Perioperative Dabrafenib/Trametinib Improves RFS in Stage III Melanoma

Rodabe Amaria, MD

Treatment with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) before and after surgery demonstrated a dramatic improvement in relapse-free survival (RFS) compared with the standard of care for patients with stage IIIb/c or oligometastatic BRAF-mutant melanoma, according to findings from the small phase II COMBI-Neo trial presented at the 2016 Society for Melanoma Research Annual Meeting.

The response rate was 77% with dabrafenib plus trametinib and the pathologic complete response (pCR) rate was 58%. The estimated 6-month RFS rate was 100% in the dabrafenib/trametinib arm versus 28.6% with standard therapy. The median RFS was 2.8 months with the standard of care and was not yet reached for those treated with the BRAF and MEK inhibitor regimen (HR, 60.2; 95% CI, 6.7-7965; P <.0001).

The improvement in RFS with dabrafenib/trametinib was so dramatic that the trial was stopped early, after just 21 patients had been enrolled. The study was designed to enroll 84 patients. The decision to stop the trial came from the independent data monitoring committee, according to lead investigator Rodabe Amaria, MD.

"Treatment with neoadjuvant and adjuvant dabrafenib and trametinib did statistically significantly improve relapsed-free survival compared with standard of care in patients with high-risk resectable melanoma," said Amaria, assistant professor, Melanoma Medical Oncology, from the University of Texas MD Anderson Cancer Center. "The safety profile was easily manageable and we did not find that it increased perioperative risks."

In the study, 21 patients were randomized in a 1:2 ratio to receive upfront surgery followed by physician's choice of therapy (n = 7) or neoadjuvant and adjuvant therapy with dabrafenib/trametinib (n = 14). Neoadjuvant therapy was given for 8 weeks and adjuvant therapy was administered for up to 44 weeks. Dabrafenib was administered at 150 mg twice daily and trametinib was given at 2 mg once daily. The physician's choice arm included interferon, ipilimumab, or observation.

Patients in the study had clinical stage III melanoma with ≤3 sites of metastatic disease. All patients were judged as resectable and had BRAF V600E/K-mutant tumors. Those with baseline CNS or bone metastasis were excluded from the study. In general, the arms were well balanced for all measures except for age. Those in the control arm had a median age of 46 years versus 59 years for those in the combination arm (P = .02).

Only 12 of the 14 patients enrolled in the combination arm went on to receive surgery. One patient withdrew consent early in the study, without receiving therapy, and the second patient received 8 courses of neoadjuvant therapy and decided they did not want surgery. "After seeing his disease basically melt away, he decided that he no longer wanted surgery, and so he came off and didn't receive surgery," explained Amaria.

"We don't see a very close correlation between RECIST responses and pathologic responses. The overall agreement between those two factors is only 58%," said Amaria. "There's limited ability for radiologic responses to predict pathologic responses and subsequent patient outcomes."

The perioperative complication rates were similar in each arm. Ninety-two percent of patients required dose interruptions in the first 8 weeks of neoadjuvant therapy and 38% required a dose reduction in the neoadjuvant phase.

The most common all-grade adverse events (AEs) with the combination were pyrexia (69%), chills (62%), fatigue (54%), nausea (38%), myalgia (38%), rash (38%), wound infection (38%), diarrhea (31%), and ALT/AST elevation (23%). The most common grade 3/4 AEs were diarrhea and wound infection, which were experienced by 2 patients each.

"There are many potential advantages to neoadjuvant therapy, including the tumor shrinkage to potentially decrease surgical morbidity and importantly destroying micrometastises to prevent our patients from relapsing further," said Amaria. "We can also use neoadjuvant therapy as an objective measure of how a patient responds."

Amaria RN, Prieto P, Tetzlaff M, et al. Treatment with neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016.

The study will be reopened as a single arm study, with a focus on the characteristics of pCR with dabrafenib and trametinib, according to Amaria. Additionally, there is a need for greater focus on the use of neoadjuvant therapies for patients with melanoma, she noted.

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Overall, 16% of patients had a pathologic partial response following surgery and neoadjuvant treatment. Three patients who received neoadjuvant treatment and did not achieve a pCR remained relapse-free after 14 months of follow-up and another 3 patients, following the full course of adjuvant treatment, developed CNS metastasis.