- The launch of darafenib makes the BRAF gene the fourth biomarker for metastatic NSCLC in clinical use, after EGFR, ALK, and ROS-1, an important milestone in lung cancer.
- For patients with advanced NSCLC with BRAF V600E gene mutations, darafenib + trametinib is the first specific combination therapy approved by the FDA as a first-line treatment option.
Darafenib (Dabrafenib), is a highly selective inhibitor of BRAF mutant kinases. It effectively inhibits BRAF V600E gene mutation-associated kinase activity; at higher concentrations, it also inhibits the wild-type BRAF gene, the CRAF gene, and other kinases.
The advantage of darafenib is that it can be individualized for the rare mutation of BRAF V600E in solid tumors, which can lead to good clinical outcomes in patients with these mutations.
Today, let’s take a look at how darafenib works in lung cancer treatment.
First demonstration of the efficacy of darafenib in lung cancer
On November 21, 2013, the U.S. Food and Drug Administration (FDA) granted breakthrough therapy status to darafenib for metastatic non-small cell lung cancer (NSCLC) positive for the BRAF V600E gene mutation that had been treated with chemotherapy.
This is based primarily on the results of a phase I clinical study that showed a 45% overall effectiveness of darafenib in patients with BRAF V600E mutation-positive metastatic NSCLC who had received chemotherapy.
Further phase II clinical studies have since found that the overall effectiveness of darafenib in such patients was 33%, the disease control rate was 58%, the median time to disease control was 9.6 months, the median progression-free survival (PFS) was 5.5 months, and the median overall survival, OS) was 12.7 months. Once again, it confirms its superior efficacy in patients with BRAF V600E mutated NSCLC.
Recognition of the combination of darafenib + trametinib
In addition to its stand-alone application, on June 22, 2017, the US FDA officially approved: darafenib + trametinib for the treatment of patients with metastatic NSCLC with BRAF V600E mutations.
In the same year, the American Society of Clinical Oncology (ASCO) guidelines recommended this combination regimen for previously treated patients with BRAF V600E mutation-positive NSCLC.
The National Comprehensive Cancer Network (NCCN) guidelines also recommend that for metastatic nonsquamous NSCLC with routine testing for BRAF V600E mutations, if BRAF V600E mutation-positive, darafenib in combination with trametinib may be used as a first-line treatment option.
The approval of darafenib + trametinib, and the unanimous endorsement of major guidelines, is attributed to the results of a phase II clinical study (No. NCT01336634). The study found that in patients with advanced NSCLC carrying the BRAF V600E gene mutation, only a 27% overall effectiveness was achieved with darafenib alone; in previously untreated patients with advanced NSCLC, the overall effectiveness of the combination of darafenib and trametinib was 64%; in patients who had previously received chemotherapy, the overall efficacy rate was 63.2%.
In this study, common adverse reactions to darafenib + trametinib included fever, malaise, nausea, vomiting, and diarrhea. Most of the adverse reactions were mild, and there were no treatment-related deaths. Most adverse reactions could be controlled by dose reduction, and 18% of patients discontinued treatment due to drug-related adverse reactions.
Darafenib Ongoing Studies
While the results of studies on darafenib are promising and have led to widespread clinical use in the United States, these findings are based on white populations, and its efficacy and safety in yellow populations remain uncertain.
In addition to those described earlier, there are only 2 studies available through the US Clinical Trials Registry with a primary focus on dabrafenib for lung cancer, but reassuringly, both studies address the efficacy and safety of dabrafenib + trametinib in yellow populations.