Keith T. Flaherty, MD
The treatment of melanoma has undergone a dramatic change in the past 3 years, with the rapid development and approval of multiple novel therapies. Keith T. Flaherty, MD, director of developmental therapeutics at the Cancer Center of Massachusetts General Hospital, played an instrumental role in many of these advances, through clinical trials focused on the first-in-class BRAF inhibitor vemurafenib (Zelboraf) and the combination of the BRAF and MEK inhibitors dabrafenib (Tafinlar) and trametinib (Mekinist). To gain further insight into future strategies in melanoma, we interviewed Flaherty regarding upcoming combination therapies being explored, specifically those involving CDK4/6, BRAF/MEK, immune checkpoints, and other novel approaches.
OncLive: What potential advantages does the BRAF inhibitor LGX818 and the MEK inhibitor MEK162 combination have in your study over combinations of approved agents from previous studies?
Adding a MEK inhibitor to a BRAF inhibitor has efficacy advantages, but also advantages with respect to reduced toxicity. We have observed that already with the dabrafenib/trametinib combination, but the benefits tend to be even greater with LGX818 plus MEK162. This combination potentially gives us even greater capacity for using a higher dose of LGX818 than could safely or tolerably be administered on its own. This combination potentially offers us a chance of breaking into new territory that we have not yet reached with any of the other BRAF/MEK combinations.
Based on results you have seen to date, which BRAF and/or MEK inhibitors could you imagine would work well in combination with the CTLA-4 antibody ipilimumab (Yervoy)? Would you sequence these agents?
We are excited about the notion that BRAF inhibitor-based therapy is potentially a powerful combination strategy with any of the immune therapies, including ipilimumab and the PD-1 antibodies. A lot of questions remain to be answered in terms of how to do that clinically from a safety perspective, but also how to optimize the use of these types of combinations. It simply may not be the case that administering all the drugs on the same day and then using them continuously is the way to do it. Better efficacy and safety may instead be achieved by using various interrupted schedules.
It is easy to interrupt BRAF inhibitor-based therapy because it is pill-based, and the drugs will be cleared from the body in relatively short order, in a matter of days. So there is the possibility of having patients use an on-again/off-again inhibitor treatment schedule while they are building up immunologic effects through continuous use of agents such as ipilimumab.
Can you comment on the use of CDK4/6 inhibitors in combination therapy for treatment of BRAFV600-mutant melanoma?
There are multiple CDK4/6 inhibitors in clinical development right now, three of which look comparable, namely the ones from Pfizer, Eli Lilly, and Novartis. We are keen to deploy these agents with a MAP kinase pathway inhibitor backbone. In BRAF
-mutant melanoma it would be difficult to embrace anything other than a BRAF/MEK combination as the backbone because it is simply the most efficacious approach to block the pathway. In tumors that do not have a BRAF
mutation, and have other mutations, such as NRAS
, combining a CDK4/6 inhibitor with a MEK inhibitor is the strategy we think is the most scientifically and clinically relevant.
What are some of the other combinations of interest currently being investigated?
Other agents drawing a fair amount of attention are combinations with the same MAP kinase pathway, either a BRAF/MEK combination or a MEK inhibitor alone in the relevant genetically defined subsets, combined with MDM2 antagonists. These are drugs we hope will be useful in at least a subset of tumors where p53 is not mutated. More specifically, some tumors have MDM2 that is responsible for essentially shutting down or silencing p53 function. Blocking MDM2 in the laboratory seems capable of restoring p53 function and therefore restoring some of the damage-sensing and stress-sensing apparatus within cells. We think that MDM2 blockers could be advantageous in combination with molecular-targeted therapies such as BRAF inhibitor-based therapy. Interesting preclinical data have been produced by our group and others that support this approach. So that is another direction that over the next year or 2 is going to receive attention, because, thankfully, there are multiple MDM2 inhibitors moving forward in clinical development.
Another topic that has been on the radar for quite some time, but remains an area of interest, is trying to cotarget the PI3K pathway, either PI3K itself or Akt, in combination with BRAF, BRAF/MEK, or MEK inhibitors. These targeted therapy combination approaches are front and center in the field right now. The other category, as noted, that is really a major area of focus is the targeted therapy/immunotherapy intersection.