Breakthrough Designation Granted to BRAF/MEK Combo for BRAF V600 NSCLC

Breakthrough therapy designation has been granted by the US Food and Drug Adminstration (FDA) to the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) as treatment for patients with BRAF V600E-mutant non–small cell lung cancer

Bruce E. Johnson, MD

Breakthrough therapy designation has been granted by the US Food and Drug Adminstration (FDA) to the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) as treatment for patients withBRAF V600E-mutant non—small cell lung cancer (NSCLC), according to a second-quarter financial statement released by Novartis.

The FDA designation was supported by evidence from a single-arm phase II clinical trial1presented at the 2015 ASCO Annual Meeting by Bruce E. Johnson, MD.

“Dabrafenib plus trametinib demonstrated clinically meaningful antitumor activity with a higher ORR when compared indirectly with dabrafenib monotherapy inBRAF V600E-mutated NSCLC,” said Johnson, chief clinical research officer at the Dana-Farber Cancer Institute, during his presentation of the results. “The safety profile is manageable and similar to previous studies in melanoma.”

As noted, the combination of dabrafenib and trametinib showed promising efficacy and a tolerable safety profile in the study. The objective response rate (ORR) with the combination was 68% in patients withBRAF V600E-mutant NSCLC, according to independent review.

Dabrafenib was administered to 33 patients at 150 mg twice daily and trametinib was given at 2 mg once daily during this ongoing study. Patients had received at least one prior line of chemotherapy. The majority of patients were former smokers (73%) and had adenocarcinoma histology (88%). The primary endpoint of the study was ORR by RECIST criteria.

The ORR was 63% (all partial responses [PR]), according to investigator assessment. The stable disease rate was 25%, leading to a disease control rate of 88% (95% CI, 67.6-97.3). In those reviewed independently, the ORR was 68% (all PRs), and the disease control rate was 86% (95% CI, 65.1-97.1).

The most common adverse events observed in the trial were pyrexia, diarrhea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, and rash. Grade 3 toxicity was seen in 39% of patients, including hyponatremia (6%), neutropenia (6%), and dehydration (6%).

Dose reductions were required in nine patients (27%), and one patient (3%) experienced grade 4 hyponatremia. There was one case of fatal pleural effusion. Cutaneous squamous-cell carcinoma and keratoacanthoma were apparent in 6% of patients.

Novartis acquired dabrafenib and trametinib from GlaxoSmithKline (GSK) in a multi-billion-dollar product exchange that completed in March 2015. The deal included the transfer of Novartis’s portfolio of FDA-approved cancer therapies, which included dabrafenib, trametinib, pazopanib (Votrient), lapatinib (Tykerb), and ofatumumab (Arzerra).

In January 2014, dabrafenib monotherapy received a breakthrough therapy designation from the FDA for its potential as a treatment for patients with metastaticBRAF V600E-mutation—positive NSCLC who received prior chemotherapy. In a phase II single-arm clinical trial, 78 patients with previously treatedBRAF-mutant NSCLC received single-agent dabrafenib at 150 mg twice daily. The ORR was 32% (all PRs). Once including stable disease, the disease control rate was 56%.

Outside of NSCLC, the combination of dabrafenib and trametinib became the first FDA-approved combination therapy approved for patients with metastatic melanoma in January 2014. This approval was based on early-phase data, with additional trials conducted to support the approval.

In the phase III COMBI-d trial, which was also presented at the ASCO meeting, dabrafenib plus trametinib demonstrated superior overall survival (OS) compared with dabrafenib alone.2The median OS with the combination was 25.1 months compared with 18.7 months for dabrafenib alone in the final analysis of the study.

  1. Planchard D, Groen HJM, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC).J Clin Oncol. 2015;33 (suppl; abstr 8006).
  2. Long GV, Stroyakovskiy D, Gogas H, et al. Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma.J Clin Oncol.2015;33 (suppl; abstr 102).