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Nivolumab superior to ipilimumab for adjuvant treatment of surgically resected melanoma
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MADRID — Adjuvant treatment with nivolumab significantly prolonged RFS compared with standard ipilimumab for patients with surgically resected stage III or stage IV melanoma at high risk for recurrence, according to results of the randomized, phase 3 CheckMate 238 trial presented at the European Society for Medical Oncology Congress.
The trial — stopped at a planned interim analysis — also showed nivolumab (Opdivo, Bristol-Myers Squibb) demonstrated a superior safety profile to ipilimumab (Yervoy, Bristol-Myers Squibb).
“I was very surprised the trial read out so quickly. I wasn’t expecting that to happen until the middle of 2018,” Jeffrey S. Weber, MD, PhD, deputy director of Perlmutter Cancer Center at NYU Langone Health, told HemOnc Today. “This shows the magnitude of benefit is impressive, and that this is the real deal.”
Nivolumab, an anti-PD-1 antibody, and ipilimumab, a CTLA-4 antibody, both are approved for treatment of advanced melanoma. Ipilimumab also is approved in the United States for treatment of resected stage III melanoma.
A prior trial showed adjuvant ipilimumab conferred significant RFS and OS benefits compared with placebo.
CheckMate 238 is the first trial designed to compare nivolumab with ipilimumab as adjuvant therapy for patients with resected stage III or stage IV melanoma at high risk for recurrence, defined as greater than 50% risk for relapse over 5 years.
The analysis included 906 patients aged 15 years or older.
The majority (81%) of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement and 42% harbored BRAF mutations.
“The majority of patients had higher-risk disease than in most prior adjuvant melanoma trials, which makes the findings even more encouraging,” Weber said.
Researchers randomly assigned 453 patients to nivolumab 3 mg/kg via IV every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses, then every 12 weeks from week 24 up to 1 year.
Treatment continued until disease recurrence or unacceptable toxicity. RFS in the intent-to-treat population served as the primary endpoint.
Median follow-up was 18.5 months.
The results — published simultaneously in The New England Journal of Medicine — showed a significantly higher 18-month RFS rate for nivolumab compared with ipilimumab (66.4% vs. 52.7%; HR = 0.65; 95% CI, 0.51-0.83). Researchers observed a consistent benefit in all prespecified subgroups, including those analyzed by age, disease stage, PD-L1 staining, BRAF mutation status and ulceration of primary tumor.
OS served as a secondary endpoint. That analysis will be complicated by the expectation that patients will cross over to the alternative treatment upon relapse, Weber said.
More ipilimumab-treated patients experienced grade 3 or grade 4 adverse events (46% vs. 14%). Ipilimumab-treated patients also were more likely to stop treatment due to any-grade treatment related adverse events (43% vs. 10%), as well as grade 3 or grade 4 treatment-related adverse events (31% vs. 5%).
“To me, as a clinician, that is really the most practical issue when administering adjuvant therapy,” Weber said during a press conference.
Organ systems with the highest rates of select treatment-related, immune-related grade or grade 4 adverse events included the gastrointestinal system (16.8% for ipilimumab vs. 2% for nivolumab), hepatic system (10.8% vs. 1.8%) and the skin (6% vs. 1.1%).
No patients assigned nivolumab died due to study-drug toxicity. Two patients assigned ipilimumab died more than 100 days posttreatment; one died of colitis and the other died of medullary aplasia.
“Nivolumab provides a very acceptable benefit-risk ratio as adjuvant therapy for high-risk resected melanoma and has the potential to be an effective treatment option with resected stage III or stage IV disease, of which in the United States we have at least 20,000 patients who fit that category,” Weber said.
Although adjuvant nivolumab after resection may benefit more patients with high-risk disease, several interesting questions arise, Weber said.
“Almost all patients who relapse and develop metastatic disease will be nivolumab-experienced or BRAF [inhibitor]/MEK [inhibitor]-experienced,” Weber told HemOnc Today. “The concern about BRAF/MEK is it clearly induces resistance.
“Not as much is known about nivolumab or ipilimumab or the combination, but the concern is you’re going to change the biology because now you’re going to have a resistant population,” he added. “This is going to need to be studied, and we’re going to have to biopsy every patient who relapses and do gene expression analysis, PD-L1 staining and so forth. It’s going to be a huge endeavor.”
John Haanen, PhD, head of the division of medical oncology at Netherlands Cancer Institute, called the CheckMate 238 findings exciting. He also noted a trial in Europe is evaluating pembrolizumab (Keytruda, Merck), another anti-PD-1 therapy, versus placebo as adjuvant therapy for patients with resected stage III melanoma.
“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,” Haanen said in an ESMO-issued press release. – by Mark Leiser
Reference:
Weber J, et al. Abstract LBA8_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.
Disclosures: Bristol-Myers Squibb funded this study. Weber reports research funding, honoraria, and travel accommodates and expenses from Bristol-Myers Squibb. Please see the abstract for a list of all researchers’ relevant financial disclosures.
Perspective
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Omid Hamid, MD
Once we knew that ipilimumab in the adjuvant setting for melanoma was better than placebo, and we knew that PD-1/PD-L1 therapies were better than anti-CTLA-4 therapy in the first-line setting, the next logical progression was to look at anti-PD-1 in the adjuvant setting.
Checkmate 238 clearly showed a relapse-free survival benefit with PD-1 therapy over anti-CTLA-4 therapy. It also showed a toxicity benefit.
Do the overall survival results mimic the relapse-free survival benefit? We will have to wait and see, and we may not see the OS benefit for a long time.
The bigger question is: Is this the right thing for our patients in the community? Absolutely. The toxicities associated with ipilimumab in the adjuvant setting are significant, and the physicians who utilize that therapy have to be very careful in identifying the appropriate patients and managing those toxicities. The incidence and severity of those toxicities in the adjuvant setting is much less with PD-1 therapy.
There is another important consideration: How does this change how we evaluate our patients who show up in our offices presenting with metastatic disease, and what are the next regimens we can offer to them? This is going to be a huge change in our thinking.
We are going to have to get better at identifying who needs what. That means looking at blood, tissue, predictive biomarkers and circulating tumor DNA to develop an understanding not just about who relapses and how they do, but who never relapses and what they need. Toxicity is very important here, so it comes back to the idea of identifying the subset that only needs a single agent in the adjuvant or metastatic setting, and then moving the rest into combination.
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