COMMENTARY

Adjuvant Nivolumab: New Standard of Care for Melanoma?

Jeffrey S. Weber, MD, PhD

Disclosures

September 29, 2017

This is Dr Jeffrey Weber. I am a medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Health in New York City.

Today we are going to talk about a very interesting abstract I presented at the recent European Society for Medical Oncology (ESMO) meeting Presidential Symposium. This abstract described results from the CheckMate 238 study, a large randomized, double-blinded phase 3 study in patients with resected stage IIIB, IIIC, or IV melanoma at high risk of recurrence.

To me high risk of recurrence means > 50% risk of recurrence over 5 years and > 50% risk of death over 10 years. These patients with high-risk melanoma were randomly allocated 1:1 to receive either 1 year of nivolumab, the PD-1 blocking antibody, at 3 mg/kg every 2 weeks; or ipilimumab at 10 mg/kg every 3 weeks for 4 doses, and then every 12 weeks for the remainder of 1 year (which is the Food and Drug Administration [FDA]-approved regimen in the United States). Patients were given appropriate matching placebo.

In this study, 906 patients were randomized with 453 patients in each arm. The results showed a clear statistically significant benefit and clinically significant benefit at 18 months of follow-up for all patients who received nivolumab compared with those who received ipilimumab. Ipilimumab, of course, was the active control arm. Ipilimumab has a well-documented advantage in both relapse-free and overall survival compared with placebo, which was previously shown in the EORTC 18071 randomized trial.[1] Follow-up data at 5 years were published last year in the New England Journal of Medicine.[2]

In the CheckMate 238 study, the hazard ratio (HR) for benefit for those who received nivolumab compared with ipilimumab was 0.65, reflecting a 35% reduction in the risk of relapse over time, with P < .001 showing a very robust and healthy difference.

At 12 months of follow-up, the difference in relapse-free survival was 70% [for nivolumab] versus 60% [for ipilimumab]. As time went on, at 18 months the difference in relapse-free survival began to open up, at 66% [for nivolumab] versus 53% for ipilimumab. The data on the ipilimumab arm paralleled the data shown in the EORTC 18071 trial, even though the patients in the current trial had a slightly worse outcome because there were no stage IIIA patients like in the EORTC trial, but it did include a modest cadre of patients with resected stage IV disease. This is one of the first trials that included patients with resected stage IV melanoma in a large randomized adjuvant study.

The toxicity of the nivolumab regimen was clearly superior to that of the ipilimumab regimen by any standard that you set. In other words, by evaluating any adverse event, any grade 3/4 adverse event, nivolumab was the clear winner. The rate of grade 3/4 immune-related adverse events was something like 42% in the ipilimumab arm versus only 14% in the nivolumab arm. If we look at the percentage of patients who had to stop because of any adverse event or any grade 3/4 adverse event, it was 4% for nivolumab versus 30% for the ipilimumab arm, showing a very significant, clinically significant difference in side effects and toxicity.

The predetermined specified subgroup analysis on a forest plot demonstrated that for almost every prespecified subgroup, there was benefit for nivolumab. This trial was stratified by PDL-1 staining positive or negative and by stage (stage IIIB/C versus stage IV M1a or M1b, or stage IV M1c). There were very few M1c patients. If you compare the stage IV patients as a whole versus all stage III patients, there was a clear difference for nivolumab in both cohorts. There is no question that the HRs were between 0.65 and 0.7, whether it was resected stage III or resected stage IV. When you looked at PDL-1 positive or negative, again there was benefit favoring the nivolumab arm (HRs of between 0.55 and 0.7). Finally, if we looked at the BRAF mutated versus the BRAF wild-type population, although the BRAF wild-type patients had a slightly better HR at about 0.55, there was a healthy HR of 0.7 favoring nivolumab in the BRAF-mutated population.

In conclusion, this study may set a new standard of care for adjuvant therapy in resected stage III and IV melanoma. We await long-term survival results and whether the FDA will approve this drug for adjuvant therapy for resected stage III and IV melanoma. We will hopefully find out sometime in the next few months.

Please do call in with questions, and thank you for listening. We will soon be talking about some more of the fantastic melanoma abstracts presented at 2017 ESMO. Thanks very much.

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