By Kim Margolin, M.D.

A “triplet” is the casual term to describe the combination of three drugs to treat cancer. Multiple two-drug combinations (“doublets”) are approved to treat melanoma, but only recently have clinical trials tested triplets. One of those triplets has been newly approved to treat BRAF-mutant melanoma. Two of the three drugs are targeted therapies, and the third drug is an immunotherapy.

Before we get to explaining more about the triplet, let’s review the meanings of BRAF-mutant, targeted therapy, and immunotherapy.

Half of all patients diagnosed with melanoma originating in the skin (not the eyes, the internal mucous membranes like mouth, anus or female genital tract, or the extremities such as under nails, palms or soles) have a genetic mutation called BRAF in their melanoma cells. If you have this genetic mutation, your melanoma will be referred to as BRAF-mutant or BRAF-positive.  If you are a Stage III or Stage IV patient, you should make sure your melanoma has been tested for BRAF mutation.

BRAF mutation can cause more rapid growth and resistance to immune system control of the melanoma cells.  Fortunately, researchers have found that these BRAF-mutated melanomas are uniquely susceptible to being inhibited or even killed by certain pairs of drugs. These drugs block (or inhibit) the action of mutant BRAF as well as the next biochemical step in the cell, MEK, which is enhanced because of mutant BRAF (MEK itself is not mutated).  You’ll hear these drugs referred to as targeted therapies—because they target these specific mutations that power the melanoma cells. Although there are single-agent BRAF and MEK inhibitors approved for use in melanoma, they work better when used together—one BRAF inhibitor and one MEK inhibitor—for those who have BRAF-mutant melanoma. Patients who do not have BRAF-mutant melanoma do not benefit from these targeted therapies.

By contrast, immunotherapies—of which there are several with high activity in melanoma— work by stimulating the immune system, which in turn can allow the immune cells to seek, find, and kill cancer cells. Immunotherapies are effective for both BRAF-mutant and BRAF-non-mutant (also termed “wild-type”) melanoma.

Since the first effective immunotherapy and targeted therapies both came out in 2011, with several additional drugs in the subsequent years, the decision about which type of drug to use first (targeted or immunotherapy) in patients with a BRAF-mutant advanced melanoma has been challenging.  In other words, since both immunotherapies and targeted therapies can be successful in BRAF-mutant melanoma, but the likelihood of remission and the chance of cure may be different, it’s difficult to decide which therapy to give first. This question is important not just because physicians want to select the most likely treatment to work for their patients, but also because researchers have found that sometimes a first, unsuccessful therapy can affect the success of the second therapy.

Doctors must weigh various available data on immunotherapies and targeted therapies in order to decide which treatment to give first. Here are some of the data they take into consideration:

In general, immunotherapy works more slowly and produces tumor responses in a lower percentage of patients than BRAF plus MEK targeted therapy.  But a higher percentage of patients receiving immunotherapy maintains their response even after stopping therapy.  Additionally, treatment durations with immunotherapy may be as short as a few months.  In contrast, the targeted drugs need to be taken for a longer duration in order to sustain the response, and if they are stopped for side effects, the response is usually lost. Patients whose melanoma begins to grow after an initial response to targeted therapy have been reported to respond poorly to immunotherapy, while patients whose melanoma grows during or after immunotherapy seem to respond as well to targeted therapy as those who receive targeted therapy as their first treatment.  This question of which therapy should come first is an important one, and researchers are currently running randomized trials to learn which is the overall better way to initiate therapy, but results are not yet ready to analyze.

Meanwhile, researchers have been pursuing other approaches to melanoma treatment and then putting them to the test of randomized studies. Specifically, researchers have been studying whether it’s effective to combine a single immunotherapy (a PD-1 antibody, the single most active immunotherapy drug in melanoma, and many other cancers) with a BRAF and a MEK inhibitor at doses that are generally safe and well-tolerated. These researchers want to know if specific triplets (a PD-1 antibody plus two targeted therapies) are effective for treating melanoma.

This article will summarize the results of three very recent trials that randomized patients with BRAF-mutant advanced melanoma to receive a doublet of targeted therapy with a PD-1 antibody or with a placebo.  While each of these trials demonstrated superior outcomes for the treatment that included PD-1 blockade, only one of the trials showed sufficient power to reach statistical significance—and this difference was so strong that the results were used by the Food and Drug Administration (FDA) to support almost instantaneous approval of the triplet for first-line therapy of advanced BRAF-mutant melanoma.  The National Comprehensive Cancer Network has now incorporated this recommendation into its list of initial therapies available for BRAF-mutant melanoma. More on the successful triplet, below.

The first of the three randomized trials to be reported was the smallest, containing 120 patients, from Paolo Ascierto and colleagues in a letter to Nature Medicine, 2019.  Note that this trial was a randomized Phase II, which means that the statistical design was for a relatively small study that would not be sufficient to declare a significant difference between the outcomes of the two patient groups.  While there may be subtle differences in the statistics behind randomized Phase II trials and the more rigorous and always larger randomized Phase III trials, it would require an enormous difference in one of the critical outcomes (like response rate or survival) for a randomized Phase II to support a drug approval or its adaptation into routine use because Phase II testing is primarily intended to figure out whether the treatment works or not; Phase III trials tell us if the new treatment is better than what we already have. Successful Phase III trials are usually needed for FDA approval.

The Ascierto trial (also known as the Keynote-022, because Merck has designated its pembrolizumab [Keytruda]-containing, sponsored trials with the “Keynote” nickname), had equal numbers of patients in both groups, one group receiving the BRAF plus MEK inhibitors dabrafenib (Tafinlar) and trametinib (Mekinist), plus the PD-1 blocking antibody pembrolizumab (all at standard doses) and the other group receiving the targeted therapies doublet plus a placebo instead of pembrolizumab.  The outcomes of this trial were positive in that both the average progression-free survival (time to tumor growth or death from melanoma) and the duration of response to therapy was six months longer for the triplet therapy.  However, there were more than twice as many serious toxicities (especially fever, liver test abnormalities, and rash) among patients receiving all three drugs versus those receiving only the targeted therapies.

The second trial—the one that led to the FDA approved triplet—was a large, randomized Phase III study comparing another targeted combination, vemurafenib (Zelboraf) plus cobimetinib (Cotellic), with either the PD-L1 antibody atezolizumab (Tecentriq) or placebo. The results were reported by Grant McArthur at the virtual meeting of the American Association for Cancer Research in April 2020.  In this study, termed IMspire150 and sponsored by Roche-Genentech (which makes all three drugs), 514 patients were randomized, with stratification (equal assignment) by their geographic region and their blood level of the enzyme lactate dehydrogenase, which has prognostic importance in melanoma.  For safety, patients started with the targeted doublet and then had the atezolizumab or its placebo added; the BRAF inhibitor vemurafenib was given at a 75% dose in patients randomized to atezolizumab.

The results favored the triplet:  The average progression-free survival was four months longer and the duration of remission was eight months longer for the triplet.  Most importantly, the average overall survival for triplet therapy was also four months longer, which may not sound dramatic, but when you look at the number of patients affected by the superior results, there was a 33% lower chance of dying from melanoma for patients who received the triplet.  The side effects and toxicities were moderate but tolerable, mainly consisting of fatigue, fever, joint pains, disturbances of liver enzymes, and thyroid dysfunction.  Because this trial was large with very little patient dropout, all outcomes were mature at the time of reporting. It also had the advantage of an independent review committee and was designed as a “registration” trial (one that is intended to be brought to the FDA in support of a new drug approval or a new use for an already-approved drug), so it was very rapidly reviewed and approved, even before the results of the third study, described below, were reported.  Again, FDA approval is generally based on a large and statistically sound Phase III trial with the investigational regimen providing a clear benefit either in survival or in symptoms/quality of life.

The final randomized trial of combination BRAF/MEK inhibitors plus PD-1 inhibition was the Combi-I trial, sponsored by Novartis, consisting of dabrafenib plus trametinib and the investigational PD-1 antibody spartalizumab versus placebo.  This study was also large, with 532 patients randomized, and the outcomes—reported in September, 2020 at the virtual meeting of the European Society of Medical Oncology (ESMO)—also favored the triple-drug regimen.  However, the differences were not sufficiently large to meet the requirements of the FDA to approve the triplet combination.  While this trial also showed a four-month difference in the average progression-free survivals the overall survival results curves (preliminary) did not appear to provide a clear benefit.  The side effects of the triplet were not much worse than the doublet—mainly a low incidence of liver and muscle enzyme abnormalities, fever, and fatigue.  Interestingly, in this study, patients on the triplet combination who had high numbers of mutations in melanoma cells—a sign of more sun damage—fared better than those receiving only the targeted drugs.  This difference is not surprising, because the immune system recognizes mutations due to genetic damage to cancer cells, while targeted therapies only work against melanoma cells with the BRAF mutation.

It’s interesting that all three of these trials looked very similar in terms of their progression-free survival differences when comparing triplet with targeted therapy, yet only one trial showed enough statistical power to meet the stringent criteria of the FDA to get the drugs approved as a triplet.  While the drugs used in the three studies were slightly different, they act against cancer cells in a similar way, and it’s likely that the differences in the trial outcomes were due to minor variations in the way the studies were designed or slight differences in how many patients had to stop targeted drugs or immunotherapy for side effects.  There will be plenty of commentary from experts in the field about whether triplet combinations of targeted BRAF plus MEK inhibitors plus immune checkpoint blocking therapy is better than sequences starting with immunotherapy or targeted therapy and switching over if the melanoma grows.

Also of importance is that none of the three studies had a comparison with single-agent PD-1 antibody (such as pembrolizumab or nivolumab [Opdivo]) or with double immunotherapy (such as the combination of ipilimumab [Yervoy] and nivolumab), which are now the most commonly used drugs for first-line treatment of advanced melanoma. Most importantly, we do not yet have the results of mature studies designed to test sequences of immunotherapy or targeted therapy (when the melanoma has a BRAF mutation), such as the so-called DreamSeq or EA6134 study. Again, answering the question of which type of therapy should be administered first to a patient with BRAF-mutant melanoma is critical.  Other, more complex sequencing designs are also under evaluation.

It is clear that even though melanoma patients and their physicians have a relatively limited number of drugs, compared with some other tumors like breast cancer and colon cancer, the selection of regimens can be extremely challenging, particularly when the question of brain metastases and local therapies for single-site disease are also considered.  Stay tuned for more articles in the In Plain English series to explain other exciting new information for patients, families, and practitioners in the complex world of melanoma.

Kim Margolin, M.D.

Dr. Margolin earned her undergraduate degree summa cum laude from the University of California, Los Angeles, graduating Phi Beta Kappa, then went on to receive her medical degree from Stanford University School of Medicine. After an internal medicine residency at Yale-New Haven Hospital in New Haven, CT, Dr. Margolin began her fellowship in hematology/oncology at the University of California, San Diego School of Medicine and completed the fellowship in medical oncology and hematology and bone marrow transplantation at City of Hope. 

Triple board-certified in internal medicine with subspecialties in medical oncology and hematology, Dr. Margolin is a fellow of the American College of Physicians. She is on the editorial board of the Journal of Immunotherapy and is section editor in melanoma for the journal Cancer. Dr. Margolin has chaired numerous institutional committees, professional societies, and advisory boards. She has been the Chair of the Cancer Education Committee and a member of the Nominating Committee of ASCO and previously served as a member of the Oncologic Drug Advisory Committee (ODAC) of the FDA.

Dr. Margolin is also an active member of several foundations and federal grant review committees. Among her 180 peer-reviewed articles, 60 invited reviews or editorials, and 16 book chapters, her most recent work has been in the area of melanoma metastatic to the brain and immunotherapy strategies for melanoma and other skin cancers. Dr. Margolin is frequently invited to present her work at national and international conferences and symposia.