Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial

doi:10.1016/S1470-2045(16)00077-2

The Lancet Oncology

Volume 17, Issue 5, May 2016, Pages 642-650

https://doi.org/10.1016/S1470-2045(16)00077-2 Get rights and content

Summary

Background

Activating BRAF^V600E (Val600Glu) mutations are found in about 1–2% of lung adenocarcinomas, which might provide an opportunity for targeted treatment in these patients. Dabrafenib is an oral selective inhibitor of BRAF kinase. We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer (NSCLC) positive for the BRAF^V600E mutation.

Methods

In this phase 2, multicentre, non-randomised, open-label study, we enrolled previously treated and untreated patients with stage IV metastatic BRAF^V600E-positive NSCLC. Patients received oral dabrafenib 150 mg twice daily. The primary endpoint was investigator-assessed overall response, which was assessed in patients who had received at least one dose of dabrafenib; safety was also assessed in this population. The study is ongoing but not enrolling patients in this cohort. This trial is registered with ClinicalTrials.gov, number NCT01336634.

Findings

Between Aug 3, 2011, and Feb 25, 2014, 84 patients were enrolled, six of whom had not previously received systemic treatment for NSCLC. 26 of the 78 previously treated patients achieved an investigator-assessed overall response (33% [95% CI 23–45]). Four of the six previously untreated patients had an objective response. One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten (12%), asthenia in four (5%), and basal-cell carcinoma in four (5%).

Interpretation

Dabrafenib showed clinical activity in BRAF^V600E-positive NSCLC. Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options.

Funding

GlaxoSmithKline.

Introduction

Non-small-cell lung cancer (NSCLC) accounts for around 85% of all lung cancers and remains a major cause of cancer-related deaths worldwide.¹ In the past few decades, important advances have been made in defining the molecular pathogenesis of lung cancers—particularly detection of crucial oncogenic drivers—that have accelerated development of targeted agents. Constitutively activating mutations in the BRAF gene, which were first described in lung cancer,2, 3 drive growth and survival of the cancer cells that harbour them, and are extremely sensitive to selective BRAF-inhibitor therapy across multiple tumour types.⁴ In a transgenic murine lung cancer model, BRAF^V600E (Val600Glu) mutations behaved as oncogenic drivers.⁵

BRAF mutations are present in about 2–4% of lung adenocarcinomas, and roughly 50% of those are BRAF^V600E mutations.2, 6, 7, 8 Patients with BRAF^V600E mutations have shorter overall survival and smaller proportions of patients respond to platinum-based chemotherapy than patients with wild-type BRAF.9, 10 Treatment options for patients with BRAF^V600E mutations are limited and outlook is poor; therefore, novel therapeutic strategies are needed. Of note, BRAF mutations and other oncogenic drivers, including EGFR and RAS mutations and ALK rearrangements, are typically mutually exclusive. This finding is consistent with the notion that the BRAF mutation defines a unique molecular subset of patients with NSCLC who might benefit from treatment with BRAF inhibitors.

Much of the clinical experience with BRAF inhibitors in BRAF^V600E-positive NSCLC has been limited to isolated cases and a retrospective case series.11, 12, 13, 14 The activity of the BRAF^V600E inhibitor vemurafenib was assessed in patients with various solid tumours and haematological malignancies in a basket study that included 19 patients with BRAF^V600E-positive NSCLC, of whom 42% achieved an overall response.¹⁵ Dabrafenib is a potent adenosine-triphosphate-competitive inhibitor of BRAF kinase selective for the BRAF^V600E mutation in kinase panel screening, cell lines, and xenografts.¹⁶ This drug is approved in the USA and Europe for the treatment of unresectable or metastatic BRAF^V600E-positive melanoma. We aimed to investigate the clinical activity and safety of dabrafenib for the treatment of patients with advanced or metastatic BRAF^V600E-positive NSCLC.

Research in context

Evidence before this study

For most patients with advanced non-small-cell lung cancer (NSCLC), conventional cytotoxic chemotherapy, with or without bevacizumab, is the standard treatment, but it offers only a small survival benefit. Oncogenic drivers of NSCLC have been identified, which has led to the development of targeted agents, particularly small-molecule tyrosine-kinase inhibitors targeting EGFR and ALK. Oncogenic mutations of BRAF, a serine-threonine protein kinase in the RAF/MEK/ERK pathway, are rare in NSCLC (around 2% of tumours). Importantly, most cancer cells harbouring BRAF^V600E (Val600Glu) mutations are dependent on the activity of this oncogene for growth and survival, and are exquisitely sensitive to selective BRAF and MEK inhibitors. In melanoma, two selective BRAF inhibitors, vemurafenib and dabrafenib, have gained regulatory approval in the USA and Europe for the treatment of patients with unresectable or metastatic BRAF^V600-positive disease. Importantly, BRAF^V600E mutations are thought to correlate with more aggressive tumours, which implicates the BRAF^V600E mutation as an oncogenic driver and provides a robust rationale for the use of dabrafenib in genotype-selected patients.

We searched PubMed for studies of BRAF inhibitors in the treatment of BRAF^V600-positive NSCLC, without date limitations. We used the search terms “dabrafenib”, “vemurafenib”, “GSK2118436”, and “PLX4032”, all with “non-small cell lung cancer OR NSCLC”. We identified a prospective basket study of vemurafenib used to treat non-melanoma cancers, including 19 patients with BRAF^V600-positive NSCLC. Other reports were case studies and a retrospective case series that involved 35 patients in total. We found no studies of targeted BRAF-inhibitor therapy exclusively in patients with BRAF^V600E-positive NSCLC.

Added value of this study

We found that dabrafenib had substantial antitumour activity (proportion with overall response 33%) in patients with BRAF^V600E-positive advanced NSCLC. The clinical responses were durable in a substantial proportion of patients in our study and the safety profile was tolerable.

Implications of all the available evidence

In this prospective trial assessing targeted BRAF-inhibitor treatment exclusively in patients with BRAF^V600E-positive NSCLC, our results highlight the importance of screening for specific genetic alterations before treatment in patients with advanced NSCLC. The clinical benefit of dabrafenib seems to be better than that associated with unselected treatments in NSCLC, including docetaxel and EGFR tyrosine-kinase inhibitors, although cross-trial comparisons must be done with caution. Because BRAF^V600 mutations are rare in NSCLC, which limits the possibility of doing randomised trials, and because benefits derived from second-line chemotherapy are small, our results could potentially change management strategies in this cancer.

Section snippets

Study design and participants

This study was part of a continuing phase 2, multicentre, non-randomised, open-label study and recruited patients from 34 centres in ten countries within North America, Europe, and Asia (appendix pp 3–4). Enrolment for the cohort reported here has been completed. In two other cohorts, clinical activity and safety of the combination of dabrafenib plus trametinib is being assessed in patients with previously treated advanced or metastatic BRAF^V600E-positive NSCLC and in treatment-naive patients.

Results

Between Aug 3, 2011, and Feb 25, 2014, 84 patients were enrolled, 78 of whom had received at least one previous chemotherapy regimen (table 1) and six patients who were receiving dabrafenib as first-line treatment (figure 1). Central confirmation of BRAF^V600E mutation status has not yet been completed.

Baseline characteristics of the 78 patients receiving dabrafenib as a second-line or later treatment (previously treated patients) are shown in table 1. Baseline characteristics for the six

Discussion

This phase 2 study showed antitumour activity of dabrafenib in patients with BRAF^V600E-positive NSCLC. The confirmed overall response was 33% and disease control was achieved in 58% of 78 patients who had previously received treatment for metastatic disease. Additionally, response was rapid, with 73% of patients having a partial response noted at the first assessment 6 weeks from baseline. Results from an independent review of clinical activity data were consistent with those from the

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ArticlesDabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Cell

J Thorac Oncol

J Thorac Oncol

Lancet

J Thorac Oncol

Lancet

Lancet

Lancet Oncol

Lancet Oncol

Cancer statistics, 2015

CA Cancer J Clin

Mutations of the BRAF gene in human cancer

Nature

Missense mutations of the BRAF gene in human lung adenocarcinoma

Cancer Res

A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors

Genes Dev

Biomarkers (BM) France: results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4–ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts)

Proc Soc Am Clin Oncol

Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations

J Clin Oncol

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

JAMA

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

J Clin Oncol

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

Clin Cancer Res

Articles
Dabrafenib in patients with BRAF^V600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial