Neoadjuvant treatment with dabrafenib and trametinib offered significantly improved event-free survival (EFS) over standard of care involving surgery and adjuvant therapy in patients with high-risk, surgically resectable melanoma, according to a phase II trial.
“Neoadjuvant therapy for melanoma has been restricted historically, mainly because of the low activity of chemotherapy in this disease,” wrote study authors led by Rodabe N. Amaria, MD, of the University of Texas MD Anderson Cancer Center in Houston. The group hypothesized that a combined approach targeting both BRAF and MEK might offer improved activity.
The new trial was a single-center, open-label, randomized, phase II study; it enrolled 7 patients to standard of care (upfront surgery and consideration for adjuvant therapy) and 14 to neoadjuvant dabrafenib and trametinib, but the trial was then stopped early after an interim analysis showed significantly longer EFS with the neoadjuvant approach. All patients included had surgically resectable clinical stage III or oligometastatic stage IV melanoma with BRAF mutations, and no previous exposure to BRAF or MEK inhibition; the results were published in Lancet Oncology.
After a median follow-up of 18.6 months, 10 of 14 patients receiving neoadjuvant dabrafenib and trametinib remained alive without disease progression, compared with 0 of the 7 patients who received standard of care, for a hazard ratio (HR) of 0.016 (95% CI, 0.00012–0.14; P < .0001). The median EFS was 2.9 months with standard of care, and 19.7 months with neoadjuvant therapy.
The median duration of distant metastasis–free survival was not reached with neoadjuvant therapy, and it was 7.7 months with standard of care, for an HR of 0.024 (95% CI, 0.00017–0.28; P < .001). Two patients receiving standard of care and one patient receiving neoadjuvant therapy died, all from disease progression. There were no significant differences in overall survival between the groups; the median was not reached in either group.
Most of the dabrafenib plus trametinib patients (85%) achieved an overall radiographic response after the neoadjuvant therapy, and all achieved radiographic disease control.
The authors wrote that the toxicity profile of the neoadjuvant regimen was “expected” and similar to previous reports. The most common grade 1/2 adverse events included chills (92%), headache (92%), and pyrexia (77%). There were two cases of grade 3 diarrhea (15%) thought to be treatment related, and one each of grade 3 pyrexia, dehydration, rash, postoperative wound infection, atrial fibrillation, and syncope. There were no grade 4 adverse events.
“The large difference in EFS necessitated early closure of the trial, which potentially limited the generalizability of the results, but they provided important proof-of-concept and data for future studies,” the authors wrote, adding that the results “strongly support” further assessment of neoadjuvant therapy in this setting.