What do you do when you step into a pool of 33,000 cancer experts at the annual American Society of Clinical Oncology meeting and your scientific knowledge lies right around #32,995 on that list? (I had to know more than at least five people at that conference, right?) Well, I’ll tell you what you do — you wander towards the Patient Advocate area of the exhibit hall and get lucky enough to run into Alex, Wendy, Louise, and Laura from the Melanoma Research Alliance (MRA). Luckily, they felt bad enough about my lack of biology and chemistry education to lend a hand all weekend, answering my questions and explaining the science behind the posters and presentations.
Mark Twain once said, “It is better to keep your mouth closed and let people think you are a fool than to open it and remove all doubt.” I, of course, chose to ignore that sage advice and instead, posed various “so what does this REALLY mean” inquiries to Louise M. Perkins, PhD., MRA’s Chief Science Officer. She was gracious enough to respond and hold my hand through understanding what the heck just happened at ASCO.
Here is my first awkward attempt at health journalism, and Louise’s much-more-experienced answers:
T.J.: Dr. Antoni Ribas reported that Merck’s pembrolizumab had a 69% overall survival rate at year 1; a 34% Objective Response Rate (ORR, which is Complete Responders + Partial Responders), and 88% of responses ongoing. Can you give us the plain English version for what this means for melanoma patients?
Louise: One of the challenges in testing cancer drugs is determining how best to measure if, and how well, they work. The ORR for pembrolizumab means that overall, 34% of patients had a tumor that either partially shrank or completely disappeared; additionally, for those responders, 88% (of the 34% group) had a lasting response. The 69% overall survival (OS) statistic means that of the patients enrolled in the trial, 69% of them were still alive one year into the treatment. For advanced melanoma patients, these numbers are really remarkable and very, very encouraging.
T.J.: If PD-1 unlocks brakes on t-cells, how is sequencing and combination therapies being positioned in the research world – and is this any different than how those combinations would be presented to patients?
Louise: Most doctors will rely on the results of clinical trials to guide how treatments are used, including best sequences of treatments and which treatments should be used together. In cancer, that most often means that a new drug is approved for patients with very advanced disease and then studies are done to determine if and how to use it in combination with other agents, as well as whether it should be given first, last, or at the same time as something else. While sound research is critical to focus efforts on the best sequences or combinations, often the results of clinical trials reveal something that the basic biology didn't predict, so clinical trials are really the right way to answer these questions. What we're seeing for PD1 (and for ipilimumab) falls within this approach as a logical progression to understand the best approaches with these new treatments for patients.
T.J.: Another highlighted study concluded Yervoy was effective as an adjuvant therapy vs. a placebo for Stage III melanoma patients; the conclusion basically states that after a Stage III patient has all their melanoma removed, they have a longer time before disease returns using Yervoy than if they did nothing. Can you tell me what real benefit this presents, since there are existing Stage III treatment options?
Louise: What seems to be one of the greatest takeaway from this adjuvant study is the demonstration that ipilimumab did offer some benefit in extending time to relapse and therefore provided the 'proof-of-concept' for using immunotherapeutics in patients with earlier-stage disease. We don't yet know whether this intermediate endpoint will translate into improved survival, i.e. more patients living longer, because not enough time has elapsed for the study to sufficiently track that outcome. Since this research is still a work in progress and there were many patients who experienced side effects, patients and doctors will need to carefully consider whether using ipilimumab this way is a viable approach for them, or whether other options are more appropriate.
T.J.: PD-1 is the hot topic of the melanoma (and cancer) world right now, and was featured again this year after making a booming debut last year. Not every year can have these megastars, and there’s a lot more going on in Chicago than just the wonder drug. What did you see featured at ASCO that flew under the radar but can make a difference to patients as time goes on?
Louise: For melanoma, the field of immunotherapy continues to grow in importance and looks promising in other diseases like bladder cancer and Hodgkin’s lymphoma where anti-PDL1 and anti-PD1, respectively, earned Breakthrough Therapy status from the FDA recently. While anti-PD1/PDL1 is definitely the most talked about approach, there are some other things moving along including other immunotherapeutic agents exemplified by TVEC and IDO inhibitors. Molecularly targeted agents like Vemurafenib, Dabrafenib and Trametinib are still important weapons in the anti-melanoma armamentarium. The best time to use them - before or after immunotherapy - is an important area of research.
T.J.: A few studies presented allowed crossover – anyone who didn’t respond to the treatments were eligible to come off the study but still get the experimental drug. This means that Overall Survival for the control group cannot be measured. Scientifically, it seems OS would be the statistic *I* would want to know; but ethically, crossover is certainly preferred. Can PFS give us the same indication of efficacy?
Louise: There is no doubt that the issue of crossover is a challenging one. Work published by Dr. Keith Flaherty earlier this year showed that PFS is an excellent surrogate of OS, at least in those trials that used dacarbazine as the control arm. That said it is still not clear whether PFS will hold up as the best endpoint for all types of approaches, including immunotherapies.
T.J.: I noticed that on many of the Kaplan-Meier graphs, there is a leveling off of overall survival rates. While the exact rate and leveling off points varied, the trend seemed to be that around 2 years, late-stage melanoma patients still alive had a good chance of continuing to stay alive for quite some time afterwards. Are we seeing that leveling off point shifting out, shifting up, or both – and what could drive that trend to continue to improve?
Louise: This leveling off and upward shift of the survival curves (Kaplan-Meier plots) is the holy grail of cancer drug development. Whether it starts to appear at 2 years, 5 or 10, long-term survival is the key goal. The immunotherapeutics as exemplified by ipilimumab may have started melanoma down this path, with approximately 20% of people treated with ipilimumab reaching the 10-year OS mark. If the positive data for the anti-PD1/PDL1 drugs continues to be hold, we may well be talking about many multiples of this fraction of melanoma patients surviving for the long term.
T.J.: Based on what you have seen this past weekend, if you were diagnosed with Stage IV melanoma tomorrow, what would be your course of action?
Louise: Ok, I'm not just saying this, but the first thing I would do is seek out information and interaction with the melanoma non-profits, including MRA; the same would be true with any other cancer. It is worth finding the leading non-profits as sources of information and insight. Having been in the cancer non-profit world, and having lost a sister to colon cancer, I believe groups like ours offer invaluable perspectives. [T.J. note: I’ve been pushing these support/advocacy organizations on you guys for a year now, and for more than just melanomas; they offer the best knowledge you can find, as you just read.]
From a treatment standpoint, I would see several doctors for multiple opinions, and then, based on that and my individual medical data (including BRAF mutation status, approved treatments, and the severity of the disease) and how I feel, decide on a plan, which might include clinical trials. And now, there is finally some good news for patients who have been told that they have totally run out of options: Expanded Access Programs for anti-PD-1 agents are open and enrolling.
Thanks to Louise and the rest of the MRA’s scientific and leadership team for their contributions to this post and my first ASCO experience. As you can see, there are multiple reasons to be optimistic for those who are being diagnosed with melanoma. Just wait until ASCO 2015, when I will understand more and aimlessly/cluelessly walk around less – much, much less.
T.J. Sharpe shares his fight against Stage 4 Melanoma in the Patient #1 blog. Read more »