolumab (Opdivo, Bristol-Myers Squibb) is likely to become the new standard of care in this setting, says an expert involved with its development.

Nivolumab is a programmed cell death–1 (PD-1) immune checkpoint inhibitor. its indication was recently extended to include use in patients with stage III or IV completely resected melanoma. It is now indicted for adjuvant treatment of patients who have undergone complete resection and who have lymph node involvement or metastatic disease.

Another immunotherapy, the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb), has already been approved for adjuvant use in melanoma, but it has not been used much in clinical practice because of the high incidence of adverse events and the very high cost when used at the higher dose required in this setting, as previously reported by Medscape Medical News.

Adjuvant nivolumab was approved after it was shown to have superior efficacy and milder toxicity when compared to adjuvant ipilimuab in a head-to-head trial (sponsored by the manufacturers of both drugs) in the phase 3 CheckMate 238 trial.

The results, which were presented last year at the European Society for Medical Oncology (ESMO) Congress and were simultaneously published in the New England Journal of Medicine, show that adjuvant nivolumab increased relapse-free survival by 35% over adjuvant ipilimumab while cutting the rate of grade ≥3 adverse events by around a third.

As reported by Medscape Medical News at the time, the trial included 906 patients scheduled to be treated for up to 1 year. The trial was stopped early owing to benefit in the nivolumab arm. Crucially, the benefits were seen across subgroups, including patients with BRAF mutant and BRAF wild-type disease.

Principal investigator Jeffrey S. Weber, MD, PhD, deputy director, Laura and Isaac Perlmutter Cancer Center, and professor of medicine, New York University School of Medicine, New York City, said the results show that immunotherapies "help prevent the recurrence of melanoma.

"When melanoma has been removed surgically, physicians and patients alike sometimes struggle with the idea of further adjuvant treatment because the disease is no longer detectable, even though it may be likely to return," he commented.

"We recognized a need to develop new adjuvant treatments with lower toxicity compared to ipilimumab to help address this challenge," Dr Weber said. "With its impressive efficacy and broad applicability within stage III and IV melanoma, nivolumab has the potential to become the next standard of care in preventing recurrence of melanoma following surgical resection."

In the CheckMate 238, the rate of recurrence-free survival at 12 months was 70.5% with nivolumab vs 60.8% with ipilimumab. The rate dropped to 66.4% and 52.7%, respectively, at 18 months.

Nivolumab was associated with significantly longer recurrence-free survival than ipilimumab on investigator assessment, at a hazard ratio for disease recurrence or death of 0.65 (P < .001).

Moreover, far fewer nivolumab patients experienced grade ≥3 treatment-related adverse events than those given ipilimumab, at 14.4% and 45.9%, respectively, and they were less likely to have treatment-related adverse events that led to discontinuation, at 9.7% vs 46.2% among ipilimumab-treated patients.

Has Been a Game Changer

Approached for comment, Derek Raghavan, MD, PhD, president of the Levine Cancer Institute, the University of North Carolina at Charlotte, described nivolumab as "one of the biggest advances in melanoma treatment in the last decade."

It "has been a huge game changer, in the sense that there are people who, without any question, would have died within 3 months but who are now living multiple years," he commented to Medscape Medical News.

Nevertheless, Dr Raghavan cautioned that nivolumab is "not a panacea" and that "not every patient is going to get a benefit.

"But it's still a pretty substantial hike [in disease-free survival] compared to so many of the agents floating around that don't work."

Dr Raghavan underlined that the drug "is not completely without side effects," adding that the drug basically "turns on immunity," which can increase the risk for conditions such as hepatitis, pneumonitis, and inflammation of the bowel.

"It's not a glass of milk, so the people who are using these drugs need to be expert ― know how to recognize the complications starting out, know what to look for, and know how to adjust to that," he said. "It's not a drug that should be used by anyone who happens to have a prescribing pen."

Dr Raghavan also noted that, although nivolumab currently appears to have a far better toxicity profile than ipilimumab, "one always has to be a little bit careful with drugs, because the breathless initial release of information is always really quite good".

He added: "Then, over a period of time, more people get exposed to the drug, they see more complications, and then you find a more realistic assessment."

Also approached for comment, John Haanen, MD, PhD, head of the Division of Medical Oncology at the Netherlands Cancer Institute, Amsterdam, told Medscape Medical News that he expects that the approval will "change the landscape of treatment for patients with melanoma."

He noted, however, that although nivolumab has a better safety profile than ipilimumab, "we have to realize that, in stage III disease, there's a proportion of patients who will be overtreated, and at the moment we have no idea who that is."

Some melanoma patients who undergo surgical treatment will not experience a relapse of the disease even without any adjuvant treatment, he explained. He said that adjuvant nivolumab "will cure more patients" but that it is important to remember that relapse-free survival "is certainly not 100%, so some patients will have a recurrence."

The question is how to treat these patients who relapse, he commented. Can we rescue them again using immunotherapy, using the same treatment? Or do we need to give them a combination of anti-CTLA-4 antibodies and anti-PD-1, or try something else?

Dr Hannen said the efficacy of nivolumab in both BRAF wild-type and mutant patients makes things "more complicated." A study that was also presented at the ESMO 2017 Congress showed that targeted agents have efficacy in the patients with BRAF mutations, as reported by Medscape Medical News.

That study was the COMBI-AD phase 3 trial with dabrafenib (Tafinlar, GlaxoSmithKline) plus trametinib (Mekinist, GlaxoSmithKline). It was conducted in patients with surgically resected BRAF-V300-positive melanoma and showed that 1 year of treatment with these oral agents reduced the risk of 3-year recurrence by 53% over placebo.

As Dr Haanen observed: "Now the question becomes: Should we give these patients BRAF MEK combination therapy, or should we give anti-PD-1 therapy, in this case, nivolumab? That is, of course, something that we just don't know."

He continued: "I think it's more complicated for oncologists if both treatments will be approved. How should we use these treatments in our patient population?

"Right now, it's not an issue, because nivolumab has been approved for both BRAF wild-type and BRAF mutant patients in the adjuvant setting, but it becomes more complicated once the other drug combination is also approved."

Neither adjuvant nivolumab nor the combination of targeted therapies has been approved for use in resected melanoma in Europe, although Dr Haanen expects that it is only "a matter of time."

He said that in the meantime, outcome data from KEYNOTE 054, in which pembrolizumab (Keytruda, Merck) was compared to placebo patients with high-risk stage III melanoma who had undergone complete resection, will be presented at the annual meeting of the American Association of Cancer Research in April.

"If that patients with stage IIIa–c melanoma is also positive, with more or less as the same results that we now see for nivolumab, then we have two drugs that clearly show that in the adjuvant situation, anti-PD-1 prolongs relapse-free survival."

In that case, Dr Haanen believes that both adjuvant nivolumab and adjuvant pembrolizumab will be approved in Europe relatively soon. "I'm convinced that it's not going to take longer than a year," he added.

CHECKMATE 238 was sponsored by Bristol-Myers Squibb. KEYNOTE 054 is sponsored by Merck Sharp & Dohme Corp. COMBI-AD was funded by GlaxoSmithKline. Dr Weber has disclosed numerous financial relationships with the pharmaceutical industry.

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