Triplet Therapy Emerges as a First-Line Option in BRAF V600–Mutant Melanoma

CancerNetwork® spoke with Dirk Schadendorf, MD, professor of dermatology and oncology and director of the Department of Dermatology and the West German Cancer Center at University Hospital Essen in Germany, about final results from the phase 3 STARBOARD trial (NCT04657991), which he presented at the 2026 European Society for Medical Oncology (ESMO) Congress.

STARBOARD compared first-line encorafenib (Braftovi), binimetinib (Mektovi), and pembrolizumab (Keytruda) with placebo plus pembrolizumab in patients with unresectable locally advanced or metastatic BRAF V600–mutant melanoma.¹ Schadendorf discussed the study’s redesign and key efficacy and safety findings, how to select patients for the triplet vs immunotherapy alone, management of overlapping toxicities, the timing of BRAF testing, options for patients who relapse after perioperative therapy or have brain metastases, de-escalation strategies, and the questions STARBOARD leaves open. He also highlighted data from the phase 3 INTerpath-001 trial (NCT05933577) of the investigational mRNA neoantigen therapy intismeran autogene plus pembrolizumab as his top presentation from the meeting.²

CancerNetwork: What did STARBOARD show for first-line encorafenib, binimetinib, and pembrolizumab vs pembrolizumab alone in BRAF V600–mutant melanoma, and how does it change the treatment landscape?

Schadendorf: STARBOARD is a trial that tries to combine both new treatments we have had in hand over the last 10 years: targeted therapy, meaning the combination of BRAF and MEK inhibition, and checkpoint blockade, a triplet therapy. We have tested triplet therapy regimens in the past in prospective clinical trials in comparison with BRAF/MEK inhibition alone. We saw only very limited clinical benefit, and there was a pressing question of whether we should also compare triplet therapy against PD-1 inhibitor monotherapy, because PD-1 monotherapy is considered the standard of care in first-line treatment in many countries.

STARBOARD compared triplet therapy with encorafenib, binimetinib, and pembrolizumab against pembrolizumab in patients with first-line BRAF V600–mutant melanoma. Initially, the study was planned as a registrational study with 600 patients. However, with the post-COVID period and the changing landscape over the 18 months of initial recruitment, from the middle of 2022 to early 2024, roughly 200 patients were included in the study. The sponsoring company, Pfizer, decided to change the design of the study and made overall response rate the primary end point, with blinded independent review required. The same was true for progression-free survival; the original primary end point of the study became the key secondary end point, also with blinded review.

We saw impressive results. The confirmed response rate was 70% for the triplet therapy, in contrast to almost 33% for checkpoint blockade. That was already a huge difference, which was statistically significant in favor of the triplet therapy. Not only that; disease control was also improved. Median PFS [progression-free survival] was 3.4 months with checkpoint blockade monotherapy vs 33 months with the triplet therapy. That is a huge difference, which was also statistically highly significant.

Because the study was closed prematurely, the survival data, which are important when we are talking about changing the landscape and changing the standard of care, were immature. Still, we saw a hazard ratio of 0.71, so a 29% reduction in the death rate in favor of the triplet therapy, which barely missed the level of statistical significance. Maybe by waiting half a year longer, or with 50 more patients, we would have seen a positive overall survival result in that clinical trial.

One has to say that the triplet therapy is obviously also a little bit more toxic. When we look at grade 3 or 4 toxicities overall, we see roughly 40% in the monotherapy arm and roughly 70% in the triplet arm. There is no doubt that we have high clinical efficacy, and now one has to discuss, even without any official registration, where the right spot is to use this triplet therapy. Easy-to-treat patients who are PD-L1 positive are probably still well served with PD-1 monotherapy or checkpoint blockade alone, but everyone else should also be considered for triplet therapy, in my view. It’s an interesting new option for treating patients in the first line, with a clear benefit across multiple end points.

How should oncologists choose between triplet combination therapy, anti–PD-1 monotherapy, and BRAF/MEK-targeted therapy, and which patient factors should drive that decision?

When we are deciding which patients should get targeted therapy and which patients should get checkpoint blockade, there is a group of patients for whom we consider targeted therapy, and all these patients, I believe, should now also be considered candidates for triplet therapy. Whether you should use BRAF/MEK inhibition on its own, without checkpoint blockade, is the big question, because given the magnitude of the PFS benefit, we have not seen a comparable median PFS in any of the BRAF/MEK clinical trials. Patients who have symptomatic disease or fast tumor kinetics are candidates for the triplet, and it is a perfect alternative to nivolumab [Opdivo] and ipilimumab [Yervoy], which would usually be considered in such a situation. In BRAF V600–mutant melanoma, I now believe this could be a good alternative.

Combining targeted therapy with immunotherapy creates overlapping toxicities. What should nurses, pharmacists, dermatologists, and ophthalmologists watch for, and how can teams tell whether an adverse event is driven by the targeted agents or by pembrolizumab?

Sorting out what is driven by targeted therapy, what is driven by checkpoint blockade, and what is driven by the cancer itself is not an easy task. Experience helps, and there are certain substance-specific adverse effects that we can identify. On the other hand, because the toxicities overlap in some areas, it’s not always easy.

Usually, if you have a substance-specific toxicity, for example, cardiologic issues such as QT prolongation or other symptoms, you would discontinue some of your targeted agents. If you have classic immune-related toxicities, you would start by discontinuing checkpoint blockade. Some symptoms are not so easy to identify or to associate with one of these drugs, and then you have to make a decision, or make an educated guess about what you are doing. For example, nausea, fatigue, or diarrhea could come from either side. These could also be an early sign of immune-related colitis, so one has to be aware of that and try to do the best. What helps is the understanding that when you discontinue targeted therapy, symptom relief is very quick, so you can also use that as a measure to pinpoint the potential cause.

How can pathology and molecular testing teams ensure BRAF status is available quickly enough at diagnosis to support first-line decisions, including for patients who received prior adjuvant therapy?

I personally believe BRAF testing should be done as early as possible, ideally when the patient is first diagnosed with melanoma, and testing should be done at the latest at stage III, meaning with regional lymph node involvement. You could also consider doing it in thick tumors. The guidelines clearly recommend testing starting with stage III. With adjuvant therapy now available, it would also be reasonable to test for BRAF when you start adjuvant treatment, because if the patient relapses, you have a quick decision-making path forward for your patient.

As more patients receive neoadjuvant or adjuvant immunotherapy, what options work best for those who relapse after perioperative treatment, and where might the triplet fit for them?

That’s an important question and one of the current challenges, because we obviously have a changing landscape in first-line stage IV disease, in that these patients are not treatment naive anymore. A large fraction of patients have received systemic treatment in the adjuvant or neoadjuvant setting. If those patients progress, they are obviously already resistant to PD-1 inhibition, or to the prior treatment regimen, and what we know is that these patients are different from the treatment-naive first-line patients we treated in all of our clinical trials, which led to these long-term benefits.

These patients should be considered PD-1 refractory. In my view, triplet therapy is a very good option to consider as the next line of treatment to rescue these patients if they are BRAF V600 positive. We are already using BRAF/MEK inhibition in patients with mutations as a rescue strategy if they have failed checkpoint blockade in the adjuvant and neoadjuvant settings.

For patients with BRAF-mutant melanoma and brain metastases, how should medical oncologists, radiation oncologists, and neurosurgeons coordinate systemic therapy with local treatment?

Brain metastases are a challenge. In most centers, dual checkpoint blockade with nivolumab and ipilimumab is the standard of care for patients with brain metastases. If that is not feasible because of comorbidities, autoimmunity, or prior failure of checkpoint blockade, then in patients with BRAF V600–mutant melanoma, triplet therapy can be considered and, in my view, should be considered.

How do you think about treatment duration and de-escalation with the triplet, such as stopping the targeted agents while continuing immunotherapy, and how should those decisions be communicated to patients?

That’s also a challenging topic. With response rates around 70% and long-term disease control, this is clearly something to discuss. We would consider stopping treatment, or giving the patient a treatment pause, only in those patients who have achieved a complete clinical response that has lasted for several months, and usually we also perform a PET/CT to confirm that there is no disease activity. If that’s the case, one needs to discuss with the patient whether they feel safe and comfortable having a longer interruption of treatment, with the chance to restart if the tumor starts to grow again. Usually you would do that only after 1 year of complete response or complete tumor control.

Particularly with triplet therapy, where you also have this mix of adverse effects, you could consider not discontinuing all drugs at once. For example, you could discontinue targeted therapy first, maintain checkpoint blockade, see how the adverse effects and other things work out, and then also stop checkpoint blockade at some point. That’s how we would do it in our patients at the moment.

What questions does STARBOARD leave open, and what should the next generation of trials in BRAF-mutant melanoma address?

Given the way this trial was conducted, and with immature OS data, the question of whether there is an OS benefit with this kind of treatment unfortunately remains open. I’m pretty sure that this trial will not be done again, so we will not be able to answer this question. New drugs will be coming; we have T-cell engagers, we have bispecifics, and various cellular therapies are coming. Different modes of action will step in. The idea that triplet therapy might benefit our patients in certain circumstances will be kept in mind by many oncologists treating melanoma, and it will be used in certain circumstances without further evidence being generated in the future, unfortunately.

What was the abstract or presentation at ESMO 2026 that you were most excited to learn more about, and why?

That’s easy. What is the major thing at ESMO 2026? I think yesterday, at the Presidential Session, we were all so excited to see that a patient-specific neoantigen vaccine added to pembrolizumab made such a big difference in relapse-free survival and distant metastasis–free survival. I believe that these mRNA vaccines will be a new step in oncology treatment over the next decade.

References

1. Schadendorf D, Dummer R, Sullivan RJ, et al. STARBOARD phase 3: a randomized, double-blind study of first-line encorafenib, binimetinib, and pembrolizumab vs placebo and pembrolizumab for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 2071O.

2. Long GV, et al. Phase 3 INTerpath-001 study of intismeran autogene plus pembrolizumab vs placebo plus pembrolizumab as adjuvant treatment for resected high-risk melanoma. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA1.