Weber Shares Insight on Future of Immunotherapy in Melanoma

Jeffrey Weber, MD, PhD

Immunotherapy continues to work its way through the treatment landscape of melanoma, with ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) leading the way in combination regimens, as well as other novel agents that are currently in development.

The combination of nivolumab plus ipilimumab was initially approved in October 2015 for the treatment for patients with BRAF V600 wild-type, unresectable or metastatic melanoma, which was based on findings from the phase II CheckMate-069 study. This indication was expanded in January 2016 to include patients with BRAF V600 mutations; the decision was based on data from the phase III CheckMate-067 trial.

Aside from this PD-1/CTLA-4 combination, a highly anticipated trial is the phase III KEYNOTE-252 trial of pembrolizumab plus the IDO inhibitor epacadostat or placebo in patients with unresectable or metastatic melanoma (NCT02752074). The study is expected to read out this year—and the results may have the potential to be practice changing, according to Jeffrey S. Weber, MD, PhD.

Weber says that although progress is being made, there is still a need for better biomarkers—if not to select patients for treatment, then at least to indicate and spare those patients who would not benefit from added toxicity.

OncLive: What is the current state of immunotherapy in the melanoma paradigm?

What is next for this type of therapy in melanoma?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Melanoma, Weber, the Laura and Isaac Perlmutter Professor of Oncology, co-director of the Melanoma Research Program, deputy director of the Perlmutter Cancer Center, NYU Langone Medical Center, and a 2016 Giant of Cancer Care^® in Melanoma, discussed the future of immunotherapy in the treatment of melanoma.Weber: As we all know, immunotherapy for melanoma has revolutionized how we treat the disease. It started out with the best news, which was the long-term survival data that we had from the original randomized trial of ipilimumab plus nivolumab versus ipilimumab alone versus nivolumab alone. You can't argue with a 58% 3-year survival in the arm that got ipilimumab/nivolumab. If you do a quick calculation, you are looking at a median survival that is 4 years, and maybe even longer—and that is a phenomenal number, better than any trial that has been done. That is an amazing record, and you have to put that up as probably the best track record that we have in a melanoma trial.In the short term, the pembrolizumab/epacadostat versus pembrolizumab/placebo trial will read out its primary endpoint of progression-free survival (PFS) in early 2018, I believe. I have high hopes based on the phase Ib/II data that it will be a positive trial for PFS, because with 60 or 70 patients and a PFS of approximately 12-plus months, I can’t argue with that; that is very impressive. A 53% to 56% response rate would suggest that, at least on the surface, it is just as good as ipilimumab plus nivolumab. And, it has a lot less toxicity. Epacadostat, or the IDO inhibitor, adds virtually nothing to the toxicity of pembrolizumab, which itself is a well-tolerated drug.

It is interesting that epacadostat has essentially no independent antitumor activity. However, of course, it has a major contribution to the efficacy of the PD-1 antibody pembrolizumab. My feeling is that it could be the new standard of care if the PFS and response rates hold up in the phase III study, and look as good as they did in the phase Ib/II studies.

Will the field start moving toward triplets or even 4-drug regimens?

In the mid- or long-term future, the LAG-3/nivolumab combination looks very promising, especially in the refractory population, and that is a tough population to treat. I assume that will be pursued in the frontline and the refractory settings. Then, there is that nivolumab trial both in renal cell carcinoma and melanoma, which was reported out at the 2017 Society for Immunotherapy of Cancer (SITC) Annual Meeting. It looks awfully promising. Finally, we get a reasonably tolerated interleukin-2 (IL-2)‒type drug—which is the pegylated IL-2 known as NKTR-214—and that looks pretty good. I would have high hopes in the middle-to-long-term future for that combination.We are already in triplets. I just got approved for a trial of nivolumab plus ipilimumab at flip doses with an HDAC inhibitor, which looks very promising and interesting when combined with PD-1. It will be even better with ipilimumab plus nivolumab.

Is there still a role for IL-2 in melanoma?

There is an ipilimumab-plus-nivolumab-plus-epacadostat trial going on—so the sky is the limit—and if you can flip the doses and arrange the schedule so that you don't have prohibitive toxicity, you can do triplets.I hope IL-2 “goes the way of the dodo bird.” I was there when it was developed in my first year of fellowship. High-dose IL-2, as we conceived it back in the mid-1980s, has been a mainstay. Although, it is limited to select centers that have experience where the nurses and doctors know how to manage the side effects. It would be nice if the NKTR-214 drug replaced [IL-2].

Looking back on the past year, what data was potentially practice changing in this landscape?

There was a single trial done at the surgery branch of the National Cancer Institute over a decade ago that showed very nice response rates for IL-2 added to checkpoint inhibition. I have high hopes that a better-tolerated IL-2 equivalent added to checkpoint inhibition will significantly increase response rates, PFS, and maybe overall survival (OS). Therefore, I look forward to seeing a larger, randomized trial of pegylated IL-2 with either nivolumab or pembrolizumab. Both I and the investigators from the COMBI-AD study presented our adjuvant data. I presented the CheckMate-238 data, which was a rehash of the 2017 ESMO Congress data that had occurred the month prior. We heard from Dr Paolo Ascierto about LAG-3 and nivolumab. Therefore, we saw some refinements on some very promising treatments. Both of the adjuvant treatments are practice changing, they both got published in the New England Journal of Medicine, and are major advances.

The only question is, “What comes next in the adjuvant mode?” There is the Bristol-Myers Squibb trial of ipilimumab/nivolumab versus nivolumab alone, and I would push for using biomarkers to restrict eligibility for adjuvant trials in the future. Looking at the PD-L1—negative population, there is the opportunity for ipilimumab/nivolumab versus nivolumab. Looking at the PD-L1–positive population, you may want to look at pembrolizumab/epacadostat versus nivolumab alone or pembrolizumab alone.

Those are all very attractive trials alone, and the CheckMate-915 trial of ipilimumab/nivolumab versus nivolumab—that is going to fill by May. Again, we are going to have to start thinking about what will be the next adjuvant trial. We have done well with ipilimumab, we have done better with nivolumab, and we may do better with ipilimumab/nivolumab. What is next?

The hope is that we will not only continue to raise the bar of relapse-free survival and OS, but you will have to treat fewer patients to benefit 1 patient. We need better drugs and better biomarkers to decide who to treat with adjuvant therapy and in whom could you avoid it—such as the Oncotype DX test for breast cancer, which tells us who not to treat. That is what we need in melanoma.