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BRAF Inhibitors in Non-Small Cell Lung Cancer

Vincenzo Sforza1, Giuliano Palumbo1, Priscilla Cascetta2

  • 1Thoracic Medical Oncology, Istituto Nazionale Tumori, "Fondazione G. Pascale"-IRCCS, 80131 Napoli, Italy.

Cancers
|October 14, 2022
PubMed

Insights

The combination of BRAF and MEK inhibitors, dabrafenib and trametinib, shows significant efficacy in treating BRAF V600E metastatic non-small cell lung cancer (NSCLC). This targeted therapy demonstrated high response rates and improved survival, leading to its approval for NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • RAF proteins are key serine-threonine kinases in the MAPK pathway, crucial for cell processes.
  • MAPK pathway deregulation is implicated in numerous cancers, with BRAF mutations found in 1.5-3.5% of NSCLC.
  • Prior success of BRAF/MEK inhibitor combinations in melanoma prompted investigation in NSCLC.

Purpose of the Study:

  • To evaluate the efficacy and safety of combining dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in BRAF-mutant NSCLC patients.
  • To assess this combination in both pretreated and first-line settings.

Main Methods:

  • The BRF113928 trial enrolled pretreated (cohort B) and first-line (cohort C) NSCLC patients with BRAF mutations.
  • Patients received a combination of dabrafenib and trametinib.
  • Outcomes measured included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Main Results:

  • In pretreated patients (cohort B), the combination yielded an ORR of 68.4%, DCR of 80.7%, median PFS of 10.2 months, and median OS of 18.2 months.
  • In the first-line setting (cohort C), ORR was 63.9%, DCR 75%, with median PFS and OS of 10.2 and 17.3 months, respectively.
  • The treatment was generally well-tolerated, with common adverse events including pyrexia, nausea, diarrhea, fatigue, edema, and vomiting.

Conclusions:

  • The combination of dabrafenib and trametinib is effective and well-tolerated for BRAF V600E metastatic NSCLC.
  • This regimen has led to regulatory approval for BRAF-mutated NSCLC patients, irrespective of prior treatment.
  • Future research will explore next-generation inhibitors and combinations for acquired resistance and other treatment strategies.
Keywords:
BRAFMEKNSCLCbinimetinibdabrafenibencorafenibtrametinib

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