As part of of our coverage of the 2018 American Society of Clinical Oncology (ASCO) meeting, being held June 1–5 in Chicago, we spoke with Ryan J. Sullivan, MD, about several melanoma presentations of interest at the meeting, as well as questions of major clinical importance in the management of melanoma today. Dr. Sullivan is a medical oncologist at Massachusetts General Hospital, Boston, Mass., who specializes in the care of patients with advanced melanoma. He is also leading clinical trials investigating the development of predictive biomarkers in the treatment of patients with melanoma.
—Interviewed by Anna Azvolinsky
Cancer Network: Are there one or two key presentations of clinical trial data at the meeting that you feel could potentially be practice-changing?
Dr. Sullivan: This is another year when the practice-changing trial results are not part of the oral abstract and poster sessions, and may or may not find their way into the poster sessions. The main issue with melanoma right now is sorting out the best way to treat patients upfront, and there are ongoing trials addressing that. Some abstracts at the ASCO meeting are presenting economic analyses of sequencing therapies and comparing different treatment approaches head-to-head.
The trials that will truly be practice-changing are the ones looking at how to treat patients after upfront immune checkpoint inhibitor therapy, because well over 50% of our patients are progressing on those treatments and we need to have better therapies for these patients. Some of these trials are early-stage, some in melanoma but some are single-agent [studies] or combinations of novel immune-targeting agents plus, usually, an anti-PD1 antibody. And ultimately, some of those strategies will be moved forward if the preliminary data hold up.
So there are a number of abstracts, some in the melanoma program and some probably in the developmental therapeutics immunology program, that give us a better sense of what types of therapies are being studied and [will provide] the preliminary evidence to understand whether we should move those approaches forward into larger trials.
Cancer Network: Are there other, specific presentations at the meeting that you would like to highlight?
Dr. Sullivan: There are some melanoma trials with additional follow-up data. One is [overall survival data from] COLUMBUS, which is a phase III trial of encorafenib (an oral BRAF inhibitor) plus binimetinib (an oral MEK inhibitor) vs vemurafenib or encorafenib in patients with BRAF-mutant melanoma. [The] phase II [data on] epacadostat (an IDO inhibitor) plus nivolumab trial data will be interesting to see, although in the context of the epacadostat-plus-pembrolizumab phase III trial that failed to show an improvement in metastatic melanoma patients compared to pembrolizumab alone, I am not sure how exciting the data will be. [I'm also in interested in] the phase III data on pembrolizumab plus epacadostat.
The 4-year survival data on patients who were on pembrolizumab for 2 years and then went off treatment [will be useful]. I always like seeing these types of data—on the patients who stopped treatment after 2 years and continued to be followed—in order to see how long these patients can go before needing new therapy and [experiencing] progression. These data are absolutely practice-affirming, because we are stopping patients who are on an anti-PD1 [programmed death 1] therapy and are having great responses. And any additional data help support us in speaking to patients and saying “here are the data, and we feel more comfortable than ever because we have these additional data.” Every year that [this type of outcome] is presented, I am thrilled, because [such findings provide] more and more confidence that it is ok to stop these therapies in patients after a while.
Also, an analysis of the COMBI-AD phase III data on adjuvant dabrafenib plus trametinib, a BRAF-inibitor plus MEK-inhibitor combination based on the AJCC 8 [American Joint Committee on Cancer 8th edition Cancer Staging Manual] classification will [likely provide some useful information]. This will not change the dataset, but at least we will be able to apply the data that are presented in the contemporary AJCC staging system—whereas the trial itself was run under the prior staging system, which is important but not particularly exciting. It will help in the day-to-day management of patients, to translate those data into this current era. In addition, [there are] updated data from the Checkmate 238 adjuvant trial of nivolumab vs ipilimumab. And it’s always great to window shop at the poster session, to see what researchers are working on that I didn't know about. That is certainly something I am looking forward to.
Cancer Network: Are there any trials you are a part of that will be presented at the meeting and which you could highlight?
Dr. Sullivan: There is a trial of entinostat (an HDAC [histone deacetylase] inhibitor) and pembrolizumab that is part of the poster session, which is a dose-expansion study in melanoma as part of a phase Ib trial. There's also a trial, in the developmental therapeutics section, of an oral PI3-gamma inhibitor, IPI-549, plus nivolumab (as part of a poster discussion session). There will not be any melanoma patient data [from the study] presented at this meeting, but this is an example of an emerging combination that could be potentially useful in [treatment of] melanoma and other tumor types.
Cancer Network: Lastly, what is your perspective on how the treatment paradigm for patients with metastatic melanoma has changed in the last 10 years? It seems that there has been quite a bit of progress, but there are still unmet needs that have to be addressed.
Dr. Sullivan: It can’t be overstated that there has been a dramatic change in the way patients with metastatic melanoma are treated in the last 10 years. There are almost a dozen drugs approved or about to be approved [for treatment of melanoma], including combination therapies. We essentially went from not having anything for our patients to having many options, and this has translated to an increase in survival.
There was a study of melanoma patients enrolled in clinical trials [that was] published in 2008 and covered the span from 1975 to 2005. And the 1-year survival to begin with was about 25%, and it hadn’t changed much in the 3 prior decades. Then, when you look at the clinical trial data from some of the really large, randomized phase III trials such as COLUMBUS, Checkmate 067, and Keynote 006, the 2-year survival is at or above 50%, up from a 1-year survival of 25%; and the 3-year survival is somewhere between 40% and 50%.
We don’t know what the 5-year survival will be for some of these trials, but contrast the 5-year survival from that meta-analysis, where the survival at 5 years was 5% or less. And [in the future] we are probably going to be [achieving survival rates] 7 or 8 times that at 5 years, which is amazing. This really highlights [not only] that a lot of drugs were approved but also that these drugs had [a significant impact] on patients’ lives. The obvious first unmet need is that the majority of metastatic melanoma patients are going to die from their disease, and so the 5-year survival rate of 30% or 40% is not good enough, even though it is so much better than before we had these drugs.
So we need to get better at upfront therapy or sequencing there. We also need to [improve how we treat] toxicity, particularly because the safety profile of the immune checkpoint inhibitors is so different from that of chemotherapy or oral agents. And we have to get better at predicting who will develop these toxicities—and ideally get better at treating and maybe even preventing these toxicities. Also [we need to get better at] figuring out who to treat with what and when, and [what are the] optimal treatments. [Management considerations may include] selection of treatments such as post–immune checkpoint inhibitor therapy, and that really speaks to us needing to understand better the innate and adaptive immune resistance to these drugs, and to oral agents.
We also need to get better at treating patients with uveal melanoma, where there has not been much progress despite [our ability to] treat these patients with the drugs available for metastatic melanoma. But we need to identify effective therapies for uveal melanoma, because the current drugs don’t work all that well for this disease. And overall, we don't have a great way to [develop] a treatment strategy for every patient who comes through the door that optimizes his or her chances of benefit.