Clear Benefit With Adjuvant Nivolumab in Resected Melanoma

Liam Davenport

September 12, 2017

MADRID ― Patients with melanoma who have successfully undergone resection but who are at high risk for relapse have substantially better outcomes with nivolumab (Opdivo, Bristol-Myers Squibb) than the current standard-of-care ipilimumab (Yervoy, Bristol-Myers Squibb).

The new results come from the phase 3 CheckMate 238, which was stopped early owing to benefit. Adjuvant nivolumab increased relapse-free survival by a significant 35% compared to adjuvant ipilimumab while also reducing the rate of grade ≥3 adverse effects by approximately a third.

The study was presented here during a presidential symposium at the European Society for Medical Oncology (ESMO) 2017 Congress. It was published online September 11 in the New England Journal of Medicine.

Speaking at an ESMO press conference for the study, Jeffrey S. Weber, MD, PhD, deputy director, Laura and Isaac Perlmutter Cancer Center, and professor of medicine, NYU Langone Medical Center, New York City, said: "Nivolumab clearly showed a very clinically and statistically significant improvement in relapse-free survival vs high-dose ipilimumab for patients with surgically resected stages IIIB, IIIC, and IV melanoma.

"The benefit for nivolumab was observed for virtually all of the prespecified subgroups, whether you look at stage, PD-L1 staining, BRAF mutational status, age, ulceration of the primary tumor, etc."

Dr Weber also highlighted the superior safety profile of nivolumab in comparison with ipilimumab, saying: "In my opinion, nivolumab provides a very acceptable benefit-risk ratio as adjuvant therapy for high-risk resected melanoma and I think has the potential to be an effective treatment option for patients with resected stage III and IV disease."

Commenting for ESMO, John Haanen, MD, PhD, Division of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, said in a release that data presented at the ESMO 2016 Congress showed that although ipilimumab offered "a survival advantage over placebo, it was highly toxic."

The toxicity has led to some reluctance to use this therapy, especially in the adjuvant setting. Although it has become the standard of care in the United States, its use in Europe "is still being debated," Dr Haanen commented.

Consequently, Dr Haanen described the current findings as "very exciting", adding: "They show, for the first time, that an anti-PD-1 drug is superior in the adjuvant setting, and because of its lower toxicity, nivolumab is much easier to give than ipilimumab.

"The same occurs in the metastatic setting, where anti-PD-1 treatment is more efficacious and has a much better safety profile and has replaced ipilimumab as first-line treatment."

With results from a phase III trial with pembrolizumab (Keytruda, Merck) in resected stage III melanoma also highly anticipated, Dr Hannen said: "If relapse-free survival is better with pembrolizumab, it is likely that adjuvant anti-PD-1 will become standard of care for high-risk melanoma in the near future, provided an overall survival benefit is also shown."

Study Details

The CheckMate 238 trial was a randomized, double-blind, phase 3 trial that included 906 patients aged 15 years or older. The patients, who had undergone complete resection for stage IIIB, IIIC, or IV melanoma, were randomly assigned to receive either nivolumab 3 mg/kg (n = 453) every 3 weeks for four doses or ipilimumab 10 mg/kg every 3 weeks for four doses and then once every 12 weeks (n = 453).

The patients were scheduled to be treated for up to 1 year or until disease recurrence, unacceptable toxic effects or withdrawal of consent.

The primary endpoint was recurrence-free survival in the intention-to-treat population, with overall survival, safety, side-effect profiles, and recurrence-free survival relative to tumor PD-L1 expression.

As per the protocol, the researchers conducted an interim analysis at the 18-month follow-up point for all the patients. The hazard ratio for disease recurrence or death was 0.75.

There were no appreciable differences in baseline characteristics between the two treatment groups. Overall, stage IIIB melanoma was diagnosed in 34% of patients; 47% of patients had stage IIIC disease, and 19% had stage IV disease.

Ulceration of the primary tumor was seen in 32% of the whole cohort, and 48% had macroscopic lymph node involvement. BRAF gene mutations were detected in 42% of patients.

The median recurrence-free survival was not reached in either patient group. At 12 months, the rate of recurrence-free survival was 70.5% with nivolumab vs 60.8% with ipilimumab. At 18 months, the rates were 66.4% and 52.7%, respectively.

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

For patients with PD-L1 expression <5% and for those with with PD-L1 expression ≥5%, 12-month recurrence-free survival was better with nivolumab than with ipilimumab, although the rate was higher in patients with PD-L1 expression ≥5%, at 81.9% vs 64.3% among those with PD-L1 expression <5%.

Substantially fewer patients experienced grade ≥3 treatment-related adverse events with nivolumab than with ipilimumab, at 14.4% and 45.9%, respectively.

Fewer nivolumab-treated patients experienced treatment-related adverse events of any grade that led to discontinuation of therapy, at 9.7% vs 42.6% in patients given ipilimumab.

Two deaths related to toxic deaths were reported in the ipilimumab arm more than 100 days after treatment. There were no death among patients treated with nivolumab.

Altering Biology of the Tumor?

Emphasizing the need for longer follow-up of the effects of nivolumab in treating stage III melanoma, Dr Weber pointed out that it is possible that nivolumab could alter the biology the tumor.

He said: "Because most patients who ultimately relapse or who have high-risk disease receive a PD-1 antibody, a number of interesting questions arise: Have we impacted the biology of the disease?

"And then, of course, questions arise, many interesting questions, about how to treat those patients once they relapse."

Dr Weber said that determining whether the nivolumab confers a survival benefit in this setting "this will be complicated by the fact that there will be a de facto crossover.

"In all of the countries in which we did this study, both ipilimumab and nivolumab were approved for metastatic therapy. So, if someone who got ipilimumab relapsed, they would be able to received nivolumab; if someone got nivolumab, they could get ipilimumab," he commented.

Another factor that may make interpretation of the data more difficult, in addition to the continual changes to clinical practice, is that the eighth edition of the AJCC cancer staging system will come into effect on January 1, 2018.

"That may complicate interpretation, but I think it's very clear that we have a very nice and beneficial regimen in the nivolumab adjuvant therapy," he said.

How to Choose Which Therapy to Use?

Today's results from CheckMate 238 were presented along with those from another trial in resected stage III melanoma that compared dabrafenib ( Tafinlar, GlaxoSmithKline) plus trametinib (Mekinist, GlaxoSmithKline) with placebo in 870 patients with a BRAF gene mutation.

As reported by Medscape Medical News, the COMBI-AD trial showed that the combined targeted adjuvant therapy was associated with a 53% reduction in the risk for disease recurrence or death vs placebo. There was also a 43% increase in overall survival and 49% improvement in freedom from distant metastases.

Axel Hauschild, MD, professor of dermatology, University of Kiel, Germany, said in a release for the study: "These are the best results ever shown for an adjuvant treatment in stage III melanomas.

"Combination treatment with dabrafenib and trametinib more than doubled the relapse-free survival time compared to placebo, and the improvement in overall survival was impressive, too."

A question then arises: How will clinicians choose between the two treatments, given that the results with both were so impressive?

Dr Weber believes that any patient BRAF wild-type disease "would be a candidate for nivolumab adjuvant therapy," adding: "When you come to the BRAF mutant population, you're going to have to do an apples-and-oranges comparison."

He said: "You can do some sleight-of-hand statistical arguing to try to compare the two trials and make a decision of what you should do with your BRAF mutation.... If you do such a, probably, as we would say, 'non-kosher' statistical analysis, you come up with a hazard ratio of nivolumab vs placebo that's at least as good as what we see in the COMBI-AD trial, maybe better."

Dr Weber continued: "At the end of the day, if you wanted to do that, I think you would have two great choices."

Regarding the greater relapse-free survival seen with immunotherapy in comparison with drugs targeted for BRAF mutations in the metastatic setting, he said: "It comes down to whether you believe there will be a tail on the curve for immunotherapy with relapse-free survival in the adjuvant mode."

He added: "It's going to be tough decision. I would speculate, in the US at least, a lot of docs will like immunotherapy and use nivolumab even in mutated patients." He expects "a considerable number of patients" to receive BRAF-targeted drugs.

There are also more practical considerations centered around the delivery of treatment. The combination BRAF-targeted therapy is given orally, whereas nivolumab requires regular intravenous infusions, making it less practical for patients living further away from the clinic.

"In my former institute in Tampa, we had patients who would travel 2 to 3 hours to come to the physician," Dr Weber observed. "Those folks may opt for targeted therapy because of the ease of administration."

Noting that the choice of treatment will, in the end, likely be made on the basis of a number of factors, he said: "I tell my patients: 'Cancer is a bad disease; the good news is you have options.' Now, our patients have clearly beneficial options, and that's great news."

"Two Fantastic New Options"

Commenting for ESMO during the press conference, Olivier Michielin, MD, PhD, Department of Oncology, Melanoma Clinic, Swiss Institute of Bioinformatics, Lausanne, Switzerland, said: "We now have, with the data at hand, two fantastic new options."

He added: "We couldn't dream those studies would be so positive. This is really something that will open up new futures for our patients."

Dr Michielin cautioned, however, that "these data might mature, so we might be clearer in the future which treatment to select for which patient.

"But clearly it's a situation that we are used to in more advanced disease, where we have to make the treatment selection between targeted therapy or immunotherapy, and this discussion we have had with our patients quite regularly."

Dr Michielin said that such discussions will focus on "the same aspects of toxicity, practicalities, and also, of course, performance as this matures over time, but clearly these are two outstanding options for our patients."

Asked from the floor what the implications of the CheckMate 238 results are for the future of ipilimumab, Dr Weber said that the drug "is and probably will only be approved in the United States as adjuvant therapy for high-risk resected stage III disease."

Expecting the combination of BRAF-targeted drugs used in COMBI-AD to eventually be licensed in the United States, he said that for patients for whom those drugs or nivolumab fails and who can undergo a second resection, "ipilimumab would be a reasonable option."

Regarding the size of that patient population, Dr Weber said that it is "not a trivial number, because...about 15% of our patients ultimately had surgery after failing."

He explained: "Let's say you fail nivolumab, and you're BRAF wild type. You could go to ipilimumab. Obviously, if you fail nivolumab and you're BRAF mutated, you could of course go to dabrafenib-trametinib, and that's what I would prefer, given the toxicity of ipilimumab.

"But there will be a small niche in those who fail other adjuvant therapies and can be re-resected."

For Dr Weber, the more interesting question is: "What do you do if someone has received nivolumab adjuvant therapy and they progress quickly? Thank goodness, there are very few patients in that category, but what if that happens?

"Do you go to ipilimumab, do you go to nivolumab in the metastatic mode, do you go to ipilimumab plus nivolumab?"

He concluded: "Like any good study, like all of the studies here, it raises as many questions as it answers, but there will be a role for ipilimumab in the future in the patients who fail these kinds of therapies."

The study was sponsored by Bristol-Myers Squibb.The study authors have numerous ties with industry, which are listed in the article published in the New England Journal of Medicine.

European Society for Medical Oncology (ESMO) 2017 Congress. Abstract LBA8_PR, presented September 11, 2017.

N Engl J Med. Published online Septermber 11, 2017. Full text


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