Efficacy and tolerability of osimertinib with dabrafenib and trametinib in V600E acquired -mutant non-small cell lung cancer: a case series.

Background: Acquired mutations within bypass pathways including V600E have been observed in post-osimertinib progression in -mutant non-small cell lung cancer (NSCLC). The combination of dabrafenib and trametinib is currently Food and Drug Administration-approved in V600E-mutant NSCLC. However, the application of osimertinib and dabrafenib and trametinib in the setting of acquired V600E mutation resistance from osimertinib therapy has not been clearly defined. In this case series, we evaluate the efficacy and tolerability of continued osimertinib in combination with dabrafenib and trametinib in V600E acquired -mutant NSCLC.

Case Description: We retrospectively reviewed our clinical patient cohort at the University of California San Diego and patients from published case studies. Individuals who had metastatic -mutant lung adenocarcinoma treated with osimertinib at any line whom subsequently developed an acquired V600E mutation confirmed by next-generation sequencing were included for analysis. All patients had subsequent dabrafenib and trametinib in combination with osimertinib after detection of the novel V600E mutation post-osimertinib therapy. We identified three cases from our practice and nine cases from literature review. In our study cohort (n=12), we observed a median progression-free survival of 7 months on triplet therapy (osimertinib, dabrafenib, and trametinib) post progression on osimertinib, median overall survival of 46.2 months, and 60% partial response on first scan after treatment initiation. Dose reductions were required in 5/12 patients due to adverse events and treatment discontinuation in 2/12 patients. The most common adverse events were pyrexia and rash, and two cases of pneumonitis were observed (grade 1 & unreported grade).

Conclusions: We concluded that the addition of combination dabrafenib and trametinib can be tolerable and effective in patients with acquired V600E mutation post progression on osimertinib. This study supports molecular profiling at osimertinib progression and provides additional information on the appropriate sequencing of targeted therapies in the EGFR tyrosine kinase inhibitor resistance setting.