CHICAGO — The longest overall survival follow-up among randomized phase 3 trials evaluating BRAF and MEK inhibitors in patients with BRAF-mutant metastatic melanoma to date has shown the best 3-year outcome with dabrafenib plus trametinib to be in patients with normal LDH and fewer than 3 disease sites, according to a presentation at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.1

These results from the COMBI-d trial found that “with additional follow-up, dabrafenib plus trametinib continued to show significant benefit over dabrafenib monotherapy, despite crossovers,” said Keith Flaherty, MD, Dana-Farber Cancer Institute/Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts.

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The 3-year overall survival rate was 44% and progression-free survival rate, 22%, with the best outcome observed in patients with normal LDH and fewer than 3 disease sites: rate of overall survival was 62% and progression-free survival, 38%, he said.

Previous analysis of the study found that compared with dabrafenib monotherapy, dabrafenib plus trametinib improved overall response rate, reduced risk of progression, and increased 2-year overall survival rate in BRAF V600–mutant melanoma.

The COMBI-d study randomly assigned 423 patients with unresectable stage IIIC or IV, BRAF V600E/K–mutant melanoma to receive frontline dabrafenib 150 mg twice daily plus trametinib 2 mg once daily (n = 211) or dabrafenib 150 mg twice daily alone (n = 212).

To further characterize BRAF V600–mutant melanoma and explore whether individual gene changes or genetic profiles were associated with treatment benefit, the investigators used whole-exome sequencing to assess somatic mutations and copy number changes in pretreatment tumor and matched normal blood samples collected from more than 140 patients.

“As expected, initial genetic analysis of 130 patients showed that BRAF was the most frequently mutated gene (V600E, 83%; V600K, 15%),” Dr. Flaherty reported.

Additional mutations were observed in genes related to tumor suppression (TP53, PTEN, CDKND2A) and resistance to MAPK pathway inhibition (MEK1, MEK2, NRAS, NF1, RAC1), with amplifications also observed in BRAF and MITF. The overall mutation rate was higher in patients with V600K versus V600E (P < .0001).

The follow-up analysis showed that “CDKIN2A loss due to genetic aberrations was significantly associated with poorer overall survival and progression-free survival,” he said.

However, in the dabrafenib plus trametinib arm, a high mutation rate was associated with longer overall survival — but not progression-free survival — with 82% of patients with high mutation rate/normal LDH in the sample alive at 3 years.

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

No unexpected toxicities were observed, and the safety profile was similar to previous reports for dabrafenib plus trametinib.



1. Flaherty K, Davies MA, Grob JJ, et al. Genomic analysis and 3-y efficacy and safety update of COMBI-d: a phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Oral presentation at: ASCO 2016 Annual Meeting; June 3-7, 2016; Chicago, IL.