Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial
Open accessAbstract
Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has demonstrated antitumor activity in patients with BRAF V600E (Val600Glu)–mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF V600E–mutant NSCLC may improve efficacy over BRAF-inhibitor monotherapy based on observations in BRAF V600–mutant melanoma. Methods In this phase 2, multicenter, nonrandomized, open-label study of patients with pretreated metastatic BRAF V600E–mutant NSCLC, antitumor activity and safety of oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) were evaluated. Adult patients (≥ 18 years) with documented progression following at least one prior platinum-based chemotherapy and no more than three prior systemic anticancer therapies were enrolled. Patients with prior BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were permitted to enroll only if the lesions were asymptomatic, untreated (or stable > 3 weeks after local therapy if treated), and measured < 1 cm. The primary endpoint was investigator-assessed overall response, which was assessed by intention-to-treat in the protocol-defined population (≥ second-line); safety was also assessed in this population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. Findings Fifty-seven patients previously treated with systemic chemotherapy for metastatic BRAF V600E–mutant NSCLC were enrolled. The investigator-assessed overall response was 63·2% (36 of 57; 95% CI 49·3–75·6). Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia (16%; 9 of 57), anemia (5%; 3 of 57), confusional state (4%; 2 of 57), decreased appetite (4%; 2 of 57), hemoptysis (4%; 2 of 57), hypercalcemia (4%; 2 of 57), nausea (4%; 2 of 57), and cutaneous squamous cell carcinoma (4%; 2 of 57). Common grade 3/4 AEs included neutropenia (9%; 5 of 57), hyponatremia (7%; 4 of 57), and anemia (5%; 3 of 57). Interpretation Dabrafenib plus trametinib represents a new targeted therapy with robust antitumor activity and a manageable safety profile in patients with BRAF V600E–mutant NSCLC. Funding GlaxoSmithKline.
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Combination therapies to suppress adaptive feedback proved key to optimizing the frequency and durability of response in each tumor type.
“Still, in all cases, combination therapies to suppress adaptive feedback proved key to optimizing the frequency and durability of response in each tumor type (34,50,51).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [50]
The Results and Discussion report frequent, durable responses to dabrafenib plus trametinib in previously treated BRAF V600E–mutant NSCLC, with higher response and progression-free survival than an indirect comparison with dabrafenib alone. But the Discussion says whether the proposed resistance mechanisms occur in these NSCLC patients is unknown. This trial therefore does not establish that suppressing adaptive feedback was the reason combination therapy improved responses, or that this was proved across tumor types. No page number is available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRegimens that combine different anticancer drugs target pro-growth or pro-survival signaling pathways in either a synergistic or additive manner, which reduces drug resistance.
“Mechanistically, regimens that combine different anticancer drugs target pro-growth or pro-survival signaling pathways in either a synergistic or an additive manner, which reduces drug resistance.77,78”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [78]
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- Authors
- Planchard, D., Besse, B., Groen, H. J. M., Souquet, P.-J., Quoix, E., Baik, C. S., Barlesi, F., Kim, T. M., Mazieres, J., Novello, S., Rigas, J. R., Upalawanna, A., D'Amelio, A. M., Zhang, P., Mookerjee, B., & Johnson, B. E.
- Affiliations
- Institut Gustave Roussy (FR)
- Université Paris-Sud (FR)
- University Medical Center Groningen (NL)
- Hôpital Lyon Sud (FR)
- University of Washington (US)
- Seoul National University Hospital (KR)
- University of Turin (IT)
- Dartmouth College (US)
- Novartis (Switzerland) (CH)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Johnson, Bruce E
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 17
- Issue
- 7
- Pages
- 984-993
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC4993103
- OpenAlex
- W3164126191
- Semantic Scholar
- ed6c0916898f90d84d671a7144a3c4cf39ac1d28
- Cited by
- 888
- References
- 38
- Citations by year
- 2026: 26 · 2025: 56 · 2024: 74 · 2023: 89 · 2022: 100 · 2021: 112 · 2020: 115 · 2019: 85 · 2018: 122 · 2017: 92 · 2016: 14 · 2015: 1 · 2014: 1
- FWCI
- 93.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- GlaxoSmithKline
- Novartis
- National Cancer Institute (P50CA090578)
- 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, trametinib, BRAF V600E mutation, metastatic non-small cell lung cancer, MAPK inhibition, second-line therapy, overall response rate, treatment safety, brain metastases, platinum-refractory disease, antitumour activity
- MeSH terms
- Adenocarcinoma, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Follow-Up Studies, Humans, Imidazoles, Lung Neoplasms, Lymphatic Metastasis, Male, Middle Aged, Mutation, Neoplasm Recurrence, Local, Neoplasm Staging, Oximes, Prognosis, Pyridones, Pyrimidinones, Biomarkers, Tumor, Survival Rate, Carcinoma, Large Cell, Proto-Oncogene Proteins B-raf
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Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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