Novartis announced the US Food and Drug Administration (FDA) approval of Tafinlar (dabrafenib) in combination with Mekinist (trametinib) to treat patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express the BRAF V600E mutation.

The FDA granted Tafinlar + Mekinist Breakthrough Therapy designation in July 2015 for the treatment of patients with advanced or metastatic BRAF V600E mutation-positive NSCLC who received previous treatment with chemotherapy.

"Patients with BRAF V600E mutation-positive metastatic NSCLC have responded less favorably to standard chemotherapy, suggesting that there is a critical need for a targeted therapy," said Bruno Strigini, CEO, Novartis Oncology. "Today's approval of the Tafinlar + Mekinist combination validates our expertise in tumor biology, which enabled us to develop the first targeted treatment for people with this rare mutation."

"The approval of Tafinlar + Mekinist makes BRAF V600E the fourth actionable genomic biomarker in metastatic NSCLC - along with EGFR, ALK and ROS-1," said Bruce Johnson, MD, Professor of Medicine, Chief Clinical Research Officer, Dana-Farber Cancer Institute and Harvard Medical School at Dana-Farber Cancer Institute. "This is an important milestone for the lung cancer community as we are continuing to better understand the genomic drivers of cancer and develop effective treatments targeted for these biomarkers."
 
The FDA approval is based on safety and efficacy of Tafinlar in combination with Mekinist in a Phase II, three-cohort, multicenter, non-randomized, non-comparative and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled (36 treatment-naïve [previously untreated] and 57 previously treated with chemotherapy).
 
Among the 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, the overall response rate (ORR) was 61% (95% confidence interval [CI]: 44%, 77%). In the previously treated population receiving the same dosage, patients demonstrated an ORR of 63% (95% CI: 49%, 76%). The ORR was assessed by independent review committee. The median duration of response in the treatment naïve cohort was not estimable (95% CI: 6.9, not estimable) and in the previously treated patient cohort was 12.6 months (95% CI: 5.8, not estimable). An in-depth analysis of data from the treatment-naïve cohort will be presented at an upcoming medical meeting.

The most common adverse events (incidence >20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough and dyspnea.

BRAF mutations appear in approximately 1-3% of NSCLC cases worldwide. There is an urgency to treat people with this mutation, as BRAF V600E mutation-positive tumors have been shown to be more aggressive and may lead to a poorer prognosis.

The treatment combination was approved with Thermo Fisher Scientific's Oncomine(TM) Dx Target Test to identify a BRAF V600E mutation in eligible patients. This qualitative in vitro diagnostic test uses targeted high throughput, parallel-sequencing technology to detect sequence variations in select genes, including BRAF V600E, in DNA and RNA isolated from formalin-fixed, paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC) using the Ion PGM(TM) Dx System.

Tafinlar + Mekinist was approved by the European Commission (EC) in March 2017 for the treatment of patients with BRAF V600 advanced mutation-positive NSCLC.

Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600E mutation is approved in the US, EU, Australia, Canada, and additional countries.  The combination of Tafinlar and Mekinist is also approved for the treatment of advanced non-small cell lung cancer with a BRAF V600 mutation in Europe.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family - BRAF and MEK1/2, respectively - in the RAS/RAF/MEK/ERK pathway, which is implicated in non-small cell lung cancer (NSCLC) and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 50 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600E mutation.