• David Planchard, Egbert F Smit, GroenHarry J MHJMUniversity of Groningen and University Medical Center Groningen, Groningen, Netherlands., Julien Mazieres, Benjamin Besse, Åslaug Helland, Vanessa Giannone, Anthony M D'Amelio, Pingkuan Zhang, Bijoyesh Mookerjee, and Bruce E Johnson.
• Gustave Roussy, Villejuif, France.
• Lancet Oncol. 2017 Oct 1; 18 (10): 1307-1316.

BackgroundBRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAFV600E-mutant metastatic NSCLC.MethodsIn this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAFV600E-mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia. Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day until disease progression, unacceptable adverse events, consent withdrawal, or death. The primary endpoint was investigator-assessed overall response, defined as the percentage of patients who achieved a confirmed complete response or partial response per Response Evaluation Criteria In Solid Tumors version 1.1. The primary and safety analyses were by intention to treat in the protocol-defined population (previously untreated patients). The study is ongoing, but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634.FindingsBetween April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR 7·8-22·0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest).InterpretationDabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC.FundingNovartis.Copyright © 2017 Elsevier Ltd. All rights reserved.

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