Elsevier

The Lancet Oncology

Volume 18, Issue 10, October 2017, Pages 1307-1316
The Lancet Oncology

Articles
Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30679-4Get rights and content

Summary

Background

BRAFV600E 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.

Methods

In 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.

Findings

Between 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).

Interpretation

Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC.

Funding

Novartis.

Introduction

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide. Progress has been made in characterisation of oncogenic driver mutations that contribute to the molecular pathogenesis of lung cancer. Activating mutations in EGFR plus rearrangements in ALK and ROS1 have been identified as contributing oncogenic drivers of molecular pathogenesis in lung cancer, which has led to a rapid development of targeted therapies and more individualised treatment strategies for patients with NSCLC.1, 2, 3

Activating BRAF mutations are considered an alternative oncogenic driver in NSCLC that are almost never observed in tumours harbouring EGFR mutations, ALK rearrangements, or ROS1 rearrangements. The most common BRAF mutation, V600E (Val600Glu), is observed in 1–2% of lung adenocarcinomas.4, 5, 6 The prognostic value of BRAFV600E in NSCLC remains unclear; however, some studies have associated this mutation with poor outcomes and lower response rates to platinum-based chemotherapy in patients with this disease compared with those without BRAF mutations.7, 8 Among patients with driver mutations, outcomes for patients treated with targeted therapies are prolonged compared with those who do not receive genotype-directed treatment.5 Immune checkpoint inhibitors as monotherapy9 or in combination with chemotherapy10 have demonstrated significantly prolonged survival for patients with NSCLC, especially those with high PD-L1 overexpression. However, nearly 50% of patients do not respond at all to these therapies. Therefore, an unmet need remains for effective targeted agents in this patient population.

Research in context

Evidence before this study

We searched PubMed for clinical studies published in English before June 12, 2017 (no start date restriction), of combined BRAF and MEK inhibition for the treatment of patients with BRAFV600E-mutant non-small-cell lung cancer (NSCLC). We used the search terms “dabrafenib AND trametinib”, “vemurafenib AND cobimetinib”, and “encorafenib AND binimetinib”, all with “non-small cell lung cancer”. Of nine publications identified, only one was a primary analysis of a prospective clinical trial, representing the previously reported analysis of dabrafenib plus trametinib in the previously treated patient cohort of the phase 2 BRF113928 study. Although dabrafenib plus trametinib demonstrated robust clinical activity with a manageable safety profile in previously treated patients with BRAFV600E-mutant NSCLC, the clinical effect of this regimen on treatment-naive patients has not yet been characterised.

Added value of this study

We found that combination dabrafenib plus trametinib had substantial and durable antitumour activity in patients with previously untreated BRAFV600E-mutant metastatic NSCLC. The safety profile was tolerable, with no unexpected safety issues observed with dabrafenib plus trametinib in this setting.

Implications of all the available evidence

To our knowledge, this trial is the first to assess combination BRAF and MEK inhibition in patients with previously untreated BRAFV600E-mutant NSCLC. Notably, the overall response and median progression-free survival observed with combination dabrafenib plus trametinib were similar when compared indirectly with those of previously treated patients in cohort B of this study. Although cross-trial comparisons should be undertaken with caution, the antitumour activity observed in the current study seems to be similar to that observed for other targeted therapies, including EGFR tyrosine kinase inhibitors and ALK inhibitors in selected patient populations. Additionally, owing to the rarity of this patient population and the loss of clinical equipoise that precludes randomisation versus chemotherapy given the data for the combination in previously treated patients, a randomised trial in patients with BRAFV600E-mutant NSCLC would be infeasible. As such, the results of this study provide evidence to support a change in the management of patients with BRAFV600E-mutant NSCLC, a population in which additional therapeutic options are still needed.

In this Article we discuss the third (cohort C) of three sequentially enrolled cohorts in this phase 2 study of patients with BRAFV600E-mutant metastatic NSCLC. The results of the first two cohorts of this trial (cohort A and cohort B) were previously reported,11, 12 demonstrating a response of 67% and duration of response of 9·8 months in patients with previously treated BRAFV600E-mutant metastatic NSCLC who received the combination of dabrafenib plus trametinib.13 Indirect comparison across cohorts showed that the antitumour activity of the combination was higher than that observed with dabrafenib monotherapy (the proportion of patients achieving an overall response was 67% with the combination vs 33% with dabrafenib monotherapy). The safety profile of the combination was manageable and similar to that previously reported for the combination in patients with BRAFV600-mutant metastatic melanoma.14, 15 In cohort C, we aimed to assess the antitumour activity of dabrafenib plus trametinib in previously untreated patients with BRAFV600E-mutant metastatic NSCLC.

Section snippets

Study design and participants

As part of a phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label trial, this study enrolled adults (≥18 years) with metastatic BRAFV600E-mutant NSCLC without previous systemic treatment for metastatic disease from 19 centres in eight countries within North America, Europe, and Asia (appendix p 4). Local testing methods chosen by each study site were implemented in laboratories approved by the Clinical Laboratory Improvement Amendments (or its equivalent outside

Results

Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled, including 34 patients in cohort C (figure 1). The cutoff date for safety and activity data was April 28, 2017. As previously reported, two patients initially enrolled in cohort B owing to protocol deviation had received no previous systemic anticancer therapy for metastatic disease, and were thus excluded from the analysis of cohort B.12 Since the requirement for previous treatment was the only major difference between the

Discussion

The results from this phase 2 trial showed substantial antitumour activity of dabrafenib plus trametinib therapy in patients with treatment-naive BRAFV600E-mutant metastatic NSCLC. The protocol-defined primary objective was met (target response rate ≥60%), with 64% of patients achieving a confirmed overall response Responses were durable, with a median response duration of 10·4 months. This study represents the first evaluation, to our knowledge, of combination BRAF and MEK inhibition in

References (30)

  • AT Shaw et al.

    Crizotinib in ROS1-rearranged non-small-cell lung cancer

    N Engl J Med

    (2014)
  • MG Kris et al.

    Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs

    JAMA

    (2014)
  • PK Paik et al.

    Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations

    J Clin Oncol

    (2011)
  • S Cardarella et al.

    Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer

    Clin Cancer Res

    (2013)
  • A Marchetti et al.

    Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations

    J Clin Oncol

    (2011)
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