BRAF Inhibitors in Lung Cancer

BRAF mutations have been reported in 3% of non-small cell lung cancers (NSCLC), only in adenocarcinoma sub-type of NSCLC. Although uncommon, BRAF mutations represent a valid potential target as multiple RAF kinase inhibitors are available. BRAF V600E mutation is reported in 2% of NSCLC.

Based on activity of BRAF targeted therapy in melanoma and demonstration of similar activating mutations of BRAF in NSCLC, a phase II study was formulated to evaluate activity of Dabrafenib in BRAF V600E mutation positive Stage IV NSCLC after failure of first-line therapy.

Interim results of this study were reported in ASCO 2013. This is an open label 2-stage phase II study with interim safety and efficacy analysis after enrollment of 20 patients in first stage prior to proceeding to stage 2, which involves accrual of an additional 20 patients. At the data cut-off for interim analysis, 25 patients were evaluable for safety and 20 patients were evaluable for efficacy. Response rate (partial and complete) was noted in 40%, while stable disease was reported in additional 20% and hence total disease control rate was seen in 60% of evaluable patients. Median duration of response was 84 days while in 8% (2 patients) it was reported to be over 12 months. Common adverse effects seen were fatigue, decreased appetite, rash, pyrexia, nausea, vomiting and diarrhea. Serious adverse events were reported in 40% (10 patients) and included squamous cell cancer, hypersensitivity reaction, intracranial hemorrhage, pyrexia amongst others.

These results established the activity of Dabrafenib in BRAF V600E mutation positive stage IV NSCLC and the sample size for the study has been expanded, including enrollment of eligible patients for first line therapy.

Based on these results, Dabrafenib was granted breakthrough therapy designation by the FDA for BRAF mutation positive NSCLC.

Additional pathways of clinical relevance for lung cancer include KRAS, PI3Kinase, ALK, FGFR amongst others.

At RPCI, ongoing protocols are evaluating clinical efficacy of additional agents like PI3 Kinase inhibitors, Wnt inhibitors, Cyclin dependent kinase inhibitors and FGFR inhibitors.