In this podcast, Dr. Paul Chapman discusses some of the research on melanoma presented at ASCO’s 2015 Annual Meeting.
ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors that care for people with cancer.
In today's podcast, we'll discuss some of the research on melanoma presented at ASCO's 2015 annual meeting. This podcast will be led by Dr. Paul Chapman, who is an attending physician in the melanoma and sarcoma service at Memorial Sloan Kettering Cancer Center and professor of medicine at the Weill Cornell Medical College. Doctor Chapman is also an associate editor for Cancer.Net.
The ASCO Annual Meeting is the premier educational and scientific event where physicians, researchers and other healthcare professionals gather to discuss the latest in cancer care and treatment. This Cancer.Net podcast helps put new research findings into context, and explains what they mean for patients. ASCO would like to thank Dr. Chapman for summarizing this research.
Dr. Chapman: I'm Paul Chapman, a medical oncologist at Memorial Sloan Kettering Cancer Center focusing on melanoma, and today I thought I would talk about some of the new findings from the ASCO meeting and how these have an impact on how we treat and are treating melanoma. There were many, very interesting innovative presentations, but I'll focus just on 3 general areas. The first part to mention was actually a surgical study. It was a very well done and very difficult study by the German Clinical Oncology Group, in which they asked the question of whether a completion lymph node dissection is important and necessary in a patient with melanoma who has a positive sentinel lymph node. Patients with positive sentinel nodes were eligible for randomization, and, in fact, they enrolled over 1,200 patients, but ultimately only 483 ended up being randomized to either completion lymph node dissection or observation.
The findings were that, although the observed patients did have higher recurrence rate—14.6% versus 8.3% in the dissected group—almost all those extra recurrences were in the lymph node basin, as expected. And, importantly, there was no other differences seen in the 2 groups, and in particular, there was no difference in overall survival. This is an important question as to whether or not a completion lymph node dissection is necessary or helpful to patients, and is the subject of a larger study, MSLT II, which has completed accrual, but which has not yet been reported. If MSLT II confirms these findings, then I think we will have extremely strong evidence to tell patients that there is no survival benefit from doing a completion lymph node dissection.
The next topic is the immunotherapy topic, which continues to make huge advances in the news. At the plenary talk, my colleague Dr. Jedd Wolchok, reported the first results from a randomized trial in which patients with metastatic melanoma were treated either with ipilimumab or the anti-PD-1 antibody nivolumab, or the combination. This is an important question, as we will see.
At this plenary talk, only response rate and progression-free survival data were available. Importantly, the overall survival data is not yet available. But what was seen was that with the combination, the response rate was close to 60%, which was significantly better than with either of the single agents alone. Importantly, the combination is associated with significantly more toxicity which is typically auto-immune in nature—diarrhea, hypophysitis, fatigue, rash were particularly common—and over half of the patients were not able to tolerate all 4 planned doses. A very intriguing observation was made regarding the role of PD-L1 expression on the tumor.
PD-L1 expression was measured in all the tumors, and the interesting and somewhat perhaps pricing result that was seen, is that in patients who were treated with nivolumab, they did better if their tumors were PD-L1 positive, than if their tumors were PD-L1 negative. On the other hand, patients who were treated with combination treatment, did well either way. And 1 possible interpretation might be that patients who have PD-L1 expression on their tumor, may not need the combination, and might do just as well with single agent nivolumab, and they would avoid a lot of the toxicities. Also related to this topic, was an update on the randomized trial of ipilimumab plus nivolumab versus ipilimumab alone. The initial results were published in the New England Journal, but here they were able to update on response rate. There's still no overall survival data, but it is clear that addition of nivolumab to ipilimumab was superior to ipilimumab alone.
We are eagerly awaiting the survival data for both of these trials, and the reason that's important, is because although it's clear that the nivolumab improves response rate and progression-free survival, ultimately we need to know if there is truly an overall survival benefit, because we know what these drugs response rate doesn't necessarily correlate with survival. And patients who get less than a partial response might have a substantial improvement in overall survival. This leads to the ultimate question of whether the combination is truly better or whether patients could enjoy the same benefit by being treated with 1 drug such as anti-PD-1 drug, and then if they don't respond, to either add or switch to ipilimumab. We await the survival data for that.
The other piece of information is the PD-L1 expression. In his commentary, Dr. Michael Atkins made the point that the PD-L1 assay is not yet ready for prime time, but we're all very eager to see if this pans out and if there really will turn out to be a biomarker that can predict whether or not a patient really needs a combination treatment.
Finally, the last group of trials I want to talk about are the RAS/MEK Inhibitor combination trials. The most mature data were from the COMBI-d trial, in which patients were randomized to receive either dabrafenib, or dabrafenib plus trametinib. These data had been previously published in the New Engalnd Journal, but those data were only for response rates and progression-free survival. At ASCO they now have overall survival data for this trial, and what they found was that the median progression-free survival in the combination was 11 months, and importantly, that the overall survival favored the combination with a hazard ratio of 0.71.
In particular, the 2-year overall survival was 51% with the combination compared to 42% with dabrafenib alone. Importantly, though, the combination is associated with significant toxicity, and 50% of the patients randomized to combination have required a dose interruption at some point. Still, there is evidence for overall survival benefits. And, as of now, dabrafenib and trametinib combination must be considered at least a standard, if not the standard, of treatment for treating patients with a BRAF mutation. There were other clinical studies reported using other combinations. The Genentech drugs, which are vemurafenib and cobimetinib, were also reported, and interestingly, that has a 70% response rate also—this combination. Similar duration of response of 13 months, and a similar median progression-free survival of 12 months. There were no overall survival data yet for this randomized trial, so we await those data. And, finally, the Novartis group reported their results with their combination of encorafenib and binimetinib. This combination has a similar overall response rate of 75%, similar duration of response, and similar progression-free survival.
This trial is not really designed for overall survival, so we probably won’t be getting survival data on that. Interestingly in this trial, there was significant toxicity, in terms of fatigue, in one-third of the patients. Still there are two MEK/RAS inhibitor combinations in the pipeline that seem to have similar efficacy compared to the currently FDA-approved combination. And there is some hope they will be associated with less toxicity, but that remains to be seen.
So, overall, what have we learned from the ASCO data? I think, one, is we now have data suggesting that completion lymph node dissection may not be necessary for patients. It may not be associated with overall survival. We heard data to suggest that ipilimumab as a single agent probably should not be our first line treatment, and rather anti-PD-1 drugs probably are first line therapy. And what we are waiting to find out more about is whether the combination should be our first line therapy for all patients, or maybe just a subset. And, finally, with the targeted therapy, the combination of a BRAF and MEK inhibitor are associated with slightly improved survival, although with a little more toxicity, and should be considered our standard treatment when we are trying to target BRAF mutation in melanoma.
ASCO: Thank you, Dr. Chapman. To find all of the science presented at ASCO's 2015 Annual Meeting, visit www.cancer.net. If you have questions about whether new research may affect your care, be sure to talk with your doctor.
Cancer.Net is supported by the Conquer Cancer Foundation, which is working to create a world free from the fear of cancer by funding breakthrough research, sharing knowledge with physicians and patients worldwide, and supporting initiatives to ensure that all people have access to high quality cancer care. Thank you for listening to this Cancer.Net podcast.