Targeted therapy combination extends survival in BRAF-mutant melanoma
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Key takeaways:
- Adjuvant dabrafenib plus trametinib improved OS in adults with resected stage III BRAF V600-mutant melanoma.
- Researchers noted a “clinically meaningful” OS benefit despite not having statistical significance.
CHICAGO — Adjuvant dabrafenib plus trametinib reduced mortality risk for adults with resected stage III BRAF V600-mutant melanoma, according to final results of the randomized phase 3 COMBI-AD trial.
The findings, presented at ASCO Annual Meeting, also reaffirmed 3- and 5-year updates on improved RFS and distant metastasis-free survival for individuals in the study’s treatment arm.
“Dabrafenib [Tafinlar, Novartis] and tramtetinib [Mekinist, Novartis] remains a standard-of-care choice as an adjuvant therapy for patients with resected stage III melanoma, especially given the persistent and durable benefit in the RFS and [distant metastasis-free survival],” Georgina Long, AO, BSc, PhD, MBBS, co-medical director at Melanoma Institute Australia, told Healio.
“With this clinically meaningful OS benefit, it should be discussed as an option when patients with BRAF V600-mutant resected stage III melanoma are considering adjuvant therapy,” she added. “Importantly, patients with V600E derive the greatest benefit.”
Background and methodology
Surgery can cure many individuals with localized melanoma, but those with stage III malignancies have an increased risk for relapse and death following resection, according to background information Healio previously reported.
Researchers evaluated dabrafenib, a BRAF inhibitor, plus trametinib, a MEK1/2 inhibitor, as an adjuvant therapy in the COMBI-AD trial.
The study included 870 adults with high-risk stage III BRAF V600E- or BRAF V600K-positive melanoma who had undergone complete surgical resection.
Researchers randomly assigned 438 patients to dabrafenib 150 mg twice daily and trametinib 2 mg daily. The other 432 patients received matched placebo.
Study investigators stratified patients by BRAF status and disease stage.
Most patients (91% in both cohorts) had a BRAF V600E mutation.
RFS served as the study’s primary endpoint, with OS and distant metastasis-free survival as secondary endpoints.
The treatment arm had a median follow-up of 100 months, and the placebo arm had a median follow-up of 82.5 months.
Results and next steps
Median OS has not been reached in either cohort, study investigators reported.
Patients in the investigative arm had numerically improved OS (HR = 0.80; 95% CI, 0.62-1.01), but researchers did not see an overall statistical significance.
“With modern era drug therapies available for patients with advanced melanoma, moving forward it is unlikely we will see a separation in OS curves for adjuvant studies like this,” Long said.
“Given we did not see a separation of OS curves for adjuvant ipilimumab [Yervoy, Bristol Myers Squibb] vs. nivolumab [Opdivo, Bristol Myers Squibb], and OS is not reported for pembrolizumab [Keytruda, Merck] vs. placebo as yet, this is clinically meaningful,” she added. “We must be cautious though, as the trial was commenced when BRAF and MEK inhibitors were not widely available for stage IV melanoma, so very early on in the trial, patients who recurred may not have accessed a BRAF-plus-MEK inhibitor combination, whereas they would today.”
Most subgroups in the dabrafenib plus trametinib group had an OS benefit compared with placebo, including individuals with a BRAF V600E mutation (HR = 0.75; 95% CI, 0.58-0.96) and those with ulceration
Patients with a BRAF V600K mutation had improved OS compared with placebo, but Long cautioned about the small subgroup size (HR = 1.95; 95% CI, 0.84-4.50).
“We know that V600K have a high tumor mutation burden,” Long said in response to a question after her presentation. “We do know that they respond to immunotherapy better than the V600E counterparts, and so, as a field, I think we have to think together about what we do with this data. I actually would flip it and more focus on the fact that 91% of the patients in the trial had V600E mutant melanoma and that they may be the patient population we need to focus on for adjuvant therapy.”
Participants in the dabrafenib and trametinib arm also had superior melanoma-specific survival (HR = 0.78; 95% CI, 0.59-1.02).
The treatment arm had significantly improved RFS (HR = 0.52; 95% CI, 0.43-0.63) and distant metastasis-free survival (HR = 0.56; 95% CI, 0.44-0.71).
As Healio previously reported, the dabrafenib and trametinib group had improved RFS at 3 years (58% vs. 39%) and 5 years (52% vs. 36%), which researchers observed in patients with stage IIIA, IIIB and IIIC malignancies. Distant metastasis-free survival also improved at 3 years (71% vs. 57%) and 5 years (65% vs. 54%).
“These are great results,” Long said.
Researchers did not report any new adverse events. Pyrexia, the most common adverse event, could be reversed with pause of treatment or corticosteroids, Long said.
“It is interesting to note we see more skin cancers diagnosed in the first 3 years for patients on the dabrafenib plus trametinib arm, but this can be explained by the mandatory skin surveillance on trial, and if patients in that arm had an RFS benefit, then they would undergo more rigorous skin surveillance for longer than patients on the placebo arm,” Long added. “The majority of recurrences occur in the first few years, thus supporting this hypothesis.”
Long and colleagues plan on reporting updated biomarker data from the study in the future.
“For now, we have no evidence that our best adjuvant therapies improve overall survival, but personally I think the point is becoming a little moot because the data are moving us towards immunotherapy as upfront therapy in stage III patients instead of adjuvant therapy,” Paul B. Chapman, MD, chief medical research officer at Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian Hospital, said as an expert discussant following the presentation, referencing a pair of other studies.
“I think we’re looking at the end of adjuvant therapy for melanoma. In fact, in melanoma, I think we should drop the archaic term of neoadjuvant since it implies that the real treatment is surgery,” he added “We’re learning that the real treatment is checkpoint inhibitor therapy in stage III patients and the question for our field going forward ... will be which patients benefit from subsequent adjuvant surgery.”
For more information:
Georgina Long, AO, BSc, PhD, MBBS, can be reached at georgina.long@sydney.edu.au.
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Hauschild A, et al. Abstract 9500. Presented at: ASCO Annual Meeting 2024; May 31-June 4, 2024: Chicago.
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