Are Triplets Necessary for BRAF-Mutated Melanoma?

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Where does triplet therapy fit in the treatment of patients with stage IV BRAF-mutated melanoma? Is there strong evidence for combining a BRAF inhibitor, MEK inhibitor, and checkpoint inhibitor? Ragini Kudchadkar, MD, Chair of the Protocol Review and Monitoring Committee at Winship Cancer Institute of Emory University, shared her thoughts on these questions at the 2021 Debates and Didactics in Hematology and Oncology conference, sponsored annually by Winship Cancer Institute.1

One such triplet has been approved by the U.S. Food and Drug Administration and is listed in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for melanoma: vemurafenib/cobimetinib plus atezolizumab. This approach showed an improvement in progression-free survival in one pivotal trial,2 although it failed to show such improvement in two other trials.3,4

Ragini Kudchadkar, MD

Ragini Kudchadkar, MD

“The studies do tell us that BRAF-mutant melanoma is a higher-risk population than wild-type, and it does need a combination approach. But whether a triplet is the right approach is something we have yet to see, especially with the advent of some of the newer immunotherapy combinations. Right now, triplet therapy has significant clinical and financial toxicity, and it’s not clear that it’s better than sequencing drugs,” Dr. Kudchadkar maintained.

Three Pivotal Trials of Triplet Regimens

Triplets aim to harness the high response rates known to occur with BRAF/MEK inhibitors and the long-term durability of PD-1/L1 agents. “It’s the oncology sink approach. We’ve got drugs that work, so let’s put them together,” said Dr Kudchadkar. Adding the checkpoint inhibitor to targeted therapy could possibly “raise the tail on the [Kaplan-Meier] curve,” she said.

Dr. Kudchadkar discussed three pivotal clinical trials that have evaluated BRAF/MEK inhibitors with or without single-agent PD-1/L1–based therapy. All enrolled previously untreated patients with advanced melanoma and mutations in BRAF V600.

Although one trial reported positive results and the other two were deemed negative, the actual numbers reported in the three studies were quite similar. There are now questions as to whether the studies had the appropriate design and control arms—including whether the PD-1/L1 inhibitor should have been given first (as is customary), with the BRAF/MEK inhibitor as the experimental addition.

IMspire150: Vemurafenib/Cobimetinib Plus Atezolizumab

IMspire150 randomly assigned 514 patients to receive vemurafenib plus cobimetinib for one 28-day period followed by 28-day cycles of the same regimen plus atezolizumab or placebo.2 Median progression-free survival by investigator assessment was 15.1 months with the triplet vs 10.6 months with vemurafenib/cobimetinib (P = .0249). The curves separated by 9 months and remained separate with 2 years of follow-up. The median duration of response also appeared longer with the triplet: 21.0 months vs 12.6 months, reported Dr. Kudchadkar.

Both arms experienced a notable amount of grade 3 or 4 toxicity: 79% with the triplet and 73% with the doublet. This degree of toxicity makes it important to be able to identify potential responders to these drugs, she said.

Caroline Robert, MD, PhD, and colleagues sought to do this in an analysis of IMspire150 data presented at the 2021 ASCO Annual Meeting.5 They found that interferon-gamma and tumor mutational burden discriminated progression-free survival benefit in patients treated with the triplet and that patients with normal lactate dehydrogenase (LDH) levels and high interferon-gamma were most likely to achieve durable responses. “Hopefully, as the data mature, we can get an idea of which patients will do better on triplets over time,” Dr. Robert commented.

KEYNOTE-022: Dabrafenib/Trametinib Plus Pembrolizumab

The KEYNOTE-022 investigators randomly assigned 120 patients to receive dabrafenib/trametinib plus pembrolizumab and continued until disease progression.3 Similar to the IMspire150 trial, the median progression-free survival in KEYNOTE-022 was 16.0 months with the triplet vs 10.3 months with the doublet (hazard ratio [HR] = 0.66; P = .043); however, this was not statistically significant.

Also, like IMspire150, toxicity was notable in KEYNOTE-022, with 58% of the triplet arm experiencing grade 3 to 5 adverse events (including one death) and 25% of the doublet arm experiencing grade 3 or 4 toxicities.

COMBI-i: Dabrafenib/Trametinib Plus Spartalizumab

The COMBI-i trial enrolled 532 patients and reported similar results.4 Median progression-free survival was 16.2 months with the triplet and 12.0 months for the doublet (HR = 0.82; P = .042), which did not meet the threshold for statistical significance. A preplanned subset analysis found the most benefit for the triplet among patients with higher LDH levels, higher tumor mutational burden, more sites of metastasis, and more bulky disease.

Grade ≥ 3 adverse events occurred in 54.7% of the triplet arm and 33.3% of the doublet arm; those leading to study discontinuation occurred in 12.4% and 8.0%, respectively.

Trial Data Comparison

“Looking at the studies together, their numbers seem to overlap. There is no scientific reason why one should be considered better than the other,” Dr. Kudchadkar said.

Of note, IMspire150 with atezolizumab was the only trial that met its endpoint, for reasons that are not clear and could possibly include “chance,” she added. “If anything, PD-L1 antibodies such as atezolizumb, as single agents, have not been as effective as the PD-1 antibodies, but these studies have very similar results.”

“I’m not sure what that means in terms of clinical significance,” noted Dr. Kudchadkar. “You do get a slightly better median progression-free survival, but it’s probably not worth the toxicity. What we need to know is whether triplets are better than sequencing of the same agents.”

Here are two sequencing studies in stage III or IV BRAF-mutated melanoma that are asking that question:

  • SECOMBIT: This prospective, randomized phase II trial is comparing three arms: encorafenib plus binimetinib, followed at disease progression by ipilimumab plus nivolumab (arm A); ipilimumab plus nivolumab, followed at disease progression by encorafenib plus binimetinib (arm B); and “sandwich” treatment with encorafenib plus binimetinib for 8 weeks followed by ipilimumab plus nivolumab, then at disease progression encorafenib plus binimetinib (arm C).
  • DREAMSeq: This phase III trial is evaluating initial treatment with ipilimumab and nivolumab followed at disease progression by dabrafenib and trametinib vs the opposite sequence.

Early Data for SECOMBIT

Preliminary data from the SECOMBIT sequencing trial,6 analyzed after about 2 years, have not shown a “clear winner.” However, there is a suggestion that outcomes might be improved by giving the BRAF/MEK inhibitors first to shrink the tumor and then follow with immunotherapy, according to Dr. Kudchadkar. From the data so far, she added, “it’s clear that sequencing may be just as good as combining all three together to start with.”

In the study of 209 patients, response rates were 83% in arm A, 45% in arm B, and 78% in arm C. Median progression-free survival was 15.8, 7.2 months, and 11.4 months, respectively, and the 2-year progression-free survival rates were 35%, 38%, and 39%, respectively. Grade 3 or 4 adverse events were reported for 49% of arm A, 73% of arm B, and 51% of arm C.

Researchers are “dicing the data” from the clinical trials to identify patients most likely to benefit from triplets…. Hopefully, soon we will know what is better (combinations vs sequential therapy) and where triplet therapy lies, but right now, I don’t think it’s in the front-line setting,” Dr. Kudchadkar commented.

“The triplet is not a treatment to be taken lightly. Given the toxicity, you really have to ask what you are getting for your buck, especially if this is going to be a new front-line therapy,” she said. “We are shooting for the long term, and our bar is pretty high right now. For that much toxicity, we need to see a huge benefit in overall survival.” 

DISCLOSURE: Dr. Kudchadkar has received honoraria from Array BioPharma and Bristol Myers Squibb; has served as a consultant or advisor to Array BioPharma, Bristol Myers Squibb, Immunocore, Merck, Novartis, and Regeneron; and has received institutional research funding from Merck and Regeneron. Dr. Robert has served as a consultant or advisor to Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi.


1. Kudchadkar R: Triple therapy (PD-1/BRAF/MEK) in stage IV melanoma. 2021 Debates and Didactics in Hematology and Oncology. Presented July 30, 2021.

2. McArthur GA, Stroyakovskiy D, Gogas, H, et al: Evaluation of atezolizumab, cobimetinib, and vemurafenib in previously untreated patients with BRAF V600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. 2020 AACR Virtual Annual Meeting. Abstract CT012. Presented April 27, 2020.

3. Ascierto PA, Ferrucci PF, Fisher R, et al: Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med 25:941-946, 2019.

4. Nathan P, Dummer R, Long GV, et al: Spartalizumab plus dabrafenib and trametinib in patients with previously untreated BRAF V600-mutant unresectable or metastatic melanoma: Results from the randomized phase 3 of the phase III COMBI-i trial. ESMO Virtual Congress 2020. Abstract LBA43. Presented September 19, 2020.

5. Robert C, Lewis KD, Ascierto PA, et al: Effects of baseline lactate dehydrogenase, interferon gamma expression, and tumor mutational burden on treatment response to first-line atezolizumab + vemurafenib and cobimetinib in BRAF V600 mutation-positive advanced melanoma. 2021 ASCO Annual Meeting. Abstract 9523. Presented June 4, 2021.

6. Ascierto PA, Mandala M, Ferrucci PF, et al: First report of efficacy and safety from the phase II study SECOMBIT (Sequential COMBo Immuno and Targeted therapy study). ESMO Virtual Congress 2020. Abstract LBA45. Presented September 19, 2020.