Abstract
Targeted therapy with combined dabrafenib and trametinib has been proven to provide clinical benefits in patients with NSCLC with a BRAF V600E mutation. Nevertheless, the treatment strategy for patients with NSCLC with BRAF non-V600E mutations remains limited. Here, we present a patient with NSCLC with a BRAF K601E mutation, a class II BRAF mutation, who had a durable response to targeted therapy with combined dabrafenib and trametinib.
Keywords: BRAF K601E mutation, Adenocarcinoma, Dabrafenib, Trametinib, Case report
Introduction
BRAF mutations are rare driver oncogenes that were identified in 2% to 4% of patients with NSCLC. BRAF encodes a serine and threonine protein kinase that promotes cell survival and proliferation by means of the MAPK pathway. Targeted therapy with BRAF and MEK inhibitors, dabrafenib and trametinib, has been proven to be clinically effective for patients with a BRAF V600 mutation (class I BRAF mutation), which represents approximately half of BRAF mutations.1 Nevertheless, the treatment strategy for patients with BRAF non-V600 mutation remains limited.
The BRAF K601E mutation is a class II BRAF mutation that occurs in approximately 0.2% of patients with lung adenocarcinoma. It induces high intrinsic kinase activity by impairing its interaction with the phosphate-binding loop.2 In vitro study has also revealed that class II BRAF mutations could also increase the activity of downstream MAPK pathway, including the activation of MEK and ERK.2 Although trametinib provides clinical benefit in patients with BRAF K601E-mutant melanoma, the duration of response in a case report with BRAF K601E-mutant lung adenocarcinoma was only 4 months.3
Here, we present the case of a patient with NSCLC with a BRAF K601E mutation who exhibited a durable response to targeted therapy with combined dabrafenib and trametinib.
Case Presentation
A previously healthy 43-year-old woman without a history of cigarette smoking presented with chronic nonproductive cough for half a year. Computed tomography (CT) scan of the chest revealed a right lower lung mass with right pleural dissemination and mediastinal lymph node enlargement (Fig. 1A). After biopsy by means of pleuroscopic examination, the pathologic workup result revealed adenocarcinoma, which expressed thyroid transcription factor-1 but not p40. On the basis of the clinical data, the patient was diagnosed with having stage IV lung adenocarcinoma.
Figure 1.
Chest CT scan results of the patient before and after targeted therapy with combined dabrafenib and trametinib. (A) Before treatment. (B) After 3 months of targeted therapy. (C) After 6 months of targeted therapy. The white arrowhead indicates the mediastinal lymph node (cardiophrenic lymph node). CT, computed tomography.
We use the QIAGEN GeneReader next-generation sequencing system and QIAact Lung All-in-One assay, and we detected BRAF mutation (K601E) (Fig. 2A), EGFR amplification (copy number: 2.36), and RICTOR amplification (copy number: 2.74) (Table 1). The point mutation in the BRAF gene was further validated by forward and reverse sequencing using Sanger sequencing (Fig. 2B). No other genomic alterations were detected, including EGFR, ALK (immunohistochemistry), and ROS1 (immunohistochemistry). Less than 1% of all tumor cells expressed programmed death-ligand 1. After three months of targeted therapy with combined dabrafenib and trametinib, chest CT result revealed partial regression of the right lower lung tumor, in combination with regression of mediastinal lymphadenopathy and pleural effusion (without thoracocentesis) (Fig. 1B). Her cough also resolved gradually. After 6 months, her chest CT scan result revealed near-total regression of the right lower lung tumor (Fig. 1C). The patient had received dabrafenib and trametinib for 9 months with a durable response. Only grade 1 skin rashes and grade 1 pyrexia developed, which were controlled using antihistamines and antipyretics. No newly onset cutaneous malignancies developed.
Figure 2.
Genomic sequencing data. (A) Next-generation sequencing of tissue from the pleural metastasis revealed a c.1801A>G (p.K601E) mutation (26.44%) in BRAF gene. (B) Sanger sequence confirmed a c.1801A>G (p.K601E) mutation in BRAF gene with forward and reverse sequencing.
Table 1.
Results From NGS Panel Testing
| Gene | cDNA | Amino Acid | Allele Frequency, % | Verdict |
|---|---|---|---|---|
| BRAF | c.1801A>G | p.K601E | 24.66 | Pathogenic |
| EGFR | Amplification | — | — | Pathogenic |
| RICTOR | Amplification | — | — | Pathogenic |
Note: NGS DNA panel testing revealed wild-type sequences in hotspots of the following genes: ALK, AKT1, DDR2, EGFR, ERBB2, ESR1, FGFR1, KRAS, KIT, MAP2K1, MET, NRAS, NTRK1, PDGFRA, PIK3CA, PTEN, and ROS1.
cDNA, complementary DNA; NGS, next-generation sequencing.
Discussion
To the best of our knowledge, this is the first case demonstrating a near-complete and durable response to targeted therapy with combined dabrafenib and trametinib in a patient with BRAF K601E mutation. The K601E-mutated BRAF was activated as a dimer, which has been discovered to interfere with the binding ability of BRAF inhibitors, including dabrafenib and vemurafenib.4 Given the activation of downstream signaling of the MAPK pathway in melanoma, several case reports on melanoma have a clinical response to the MEK inhibitor trametinib.4 Nevertheless, in a case report of a patient with BRAF K601E mutation, the duration of response was only four months. Moreover, considerable trametinib-related adverse events led to dose reduction and interruption.3
In a patient-derived murine xenograft model of BRAF K601E-mutant melanoma, the targeted therapy with combined dabrafenib and trametinib provided higher tumor volume reduction and longer duration of response compared with trametinib monotherapy.5 In addition, the patient from whom the model was derived had a partial response after the targeted therapy with combined dabrafenib and trametinib.5 In general, the use of trametinib and dabrafenib is not recommended in non-V600E because there are patients with NSCLC with BRAF K601E mutation who did not respond to this combination.6,7 Future clinical trials studying targeted therapy with combined dabrafenib and trametinib in patients with BRAF K601E mutation are warranted. There are ongoing clinical trials with the targeted therapy of combined BRAF inhibitors and MEK inhibitors in patients with BRAF V600E and non-V600E mutation–positive NSCLC and melanoma (ERCRAF study) (ClinicalTrials.gov identifier: NCT02974725) and in patients with advanced solid tumors with non-V600E BRAF mutations (BEAVER study) (ClinicalTrials.gov identifier: NCT03839342).
Conclusion
We report a case of lung adenocarcinoma with a BRAF K601E mutation that responded to targeted therapy with combined dabrafenib and trametinib. This case reveals the potential clinical benefit of combined dabrafenib and trametinib in patients harboring the BRAF non-V600E mutation.
CRediT Authorship Contribution Statement
Po-Lan Su: Conceptualization, Data curation, Formal analysis, Writing—original draft.
Chien-Yu Lin: Conceptualization, Writing—original draft.
Yi-Lin Chen, Wan-Li Chen: Conceptualization, Data curation, Methodology, Software.
Chien-Chung Lin, Wu-Chou Su: Conceptualization, Data curation, Formal analysis, Writing—review and editing.
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The patient involved in this case report gave her informed consent authorizing use and disclosure of her health information.
Footnotes
Drs. PL Su and CY Lin contributed equally to this work.
Disclosure: The authors declare no conflict of interest.
Cite this article as: Su PL, Lin CY, Chen YL, et al. Durable response to combined dabrafenib and trametinib in a patient with BRAF K601E mutation-positive lung adenocarcinoma: a case report. JTO Clin Res Rep. 2021;2:100202.
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