Adjuvant Clinical Trial Data Impact on Treatment Selection

Evan J. Lipson, MD: CheckMate 238 is an important study. It is a multicenter, double-blind, randomized phase 3 trial. It’s in the adjuvant setting for patients with resected stage IIIB, IIIC, or IV melanoma by the AJCC [American Joint Committee on Cancer] Cancer Staging Manual, 7th edition. This trial required that patients undergo complete regional lymphadenectomy prior to enrollment. This was important for several reasons. This trial is several years old, but there is an active comparator arm, which is the ipilimumab. We know that ipilimumab has a benefit in the adjuvant setting from prior studies.

Additionally, this was 1 of the trials that included patients with stage IV disease; not all the adjuvant therapy trials have. This also included mucosal melanoma, which is important because not all the adjuvant therapy trials have included mucosal patients. Lastly, this trial included patients with in-transit metastases that did not have nodal involvement, so that oftentimes makes patients stage III but without lymph node involvement. That’s an important patient population to think about.

In terms of relapse-free survival and distant metastasis-free survival, nivolumab was statistically better than ipilimumab on both of those counts. The median recurrence-free survival in the nivolumab group was about twice as long as it was in the ipilimumab group. It was about 52 months vs 24 months. This appeared to be maintained across the subgroups that were analyzed. The patients with BRAF mutations vs patients with BRAF wild type 2 were particular patient populations of interest, and both of those groups demonstrated benefit in CheckMate 238.

The same was true of PD-L1 expression, so patients with or without PD-L1 expression benefited. Disease stage was also an important consideration: patients with stage III and IV resected melanomas seemed to benefit.

Overall survival was looked at as a part of the study. Though there was no significant difference in overall survival between the 2 treatment groups, it is important to note that patients were allowed to go on to get another therapy after progressing on either of the arms. Oftentimes, patients who received ipilimumab in the adjuvant setting and then progressed would go on to get anti–PD-1 therapy. You can see how that would confound the overall survival calculation.

It is worth noting that fewer patients needed subsequent systemic therapy who were in the nivolumab group than patients who were in the ipilimumab group. Although the overall survival analysis was a bit confounded by patients who went on to receive alternative therapies, the data about RFS [recurrence-free survival] and distant metastasis-free survival are enough to make this an encouraging study. Nivolumab is now 1 of the standard-of-care options that we commonly use for patients with resected melanoma in the adjuvant setting.

Another trial that looked at anti-PD-1 treatment in the adjuvant setting was KEYNOTE-054. This was a phase 3, double-blind trial that looked at pembrolizumab, which is another anti–PD-1 agent, vs placebo in patients with resected high-risk stage III melanoma. The patient population here was a bit different from the KEYNOTE-054 trial. This study included patients with stage III disease but not patients with stage IV disease. In this trial, they again required complete resection of cutaneous melanoma that was metastatic to lymph nodes. This trial did not include in-transit metastases patients. 

The patients with stage IIIA disease had to have a lymph node metastasis that was greater than 1 mm of disease. This randomized about 1000 patients to either a year of pembrolizumab or a year of placebo.

There are a couple of interesting characteristics of this study. First, the placebo arm is tremendously helpful here because when these data mature, that’s going to allow us to better understand whether using adjuvant anti–PD-1 is helpful compared with waiting until the disease recurs, and it will not recur in all these patients. Some of them are surgically cured because of their lymph node dissections and the attendant surgery. It’s going to help us understand whether we need to use anti–PD-1 treatment in the adjuvant setting or if we can wait until the disease comes back and then administer the same medication. That’s tremendously important.

Without that data, even without understanding that, the latest analysis showed a 3-year median follow-up looking at sustained improvement in relapse-free survival consistent across all the subgroups similar to the KEYNOTE-054 trial.

If you take all these data looking at anti–PD-1 in the adjuvant setting together, then it’s clear that nivolumab or pembrolizumab is a relatively safe standard-of-care option for patients with resected melanoma.

Similarly, for patients with BRAF-mutant melanoma, the COMBI-AD study was a randomized, double-blind, placebo-controlled phase 3 trial that compared dabrafenib plus trametinib: BRAF inhibitor plus a MEK inhibitor compared with 2 matched placebos in patients who had undergone resection of stage IIIA, IIIB, or IIIC cutaneous melanoma.

Each of the patients received either a year of therapy or a year of placebo, and relapse-free survival was better in patients who received dabrafenib plus trametinib vs the patients who received placebo. The recently published data continued to demonstrate a benefit at 3 years and again at 4 years, so there’s approximately a 20% absolute difference between the treatment arm and the placebo arm. This effect persisted regardless of baseline disease stage, metastatic load, or tumor ulceration status. This is a terrific option for some patients with BRAF-mutant melanoma who have undergone surgical resection of disease.

The US Intergroup E1609 trial was a phase 3 randomized study looking at adjuvant ipilimumab either at 3 mg/kg or 10 mg/kg vs high-dose interferon alpha. Interferon alpha was the adjuvant therapy that was used before the immune checkpoint blockage era. This was an important study with a stepwise approach: It first compared interferon with the standard dose of ipilimumab, which is a 3 mg/kg. This included patients with AJCC7 resected stage IIIB, IIIC, or IV M1a or M1b stage 4 melanoma. It looked at overall and relapse-free survival. I say that this trial was stepwise because it first evaluated ipilimumab at 3 mg/kg vs high-dose interferon, and it then went on to compare ipilimumab at the higher dose of 10 mg/kg vs high-dose interferon.

The bottom line for the study was that adjuvant therapy with the lower 3 mg/kg dose ipilimumab benefited patients when compared with high-dose interferon. Overall survival was better, and relapse-free survival was better.

This study then went on to look at about 1000 patients in the ipilimumab 10 mg/kg vs high-dose interferon study. Here, although there were trends in favor of ipilimumab 10 mg/kg, it did not achieve statistical significance, in part because the toxicity of ipilimumab at 10 mg/kg is quite high. This was an important study because the standard-of-care adjuvant therapy prior to the immune checkpoint blockade era was high-dose interferon. This answers the question about whether survival is improved when using immune checkpoint blocking therapy: In the case of ipilimumab, the answer is yes.

Transcript edited for clarity.