Standard Adjuvant Therapy for Melanoma Within Reach

Michael B. Atkins, MD

Adjuvant treatment for patients with high-risk melanoma has seen little progress until recently. This is in large part due to the lack of consensus in the community on what treatments to use, when to use them, and in which patients to implement them, explains Michael B. Atkins, MD.

Traditional treatment options such as interferon, pegylated interferon, and high-dose ipilimumab (Yervoy) have caused debate in the melanoma community. According to Atkins, none of these options show enough benefit to justify their widespread use.

Results of the COMBI-d study showed the promise of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with BRAF-mutant melanoma. As for the all-comers population, the use of single-agent nivolumab (Opdivo) in the adjuvant setting demonstrated superior benefit to ipilimumab in a recent study presented at the 2017 ESMO Congress.

OncLive^®: Can you discuss your talk on adjuvant therapy for melanoma?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Melanoma, Atkins, deputy director, Georgetown-Lombardi Comprehensive Cancer Center, professor of oncology and medicine, Georgetown University School of Medicine, discussed hotly debated adjuvant treatment options for patients with melanoma, and the potential for neoadjuvant therapy.Atkins: Over the past 20 years, the adjuvant treatments that have been used for patients with high-risk melanoma were high-dose interferon, then pegylated interferon, and then high-dose ipilimumab. We constantly had arguments about whether these treatments should be used or not and in which patients. In truth, none of the treatments were effective enough or tolerable enough to justify their widespread use, particularly in the recent era where there are more effective systemic treatments for stage IV disease. We have been waiting for the data to come out on the treatments that we have been using in the stage IV setting [as adjuvant therapy].

At the 2017 ESMO Congress, 3 studies were reported. One looked at vemurafenib (Zelboraf) in the adjuvant setting, the second was the COMBI-d study looking at dabrafenib plus trametinib in the adjuvant setting compared with placebo in BRAF-mutant melanoma and, finally, the nivolumab (Opdivo) study compared [the PD-1 inhibitor] with high-dose ipilimumab in patients with stage IIIb, IIIc, and resected stage IV disease. Essentially, all of them were positive, although the vemurafenib study was designed in a way that it had to be interpreted as negative. However, in the stage IIIb, IIIa, and IIIc populations, vemurafenib was better than placebo.

The dabrafenib/trametinib regimen was dramatically better than placebo with a P value for relapse-free survival positive to the 13th decimal point. It also looked like there was going to be a benefit in terms of overall survival, with a portion of patients looking like they may be prevented from relapse and maybe even cured. The strongest benefit seemed to be in the earliest stage patients—stage IIIa and perhaps IIIb.

Nivolumab, which was the only one with an active control arm, also was significantly better than ipilimumab. At 18 months, it looked like there was going to be at least a 15% difference in relapse-free survival with the curves still separating, and nivolumab much better tolerated than ipilimumab.

Considering these data, will interferon ever be used again as adjuvant therapy?

Now, we can look into the future of having a least 2 different adjuvant treatments available. One is restricted to patients with BRAF-mutant melanoma, and the other is for all-comers. We will start having debates over who will get which therapy.No more interferon, and probably no more high-dose ipilimumab. There may be some situations where a patient might receive ipilimumab after nivolumab if they didn't respond; however, we are going to see a lot less of those treatments being used. What we are going to be looking for in the future will be trials of pembrolizumab (Keytruda) versus observation with a crossover in the observation arm for pembrolizumab in patients who progress. The CheckMate-915 trial from Bristol-Meyers Squibb is looking at nivolumab versus nivolumab plus low-dose ipilimumab in the adjuvant setting. Also, there is the SWOG S1404 trial looking at pembrolizumab versus high-dose ipilimumab in the adjuvant setting.

Are there any next steps with vemurafenib, even though the trial was technically negative?

If adjuvant nivolumab gets approved, how could it change the landscape?

Is there anything regarding neoadjuvant therapy that you would like to touch on?

We will also start seeing neoadjuvant studies looking at combinations of nivolumab plus ipilimumab or nivolumab alone. There are studies looking at treatment in the adjuvant setting versus the neoadjuvant setting to see what kind of outcomes happen. Perhaps there will be combinations of pembrolizumab and other agents, such as an IDO inhibitor or combinations of PD-L1 blockers plus BRAF inhibitors in patients who have BRAF mutations.I think not, because it is less effective than dabrafenib/trametinib and a little bit more toxic in the adjuvant setting. Also, the way the trial was designed was to look at cohort 2 first—which is made up of the stage IIIc patients—which did not show benefit. They weren't allowed to look at the other populations unless they saw benefit in cohort 2. Therefore, it was strictly interpreted as a negative trial.If dabrafenib/trametinib and nivolumab both get FDA approval, then the majority of patients will get adjuvant nivolumab because it is something that can be used for the BRAF wild-type as well as the BRAF-mutant patients. It is something that community oncologists are likely to have more experience with than the BRAF or MEK inhibitors because they are using it for patients with different types of cancers—they are more confident managing the adverse events and are familiar with the benefit. When they are seeing patients, they are unlikely to have information of the patients’ BRAF status, so the easiest or default approach will be to order nivolumab for those patients. On the other hand, there may be patients who might be resistant to taking an intravenous treatment, or may not be eligible to receive a checkpoint inhibitor because they have an autoimmune condition or are on immunosuppressive drugs.It looks like the combination of nivolumab and ipilimumab in the neoadjuvant setting is even more toxic than it is in the metastatic setting. Although in the 2 studies that have been done, everybody has been able to get to surgery, and it is hard to get more than 2 doses in the neoadjuvant setting with nivolumab plus ipilimumab. There are a lot of pathologic complete responses (pCRs) that have been reported, suggesting that nivolumab plus ipilimumab works fast. It remains to be seen if those pCRs in the neoadjuvant setting will translate into durable CRs. It is possible, and it may lay the groundwork for more novel regimens with lower doses of ipilimumab or other combinations with an anti—PD-1 agent that might also work quickly and enable patients to have surgery without postoperative therapy.