Long-Term Follow-Up Supports Frontline Dabrafenib/Trametinib in Melanoma

Caroline Robert, MD, PhD

Co-inhibition of BRAF and MEK pathways with dabrafenib (Tafinlar) and trametinib (Mekinist) continued to be superior to sole BRAF inhibition with vemurafenib (Zelboraf) in patients with unresectable metastatic melanoma at 3 years, according to an updated survival analysis of the large randomized phase III COMBI-v trial presented at the 2016 ESMO Congress.

BRAF V600¬—mutant patients receiving the combination of dabrafenib plus trametinib had a 3-year overall survival (OS) rate of 45% (95% CI, 39.1-49.8), compared with 31% (95% CI, 26.1-36.4) for vemurafenib monotherapy, leading to a hazard ratio of 0.68. Additionally, the 3-year progression-free survival (PFS) rates were 24% with dabrafenib/trametinib and 10% with vemurafenib.

The updated analysis occurred following 411 deaths and 16 months of additional follow-up since the 2-year data cutoff, which was July 2016.

Lead author Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, noted that COMBI-v is the second trial to show superiority for the combination versus monotherapy in advanced melanoma. The phase III COMBI-d showed 3-year OS rates of 44% versus 32% with the combination versus dabrafenib alone, respectively.

“These findings confirm improved outcomes with the dabrafenib plus trametinib combination over vemurafenib, despite crossover,” said Robert.

In the COMBI-v trial, Robert and colleagues enrolled 704 patients with advanced, treatment-naïve, BRAF-mutated, stage III/IV melanoma. Patients were randomized 1:1 to dabrafenib at 150 mg twice daily plus trametinib at 2 mg daily or to the standard dose of vemurafenib at 960 mg twice daily.

Patients in the vemurafenib arm were allowed to cross over after the interim analysis. A total of 33 (9%) patients crossed over to the combination arm. The primary endpoint of COMBI-v was OS, while secondary endpoints were PFS, overall response rate (ORR), duration of response (DOR), and safety.

The median duration of exposure was 12.2 months (95% CI, 0.1-47.3) with combination treatment versus 6.7 months (95% CI, 0.1-42.4) with vemurafenib.

More patients receiving the combination showed a response; the ORR was 67% versus 53% with monotherapy. Complete responses (CRs) were achieved by 68 patients (19%) versus 41 (12%), partial responses (PR) by 48% versus 41%, and stable disease was observed in 24% versus 31% of those receiving the combination versus vemurafenib, respectively. Progressive disease was reported for 6% and 11% of patients in the respective arms, and 8% of patients overall were not evaluable for response.

The median DOR was 13.8 months with the combination versus 7.6 months with single-agent vemurafenib.

“Fifty-three percent of patients receiving dabrafenib plus trametinib remain in complete response,” Robert noted. “These findings support the long-term use of dabrafenib plus trametinib as a standard first-line treatment for patients with BRAF V600¬—mutant metastatic melanoma.”

Subgroup analysis identified patients with baseline levels of lactate dehydrogenase (LDH) equal to or less than the upper limit of normal (ULN) who performed particularly well with combined therapy; 56% of these patients achieved 3-year OS with the combination versus 39% of patients on the vemurafenib arm.

Median OS was not reached with combination treatment in this subset versus 21.6 months with vemurafenib. Three-year PFS rates in this subset were 33% versus 13%; median PFS was 17.5 versus 9.2 months (HR, 0.56) with the combination versus monotherapy, respectively.

In contrast, in the cohort of patients with LDH > ULN, 20% of patients achieved 3-year OS versus 14% of patients on vemurafenib, median OS was 10.8 versus 8.7 months with monotherapy (HR, 0.79). Median PFS in this subset at 3 years was 5.5 months versus 4 months (HR, 0.70) with dabrafenib/trametinib and vemurafenib, respectively.

“Patients with low LDH respond extremely well to targeted treatment; targeted treatment is very convincing in this group,” Robert noted. “The benefit is always less in patients with high LDH, whatever the treatment.”

When the subset of patients with normal LDH was combined with patients having fewer than 3 sites of metastases, 3-year OS rates rose to 70% versus 46%, and PFS rates were 39% with the combination versus 15% with single-agent vemurafenib.

Dabrafenib/trametinib was found to have a manageable adverse event (AE) profile, with no new safety signals reported. Sixteen percent of patients discontinued treatment due to AEs with dabrafenib/trametinib versus 15% who received vemurafenib. The most commonly reported grade 3/4 AEs in the dabrafenib/trametinib arm included hypertension (15%) and pyrexia (5%).

Robert. C, Karaszewska b, Schachter J, et al. Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA40.