Dabrafenib/Trametinib Combo Wins EU Approval for BRAF+ NSCLC

Bruno Strigini

The European Union (EU) approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for patients with BRAF V600-positive advanced or metastatic non—small cell lung cancer (NSCLC).

Novartis, maker of both drugs, reported in a statement that this is the first targeted treatment approved in all 28 EU member states for use in this specific patient population.

“Today's approval represents an important milestone for the lung cancer community, especially those patients living with the BRAF V600 mutation who previously had few options," Novartis Oncology CEO Bruno Strigini said in a press release.

The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approving the combination in February of this year. That recommendation was based on results from a 3-cohort, multicenter, nonrandomized, open-label study of patients with stage IV NSCLC.

In this phase II study, 36 treatment-naïve patients and 57 previously-treated patients were assigned to 150 mg twice daily of dabrafenib and 2 mg once daily of trametinib. Investigator-assessed objective response rate (ORR) was the primary endpoint. Previously treated patients had undergone at least 1 prior line of platinum-based chemotherapy, and one-third underwent at least 2 prior treatment cycles.

At a median follow-up of 9 months, the ORR was 61.1% (95% CI, 43.5-76.9) in the treatment-naïve group, and 68% of patients did not show progression. The group had not reached endpoints for median duration of response (DoR) or progression-free survival (PFS) at the time of approval. Novartis reported that researchers will present an in-depth analysis of the results for the treatment-naïve arm at an upcoming meeting.

The ORR was 66.7% (95% CI, 52.9-78.6) in the previously treated population. Researchers found that the response was durable, with a median DoR of 9.8 months (95% CI, 6.9-16.0).

These data for the previously treated arm are updated from results reported at the 2016 ASCO Annual Meeting and published in The Lancet Oncology.^1,2 The earlier findings showed an ORR with the combination of 63.2% (95% CI, 49.3-75.6), which lasted for a median duration of 9.0 months (95% CI, 6.9-18.3). The overall disease control rate was 79% (95% CI, 66-89) when patients who had stable disease for ≥12 weeks were included. Median PFS was 9.7 months (95% CI, 6.9-19.6).

After a median follow-up of 11.6 months, 2 patients (4%) assigned to the combination experienced a complete response, in the earlier findings. Overall, 9 patients had stable disease as their best response (16%). Half of confirmed responses remained ongoing at the October 2015 data cutoff.

In the third arm of the phase II trial, 78 previously treated patients with metastatic BRAF V600E—mutant NSCLC received single-agent dabrafenib. The ORR in this cohort was 33% and the median PFS was 5.5 months.

In its release, Novartis reported that the most common all-grade adverse events (>20%) across the study included pyrexia, nausea, vomiting, peripheral edema, and diarrhea.

In 2015, the FDA gave the combination breakthrough designation for patients with BRAF V600E-mutant NSCLC.

The FDA first approved the combination of dabrafenib and trametinib for patients with metastatic melanoma in January 2014. The EU approved the dabrafenib/trametinib combination for adults with unresectable or metastatic melanoma with a BRAF V600 mutation a year later.

Dabrafenib and trametinib target BRAF and MEK1/2, two different kinases within the serine/threonine kinase family in the RAS/RAF/MEK/ERK pathway The pathway plays a role in the development of multiple cancers, including NSCLC and melanoma.

Worldwide, there are roughly 1.8 million new cases of NSCLC diagnosed every year. About 36,000 patients, 1% to 3% of the total, are positive for the BRAF V600 mutation.

1. Planchard D, Besse B, Groen HJM, et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E—mutant advanced non-small cell lung cancer (NSCLC; BRF113928). J Clin Oncol. 2016;34 (suppl; abstr 107).
2. Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial [published online June 6, 2016]. Lancet Oncol. DOI: 10.1016/S1470-2045(16)30146-2.