Three-drug mix kept advanced melanoma in check far longer in a trial

A combination of two targeted pills and the immune drug Keytruda kept a gene-driven form of advanced melanoma under control far longer than Keytruda alone, according to the final results of a trial called STARBOARD, presented at the 2026 European Society for Medical Oncology (ESMO) Congress.¹ The three-drug approach also brought more serious side effects, and the trial was cut short, so whether it helps people live longer is still not settled.¹

The results were discussed in an interview with Dirk Schadendorf, professor of dermatology and oncology and director of the Department of Dermatology and the West German Cancer Center at University Hospital Essen in Germany, who presented them.¹

What happened

Melanoma is a skin cancer. In some patients, the tumor carries a change in a gene called BRAF, known as a BRAF V600 mutation, which drives cancer growth.¹ STARBOARD enrolled people whose melanoma had this change, had spread or could not be removed by surgery, and had not been treated before.²

Everyone in the trial received pembrolizumab (Keytruda), an immune drug, as an infusion into a vein every 3 weeks, for up to two years.² Half of the participants also took two pills at home every day: encorafenib (Braftovi) and binimetinib (Mektovi).² These pills target the faulty BRAF signal and a partner protein called MEK. The other half took a placebo (a dummy pill) with Keytruda.¹ The trial was randomized and double-blind, meaning patients were assigned by chance and neither they nor their doctors knew who got which pills.²

The evidence so far

According to Schadendorf, the confirmed response rate, the share of people whose tumors shrank by a set amount, was 70% with the three drugs, compared with almost 33% with Keytruda alone.¹ He said that difference was statistically significant.¹

The gap was larger for the time before the cancer grew again, called progression-free survival. The median, the midpoint across patients, was 33 months with the three drugs versus 3.4 months with Keytruda alone, a difference he described as statistically highly significant.¹ Both measures were checked by blinded independent reviewers, outside experts who did not know which treatment each patient had received.¹

For survival, the picture is less clear. Schadendorf reported a hazard ratio of 0.71, which he described as a 29% reduction in the death rate in favor of the three drugs.¹ That result “barely missed the level of statistical significance,” in his words, because the study closed early and the survival data were immature.¹ He suggested that waiting half a year longer, or 50 more patients, might have produced a positive survival result, but that is his view, not something the trial showed.¹

Side effects

Serious side effects, those rated grade 3 or 4 on the standard scale, occurred in roughly 70% of people on the three drugs and roughly 40% of those on Keytruda alone.¹ Schadendorf said the combination is “obviously also a little bit more toxic.”¹

What it does not show yet

STARBOARD did not run as first planned. It was designed as a registrational study, the kind meant to support approval, with 600 patients.¹ Schadendorf said that after the COVID period and a changing treatment landscape, roughly 200 patients were enrolled over about 18 months of recruitment, from the middle of 2022 to early 2024.¹ The sponsor, Pfizer, then changed the design. Response rate became the main goal, and progression-free survival, the original main goal, became the key secondary goal.¹

The public trial record lists an actual enrollment of 257 people and includes an initial safety lead-in stage that looked at dose-limiting side effects in the first two treatment cycles.² The sources do not explain the difference between that figure and the roughly 200 patients Schadendorf described.

Other limits:

• Survival data are immature, so it is not yet known whether people live longer on the combination.¹
• The record shows main data collection completing on 2026-10-30, and no results had been posted to the registry yet.²
• The results in these sources come from a congress presentation and an interview, not a full peer-reviewed paper.¹
• Schadendorf spoke of using the combination “even without any official registration,” and the sources do not show any regulatory approval for it.¹

Who is behind it

Pfizer sponsored STARBOARD.² The study was first posted on the public registry in December 2020 and started in January 2021.² It is now listed as active but no longer recruiting.² Pfizer also made the decision to shrink and redesign the trial, according to Schadendorf.¹ The sources reviewed do not describe any financial ties between Schadendorf and the companies involved.

How it fits the field

Over the last decade, doctors have gained two main kinds of treatment for advanced melanoma: targeted pills that block BRAF and MEK, and checkpoint blockers such as Keytruda, which release a brake on the immune system.¹ Schadendorf said earlier trials tested three-drug combinations against the targeted pills alone and saw only very limited benefit.¹ Because a single checkpoint blocker that targets a protein called PD-1 is the standard first treatment in many countries, the open question was how a three-drug combination would compare with that.¹ STARBOARD was designed to answer it.

Schadendorf offered his own view of where the combination might fit. He said patients whose tumors test positive for a marker called PD-L1 and who are easier to treat are “probably still well served” by a single immune drug, while others should also be considered for the three drugs.¹ He named people with symptoms or fast-growing tumors as candidates, and called the combination a possible alternative to the two-drug immune pairing of nivolumab (Opdivo) and ipilimumab (Yervoy) often used in that situation.¹ He also said no trial of the BRAF and MEK pills on their own had shown a comparable time before the cancer grew.¹ These are one expert’s opinions, not formal guidelines.

At the same meeting, Schadendorf picked results from another late-stage melanoma trial, INTerpath-001, as his top presentation.¹ That trial, sponsored by Merck Sharp & Dohme, tests intismeran autogene, a personalized mRNA-based therapy built from each patient’s tumor, plus Keytruda, to see if it keeps high-risk melanoma from returning after surgery.³ It aims to enroll about 1,089 people, and its main data collection is not expected to finish until October 2029, according to its registry record.³

What to watch next

• Survival data: whether longer follow-up turns the 29% lower death rate into a statistically clear result.¹
• Posted results and publication: the registry record does not yet list results, and the main data collection date has just passed.²
• Regulators and guidelines: whether the smaller, redesigned trial is enough for regulators or treatment guidelines to adopt the three-drug approach as a first treatment.¹
• Side-effect management: how doctors handle the higher rate of severe side effects when combining targeted pills with immune treatment.¹

For now, STARBOARD shows a large difference in tumor shrinkage and in time before the cancer grew, at the cost of more serious side effects, in a trial that ended smaller and earlier than planned.¹