Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial
Open accessAbstract
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.
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BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type.
“For instance, BRAF inhibitors led to a monotherapy response rate of >50% in BRAFV600E melanoma and ~30% in BRAFV600E NSCLC, but only ~5% in BRAFV600E colorectal cancer, likely due to the variable robustness of adaptive feedback networks in each tumor type (45–49).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [46]
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- Authors
- Planchard, D., Kim, T. M., Mazieres, J., Quoix, E., Riely, G., Barlesi, F., Souquet, P.-J., Smit, E. F., Groen, H. J. M., Kelly, R. J., Cho, B. C., Socinski, M. A., Pandite, L., Nase, C., Ma, B., D'Amelio, A., Mookerjee, B., Curtis, C. M., & Johnson, B. E.
- Affiliations
- Institut Gustave Roussy (FR)
- Seoul National University (KR)
- Memorial Sloan Kettering Cancer Center (US)
- Hôpital Lyon Sud (FR)
- Vrije Universiteit Amsterdam (NL)
- University Medical Center Groningen (NL)
- Johns Hopkins University (US)
- Yonsei University (KR)
- University of Pittsburgh (US)
- GlaxoSmithKline (United States) (US)
- Biothera (United States) (US)
- Novartis (United States) (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Johnson, Bruce E
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 17
- Issue
- 5
- Pages
- 642-650
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC5006181
- OpenAlex
- W2335671095
- Cited by
- 453
- References
- 36
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 44 · 2023: 42 · 2022: 42 · 2021: 50 · 2020: 50 · 2019: 42 · 2018: 73 · 2017: 56 · 2016: 24 · 2015: 1 · 2014: 1
- FWCI
- 58.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- PubMed Central (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Cancer Institute (P50CA090578, P30CA008748)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- dabrafenib, BRAF V600E mutation, non-small cell lung cancer, BRAF inhibitors, targeted therapy, lung adenocarcinoma, metastatic non-small cell lung cancer, overall response rate, cutaneous squamous cell carcinoma, intracranial hemorrhage, adverse events
- MeSH terms
- Administration, Oral, Adolescent, Adult, Aged, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Female, Humans, Imidazoles, Male, Middle Aged, Mutation, Neoplasm Staging, Oximes, Disease-Free Survival, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
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