Keith T. Flaherty, MD, Harvard Medical School and Center for Targeted Therapies at Massachusetts General Hospital, spoke to Targeted Oncology about the importance of combination BRAF/MEK inhibitors in the treatment of melanoma.
Keith T. Flaherty, MD
The COMBI-d study was one of a series of trials examining the use of a BRAF inhibitor (dabrafenib) in combination with a MEK inhibitor (trametinib) for the treatment of patients with advanced melanoma.1Presentations at the 2015 ASCO Annual Meeting reported on the mature analysis from COMBI-d, which demonstrated a significant benefit of the combination versus dabrafenib monotherapy.2,3
Keith T. Flaherty, MD, associate professor in the Department of Medicine at Harvard Medical School, and director of the Termeer Center for Targeted Therapies at Massachusetts General Hospital, Boston, spoke toTargeted Oncologyabout the importance of this combination therapy.
What have been some of the drawbacks associated with therapies that targetBRAFV600E/Kmutations (eg, dabrafenib) in patients with advanced melanoma?
The common element for BRAF inhibitorbased therapy, and other so-called oncogene-targeted therapies in cancer, including epidermal growth factor receptor (EGFR)-targeted and anaplastic lymphoma kinase (ALK)-targeted therapies in lung cancer, is early efficacy. BRAF inhibitors work quite reliably in patients withBRAFmutationsnot uniformly, but fairly reliably—so the short-term to intermediate-term benefit is quite profound, but the long-term benefit is more limited. As we follow patients over years on BRAF inhibitor monotherapy, we see a fraction of patients who survive several years and counting—with some still on therapy—and that fraction is not trivial. No less than 20% of patients seem to be surviving now 4 years and beyond on BRAF inhibitor monotherapy, but that leaves 80% who aren’t. So there is obviously significant room for improvement. Even within a 1-year time frame, you see patients who lose disease control and succumb to their disease—so it’s not all a 3-, 4-, or 5-year benefit, some of [disease progression] begins even within the first year. The 1-year survival rate is 63% to 65%, depending on which trial you look at between vemurafenib and dabrafenib, so you are losing a fraction of patients—a minority—early, and then the percentage who progress and succumb to their disease—thankfully— gradually diminishes, and you end up with this 20% group who continue to make it over years. So resistance is a real problem.
Most of the problem is not so-called de novo, or upfront, resistancemost of the problem is acquired resistance. This harkens to the first principle that, for any cancer, melanoma included, these tumors are genetically complex, and we knew this when we first started investigating BRAF inhibitorbased therapy years ago. Resistance was something that one would anticipate. So we have now mapped out, with a reasonable degree of confidence, what can be accomplished with single-agent therapy, and we can ask where do we go from here in terms of combination treatment. This is not to dismiss the fact that there are patients who get long-term benefit from monotherapy. This is an important point and is true for targeted therapies in other cancers as well. While scaling up and trying to deal with resistance and develop combination treatments, we need to understand the features of patients’ cancers that are associated with long-term benefit. On the one hand, we have these ‘exceptional responders,’ and we need to understand what distinguishes them from ‘nonexceptional responders,’ and then, for the bulk of the patients who have the problem of resistance, we need to develop rational combination therapy. Certainly the first, most obvious, and most rational combination therapy is this BRAF/MEK inhibitor combination.
How was the COMBI-d trial designed to address some of these issues with BRAF-targeted agents?
In the laboratory, and more importantly in patients’ tumor specimens, [from] 2010 through 2013, we gained increasing confidence that a lack of control of the mitogen-activated protein kinase (MAPK) pathway, in which BRAF and MEK sit, was the dominant theme in terms of resistance. So studying resistancetrying to understand at a molecular level what was driving resistance—those analyses clearly demonstrated that the most common explanation is MAPK pathway re-activation or restoration, and that very much motivated the idea that adding a MEK inhibitor would be the most plausible, rational, near-term [combination] strategy.
What were the most important efficacy findings of the COMBI-d study?
Unquestionably, the most important is the improvement in overall survival (OS), which we definitively observed with combination therapy over BRAF inhibitor monotherapy. And that comes from COMBI-d, and also from COMBI-v. So that’s the most important observationthat they live longer. But the reason why it’s also scientifically compelling and interesting, is it tells you that firing two therapies simultaneously upfront [is better] than holding in reserve the BRAF/MEK combination strategy and only deploying it for patients who develop resistance. If you add up all of the data, it’s very clear that sequential therapy simply does not accomplish what simultaneous combination therapy accomplishes—and survival is the best demonstration of that. And it’s not just in the context of a single trial—and disease control as measured within a single trial—but rather, and entire arc of a patient’s, or a cohort of patients’ treatment—upfront combination therapy is clearly advantageous. This is [also] completely supported by the remarkable in magnitude, and statistically significant, impact on progression-free survival (PFS), with the combination versus monotherapy, as well as with tumor regression, or response rate data. So all of the efficacy data line up, but if you were to address the question of what’s most important, I’d say you have to look at OS. This is true because we had relatively little room for improvement in terms of upfront disease control—that’s what BRAF inhibitors do exceedingly well on their own. If you just look at the first 6 months of therapy, the combination is better than monotherapy, but that margin of improvement is not nearly as dramatic in clinical practice as what happens 12, 18 months, further out in time, where we see both PFS and OS.
What were the most important findings regarding safety/adverse events with the dabrafenib/trametinib combination?
There was good news in the skin toxicity realm. In fact, even other toxicities that come along with BRAF inhibitors, or for that matter MEK inhibitors, [such as] diarrhea, for example, actually improved in the combination, very much supporting this idea that the two drugs kind of balance each other out in normal tissues. The one thing that is made clearly worse, however, when you put these two drugs together is fever, which is significant.
A majority of patients develop fever at some point. It’s a real problem not for everybody—not for the 75% or so of patients who have some version of it—for many patients it is minor, but for a good fraction of patients —I would estimate 20% to 30%, it’s problematic, for them and for us, and it’s a challenge to manage. It’s scientifically annoying that we don’t know why it’s happening, but it’s clinically annoying as well—patients can feel poorly, and it’s the most common reason why we have to interrupt therapy. Generally, in the vast majority of cases, we can restart treatment and keep people going on therapy, treating their cancer, but [fever] definitely forces treatment interruption. In speculating about the cause, I’d say because the other combinations don’t do it, it must be something specific to these two agents, dabrafenib and trametinib, as opposed to a general BRAF/MEK phenomenon.
In view of these results, what will be important areas for further research with this, or other combination therapies, in advanced melanoma?
We have two strategies ongoing now. We now consider BRAF/MEK as a kind of unit of therapy, like a pair, and we are exploring triple combinations, adding other agents on top of that. This is supported by laboratory evidence suggesting that other points of intervention can overcome resistance even more so than just the addition of a MEK inhibitor. So BRAF/MEK plus X, Y, Z is a major emerging theme. Now, many people may react to that by saying if you have three drugs, won’t you have terrible toxicity, but I have to remind them that the BRAF/MEK combination therapyother than the fever—is actually easier for patients to take than the monotherapy. So we are rapidly pioneering the triple-agent approach, but these are phase I/II trials, and it’s still too early to call early results promising just yet.
The other theme is what to do afterward [following progression on BRAF/MEK inhibitor combination] and this requires that you focus on understanding mechanisms of resistance. My group has been diligently involved in studying what drives resistance, even with the combination, and thus faralthough these are preliminary observations in relatively small numbers of patients—the common theme is that the same pathway is again being re-activated. These tumors really seem to want this pathway back on again if they are going to work their way around treatment. Extracellular signal-regulated kinase (ERK), which lies downstream of MEK in the pathway, is the next component [being targeted], and those agents are currently in phase I trials. We and others have been working on those trials, and we are hopeful that [ERK inhibitors] may be useful in overcoming resistance to this combination.