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Dabrafenib Plus Trametinib Improves Survival in Advanced Melanoma

Fuerst, Mark L.

doi: 10.1097/01.COT.0000489509.65389.2d
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CHICAGO—Patients with BRAF V600E/K mutation-positive advanced melanoma show a significant 3-year survival benefit when treated with the first-line combination of dabrafenib plus trametinib as compared to dabrafenib monotherapy, according to a new study presented at the American Society of Clinical Oncology Annual Meeting.

Data from the study show an estimated 44 percent of patients are alive after receiving dabrafenib plus trametinib combination therapy. Of those patients still enrolled at 3 years, 58 percent were receiving the combination.

The results from the COMBI-d 3-year follow-up analysis represent one of the longest survival follow-up studies to date with BRAF mutation-positive advanced melanoma patients, said lead author Keith T. Flaherty, MD, Director of the Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School.

“The rationale behind combining a BRAF and MEK inhibitor in melanoma is well established. As monotherapy, each has single-agent benefit. This was shown in three phase III trials that met survival benefits,” said Flaherty.

“BRAF mutation remains the critical genetic feature in advanced melanoma that guides patients' treatment options,” he continued. “These results confirm that long-term survival can be achieved with this combination and it should be an important consideration for patients with BRAF mutation-positive advanced melanoma. It is particularly striking to note the excellent outcome for those with lower burden of disease at baseline.”

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Study Methodology

COMBI-d is a pivotal Phase III randomized, double-blind study comparing the combination of the BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, to single-agent therapy with dabrafenib and placebo as first-line therapy in patients with unresectable, Stage 3C or metastatic, Stage 4 BRAF V600E/K mutation-positive cutaneous melanoma.

The study randomized 423 patients from investigative sites in Australia and Europe as well as North and South America. The primary endpoint of this study was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response, and safety. There were 26 patients who crossed over from the monotherapy group to the combination group after the combination demonstrated a significant OS benefit in a prior analysis.

Baseline characteristics were well balanced between the two arms. The median age of patients in the combination arm was 55 years. The majority of BRAF alterations were found in V600E (85%) and approximately one-third of those in each arm had elevated LDH levels.

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Increased Survival Found

The results show the estimated 3-year survival rate to be 44 percent for patients receiving the combination compared with 32 percent who received dabrafenib alone. Additionally, the estimated 3-year PFS rate was 22 percent for the combination arm and 12 percent for the monotherapy arm.

In an analysis of patients with normal lactate dehydrogenase (LDH) levels and fewer than three disease sites, the 3-year survival rate for combination was 62 percent compared with 45 percent for those who received dabrafenib alone. In advanced melanoma, a patient's LDH level is often predictive of prognosis and may be a predictor of treatment response, according to Flaherty.

At 3 years of follow up, the combination continued to demonstrate a benefit on the measures of duration of response and ORR, in line with results seen at the 2-year follow up analysis.

“With additional follow-up, dabrafenib plus trametinib continued to show significant benefit over dabrafenib monotherapy despite cross-over,” Flaherty said. “The best 3-year outcome with dabrafenib plus trametinib was observed in patients with normal LDH and less than three disease sites. The safety profile was similar to previous reports for dabrafenib plus trametinib, with no unexpected toxicities.”

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Safety Concerns

The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for dabrafenib monotherapy. No new safety concerns were observed, Flaherty noted. The most common adverse events of at least 20 percent in the combination arm were pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, vomiting, arthralgia, hypertension, cough, and peripheral edema.

The combination use of dabrafenib and trametinib in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the U.S., European Union, Australia, Canada, and additional countries. The combination targets different kinases within the serine/threonine kinase family—BRAF and MEK1/2, respectively—in the RAS/RAF/MEK/ERK pathway, which is implicated in melanoma and non-small cell lung cancer, among other cancers.

The combination is also indicated in more than 35 countries worldwide, including the U.S. and European Union, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

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Further Research

Whole-exome sequencing was conducted on tumor and matched blood samples from 127 patients selected based on clinical response and LDH; 60 percent of patients had normal LDH levels in the combination arm versus 69 percent in the single-agent arm.

In examining the genetic features of the patients, Flaherty noted that CDKN2A loss due to genetic aberrations was significantly associated with poorer OS and PFS. High mutation rate was associated with longer OS, but not PFS, in the combination arm. Of the patients with high mutation rate/normal LDH, 82 percent are still alive at 3 years.

“All statistical associations between genomic profiles and clinical outcome are currently being further investigated in additional COMBI-d tumor samples,” concluded Flaherty.

Mark L. Fuerst is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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