Neoadjuvant dabrafenib, trametinib may improve BRAF-mutant melanoma outcomes

Pre- and postsurgical treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improved EFS for patients with surgically resectable stage III melanoma compared with standard of care, according to results of a single-center, open-label randomized phase 2 trial.

Standard of care — which includes upfront surgery with consideration of adjuvant treatment — is insufficient to cure most patients.

“These results are encouraging for patients with surgically resectable stage III melanoma, who face a high rate of relapse and progression to metastatic disease,” Rodabe Amaria, MD, assistant professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “Our proof-of-concept study strongly supports further assessment of neoadjuvant ... therapy for this high-risk population, which has a 5-year survival rate of less than 50%.”

Amaria and colleagues at MD Anderson evaluated data from 21 adults with surgically resectable clinical stage III or oligometastatic stage IV BRAF V600E or BRAF V600K-mutated melanoma.

Inclusion criteria included an ECOG performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors.

Researchers randomly assigned patients 2:1 to 8 weeks of neoadjuvant dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) followed by surgery plus up to 44 weeks of adjuvant combination therapy (n = 14), or upfront surgery with consideration of adjuvant therapy (n = 7).

The trial stopped early when a prespecified interim safety analysis after accrual of one-quarter of the participants showed improved outcomes.

Median follow-up was 18.6 months (interquartile range, 14.6-21.3).

Seventy-one percent of patients in the neoadjuvant/adjuvant group remained alive without disease progression at follow-up compared with zero in the standard-of-care group.

Median EFS was 19.7 months for the treatment groups compared with 2.9 months for the control group (HR = 0.016; 95% CI, 0.00012-0.14). The neoadjuvant/adjuvant groups also showed longer distant metastasis-free survival (median, not reached vs. 7.7 months; HR = 0.024; 95% CI, 0.00017-0.28),

Median OS was not reached in either group.

In the neoadjuvant/adjuvant group, 85% achieved an overall radiographic response after neoadjuvant therapy, which included two complete responses, nine partial responses and two cases of stable disease. All 13 patients achieved radiographic disease control.

Fifty-eight percent of the treatment group who underwent surgery achieved a pathologic complete response and 17% achieved a pathologic partial response.

Patients with a pathologic complete response had significantly longer distant metastasis-free survival after surgery than those who did not achieve complete response.

“The fact that three (60%) of five patients without a pathologic complete response went on to develop distant metastatic disease compared with none of the patients who achieved a pathologic complete response is striking,” Amaria and colleagues wrote.

“This result, which needs to be confirmed in larger cohorts of patients and in independent studies, suggests that neoadjuvant therapy might confer clinical benefit by providing an early surrogate marker for long-term outcomes that could be used to optimize and personalize adjuvant therapy for this patient population.”

Grade 1 and grade 2 toxicities appeared similar to reports of dabrafenib and trametinib treatment in the stage IV metastatic setting. The most common low-grade events included chills (93%), headache (92%) and pyrexia (77%).

Grade 3 adverse events included diarrhea (15%) and pyrexia, dehydration, rash, postoperative wound infection, atrial fibrillation and syncope (8% for each).

No treatment-related deaths or grade 4 adverse events occurred. However, 12 of the 13 patients temporarily stopped neoadjuvant treatment to mitigate fever episodes.

Although these data suggest neoadjuvant therapy is a promising approach for this patient population, its clinical role remains unclear, Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy and innovative therapy at the National Tumor Institute Fondazione G. Pascale in Italy, and Alexander M.M. Eggermont, MD, director-general of the Institut Gustave Roussy in France, wrote in an accompanying editorial.

“Adjuvant dabrafenib plus trametinib, as well as nivolumab [Opdivo, Bristol-Myers Squibb] monotherapy, have also achieved good results in this setting, raising the question of whether a neoadjuvant approach is really needed (especially given a possible reduction of the role of surgery in the future) or whether adjuvant therapy with more effective agents than previously available is a better way forward,” they added. – by Cassie Homer

Disclosures: Novartis contributed funding to this study. Amaria reports grants from Array Biopharma, Bristol-Myers Squibb and Merck. Please see the full study for all other authors’ relevant financial disclosures. Ascierto reports previous consulting roles with or research grants from Amgen, Array, Bristol-Myers Squibb, Genentech/Roche, Genmab, Incyte, Merck Serono, Merck Sharpe & Dohme, NewLink Genetics, Novartis and Pierre Fabre. Eggermont reports previous consulting roles with Actelion, Agenus, Bristol-Myers Squibb, GlaxoSmithKline, HalioDX, Incyte, ISA Pharmaceuticals, Merck Serono, Merck Sharpe & Dohme, Nektar, Novartis, Pfizer and Sanofi.