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Novel Doublet and Triplet Combo Studies Explode in Melanoma

Gina Columbus @ginacolumbusonc
Published: Thursday, Apr 16, 2015

Dr. Jeffrey S. Weber

Jeffrey S. Weber, MD, PhD

A range of novel combinations of immunotherapies and targeted agents, including treatment triplets, will likely be part of the future paradigm of melanoma therapy as drug discovery in the field continues at a rapid pace, according to Jeffrey S. Weber, MD, PhD.

Weber, a translational researcher whose work has helped pave the way for several new agents, listed nearly two dozen combinations under active investigation for patients with advanced or metastatic disease during a review of the landscape of emerging therapies at the recent 11th Annual International Symposium on Melanoma and Other Cutaneous Malignancies.

These regimens include combinations of immunotherapies, pairings of targeted therapies, and strategies that employ both modalities in concurrent and sequential doublet as well as triplet formats.

Weber is the director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence (MRCoE) and Skin SPORE at Moffitt Cancer Center in Tampa, Florida. He served as a program co-chair for the symposium, which Physicians’ Education Resource hosted March 7 in Miami.

Starting with ipilimumab (Yervoy) in 2011, the FDA has approved seven new therapies for patients with advanced or metastatic melanoma. Promising agents in development include the oncolytic immunotherapy talimogene laherparepvec (TVEC) and the MEK inhibitor cobimetinib.

In an interview with OncLive, Weber discussed combinations currently in development and key considerations in employing the new therapies in clinical practice.

OncLive: What developments in combination therapies are on the horizon in melanoma?

Dr Weber: The future of the treatment of melanoma is clearly going to be in combinations, both for targeted therapy and for immunotherapy. Already, there is an FDA-approved combination therapy that is targeted; that is dabrafenib [Tafinlar] and trametinib [Mekinist]. There are new combinations coming up, mainly concerning CDK 4/6 and MEK inhibitors in NRAS-mutated but BRAF wild-type melanoma, which is an unmet medical need.

There is a new BRAF/MEK combination with vemurafenib [Zelboraf] and cobimetinib. This looks very promising. The initial data from a randomized trial of vemurafenib and cobimetinib versus vemurafenib alone was presented at ESMO1 and just published in The New England Journal of Medicine.2 It looks very impressive. In many ways, the data are probably comparable to the existing dabrafenib and trametinib data that led to the FDA approval a year ago of that doublet.

Obviously, the people who make the dabrafenib and trametinib combination [GlaxoSmithKline] have a long head start on those who make the vemurafenib and cobimetinib combination [Genentech], but they perhaps will have a different side effect profile. We will see whether oncologists adopt the newer one, but oncologists are like most people. Once they get into a way of doing things they tend to stick with it so I suspect, for the time being, that dabrafenib and trametinib will stay as sort of the standard of care in treating high-risk aggressive BRAF-mutated melanoma that has metastasized.

Of course, much of the action in the combinations will be in the immunologic sphere, where nivolumab [Opdivo] and ipilimumab look very promising. We’ve heard about the excellent possibilities, and we’ve also heard it’s a very toxic regimen. We have talked about things such as ipilimumab with bevacizumab [Avastin], and ipilimumab with GM-CSF. There are ongoing trials with nivolumab and pembrolizumab [Keytruda], and MPDL3280A, the PD-1 and PD-L1 antibodies, respectively, with other biologics. There must be at least 20 such combination trials.

There are relatively few data available for most of those combinations. We will be hearing more about them at ASCO and ESMO 2015. The future of oncology treatment for melanoma is going to be in combinations and, mostly, I think it’s going to be in immunologic combinations.

Why is there so much debate over the BRAF/MEK combo with trametinib and dabrafenib?

Dabrafenib and trametinib are terrific drugs given as frontline therapy for BRAF-mutated patients, and the debate that goes on is whether you should start with targeted therapy in a patient or immunologic therapy. This is because of the “urban legend” that the targeted therapy is going to have a pretty short progression-free survival. That is probably true; however, anyone who has used these drugs in detail knows that there is a cadre of long-term survivors who get complete responses to the dabrafenib and trametinib combination and who have been on them for 4 or 5 years. Maybe they are cured, just like maybe a lot of those immunotherapy patients who are on [those therapies] for 5 years and are cured.




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