Novel Doublet and Triplet Combo Studies Explode in Melanoma

In an interview with OncLive, Jeffrey S. Weber, MD, PhD, discussed combinations currently in development for patients with advanced metastatic melanoma, and key considerations in employing the new therapies in clinical practice.

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.

The “urban legend” is that there is more of a tail on the curve of “cured patients” with immunotherapy than targeted therapy. That has yet to be tested, and there is a randomized trial of a targeted combination followed by an immunotherapy combination when you progress, versus the other way around. That is the only way to answer that question. Meanwhile, indolent, slow-growing, low-burden patients who are BRAF-mutated are going on immunologic therapy in most academic institutions such as mine. High-burden patients, rapid growers, and bad-outcome players are all going on targeted therapy.

What are some unanswered questions about these combination therapies?

The question primarily for immunotherapy but also for targeted therapy in melanoma is: How could you sequence these drugs? Could you take a patient with aggressive melanoma who has high LDH and a bulk, serious disease that is symptomatic and, if they are mutated for BRAF, can you treat them with BRAF plus MEK inhibitors? Can you then stop and go to ipilimumab or pembrolizumab? Those are interesting questions that are not easy to resolve without the benefit of a large randomized trial, but those are real-world questions that a lot of doctors have to face.

Another question is: If you had the opportunity to start with a PD-1 antibody up-front or ipilimumab, which would you prefer, depending on the type of patient you’re dealing with? The sequencing and combination questions are very much on oncologists’ minds.

What are the most significant changes under way in the treatment paradigm for melanoma?

The most significant change in the targeted sphere is the fact that BRAF/MEK is now the treatment of choice up-front for patients with aggressive, high-disease burden, BRAF-mutated disease. There is no question there.

Now, we are into triple combinations. First, it is the single drug vemurafenib, and then it is the dabrafenib and trametinib combination. Now, who knows? It’s going to be either triple therapy with targets, or a combination of targeted and immunotherapy. If it’s dabrafenib, trametinib, and pembrolizumab, now it is a triple therapy. On the immunologic side, it is now double and triple immunologic combinations.

The pharmaceutical/economical question is: Where does that all end? Again, these are expensive drugs and you wonder, who is going to pay for all of this? However, if you can prolong survival, put people back in the workforce, have them return to productive life in a significant proportion of cases, it is worth a lot to many people to be in that scenario. The future is all in combinations, and now we’re into triple combinations.

What clinical trials will help define the emerging treatment paradigm?

There must be 20 combination trials that are coming along in phases I and II. All of them will shed significant light on what the best leads are for double and triple therapies. The current and most interesting trials, that have not matured but are finished with accrual, would be the Bristol-Myers Squibb trial of ipilimumab and nivolumab concurrent versus each drug alone.3 There is a pembrolizumab versus ipilimumab trial that will also shed light on whether pembrolizumab is a more effective frontline drug than ipilimumab.4 The irony is that the NCCN Guidelines now favor using either of those PD-1 drugs up-front, so a lot of doctors are using them in frontline therapy.

There has been much research and discussion about the side effects of the new treatments for melanoma. How are patients tolerating the toxicities? Is there a high rate of discontinuation and, if so, can anything be done about that?

It is a major issue when you are at 10 mg/kg of ipilimumab, which is now going to go to the FDA for approval as an adjuvant therapy in stage III, high-risk disease. It is a big deal when you’re looking at the possibility of a frontline approval of ipilimumab with nivolumab concurrent therapy. These are things that will weigh on the minds of the investigators like us, and the community doctors who are going to have to deal with this in the community setting.

I think that it will be a risk-benefit analysis in patients at risk for a significant level of toxicity from ipilimumab, or ipilimumab with nivolumab. You are going to weigh the odds, and you are going to treat the patients who are at the highest risk of death, progression, or relapse, depending on if it’s the adjuvant or metastatic mode. You are going to treat the highest-risk patients with the most aggressive therapy. On the other hand, you potentially will only give pembrolizumab or nivolumab alone, for example, to someone up-front who has low-risk or low-burden disease, or pretty small-volume indolent disease.

Do you think molecular testing should be routinely performed on melanoma tumors? If so, which patients should be tested and when?

We are now in the molecular and targeted age, and every new patient with metastatic disease and high-risk stage III disease with melanoma should get molecular testing. We routinely do a panel of 40 to 50 genes, and at an academic center, I think that is appropriate because we’re going to go back and undoubtedly reuse that data in the future. Right now, the actionable mutations are few: KIT, RAS, and BRAF. It should occur at the first diagnosis of metastatic disease. Anyone with stage III disease should get molecular testing done at the diagnosis of locoregional recurrent disease.

What is the practice concerning molecular and biomarker testing for patients treated at Moffitt Cancer Center?

We will get molecular testing with our own custom panel of 50 genes, which is partly for research purposes, but it is a CLIA-certified test. We will do that on every single patient we see with stage III or IV disease.

What are some important take-away messages for oncologists treating patients with melanoma?

The most important take-home messages are, as always, put your patient on a clinical trial when possible. Also, do not be afraid of the toxicities of ipilimumab or ipilimumab with nivolumab. They should know that PD-1 drugs are excellent frontline therapies, and that new combinations will be coming very soon.

If you treat someone up-front with BRAF plus MEK inhibitors, you are likely to see a relatively short duration of response. Therefore, sometimes it might pay to jump to an immunologic treatment sooner than later. Local therapies with things like T-VEC may be very useful. Those are up for approval by the FDA, so we will find out soon enough.


  1. McArthur G, Ascierto P, Larkin J, et al. Phase 3 double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519). Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA5.
  2. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma [published online September 29, 2014]. N Engl J Med. 2014; 371(20): 867-1876.
  3. NIH Clinical Trials Registry. Identifier: NCT01844505.
  4. NIH Clinical Trials Registry. Identifier: NCT01866319.