Lung Adenocarcinoma Harboring Concomitant EGFR Mutations and BRAF V600E Responds to a Combination of Osimertinib and Vemurafenib to Overcome Osimertinib Resistance

Clinical Practice Points•Genetic alterations in v-Raf murine sarcoma viral oncogene homolog B (BRAF), including V600E, are implicated as bypass mechanisms in developing resistance to osimertinib; however, treatment strategies that simultaneously target concomitant actionable mutations in BRAF and epidermal growth factor receptor (EGFR) remain limited.•A combination of osimertinib and vemurafenib was administered as third-line therapy to two patients with advanced lung adenocarcinoma after BRAF V600E was identified by targeted sequencing of plasma samples at osimertinib progression.•Our report provides clinical evidence of the effectiveness of osimertinib and vemurafenib combination therapy to overcome BRAF V600E–mediated osimertinib resistance, suggesting the potential of this treatment regimen as an option in similar situations. •Genetic alterations in v-Raf murine sarcoma viral oncogene homolog B (BRAF), including V600E, are implicated as bypass mechanisms in developing resistance to osimertinib; however, treatment strategies that simultaneously target concomitant actionable mutations in BRAF and epidermal growth factor receptor (EGFR) remain limited.•A combination of osimertinib and vemurafenib was administered as third-line therapy to two patients with advanced lung adenocarcinoma after BRAF V600E was identified by targeted sequencing of plasma samples at osimertinib progression.•Our report provides clinical evidence of the effectiveness of osimertinib and vemurafenib combination therapy to overcome BRAF V600E–mediated osimertinib resistance, suggesting the potential of this treatment regimen as an option in similar situations.