Dabrafenib/Trametinib Combo Receives Breakthrough Designation for NSCLC

Bruce E. Johnson, MD

The FDA has granted a breakthrough therapy designation to the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) as a potential treatment for patients with BRAFV600E-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 trial that was presented at the 2015 ASCO Annual Meeting by Bruce E. Johnson, MD.¹ In the study, the combination of dabrafenib and trametinib showed promising efficacy and a tolerable safety profile. The objective response rate (ORR) with the combination was 68% by independent review in patients with BRAFV600E-mutant NSCLC.

"Dabrafenib plus trametinib demonstrated clinically meaningful antitumor activity with a higher ORR when compared indirectly with dabrafenib monotherapy in BRAFV600E-mutated NSCLC," Johnson, chief clinical research officer at the Dana-Farber Cancer Institute, said during his presentation of the results at the ASCO meeting. "The safety profile is manageable and similar to previous studies in melanoma."

In the ongoing study, dabrafenib was administered to 33 patients at 150 mg twice daily and trametinib was given at 2 mg once daily. Patients in the study had received at least 1 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.

By investigator assessment, the ORR was 63% (comprised of all partial responses [PR]). 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 9 patients (27%), and 1 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 mult-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 metastatic BRAFV600E mutation-positive NSCLC who received prior chemotherapy. In a phase II single-arm clinical trial, 78 patients with previously treated BRAF-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.² In the final analysis of the study, the median OS with the combination was 25.1 months compared with 18.7 months for dabrafenib alone.

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).