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Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved the prognosis of advanced-stage non-small cell lung cancer (NSCLC) with ALK rearrangement, but resistance mechanisms limit their efficacy. We describe the case of a 63-year-old man with a stage cIVA ALK-rearranged lung adenocarcinoma who developed a BRAF A598-T599insV mutation as a potential resistance mechanism to alectinib, a second-generation ALK TKI. He was treated with an association of BRAF and MEK inhibitors but death occurred two months after treatment initiation in a context of tumor progression and toxicity. Based on this first report of BRAF A598-T599insV mutation occurring in lung cancer, we discuss resistance mechanisms to ALK TKIs, implications of BRAF mutation in NSCLC, and BRAF A598-T599insV mutation in other cancers.

Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare subset of lung carcinoma associated with poor overall survival. Due to its rarity, little has been established about its optimal treatment in the advanced stage. We report the case of a 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC who presented an impressive tumor response to immunotherapy with nivolumab after non-curative thoracic radiotherapy. Salvage surgery was then performed, and pathologic analysis of the resected piece revealed the absence of residual viable tumor cells. Based on this case report, we discuss the literature regarding the efficacy of inhibitors of programmed death-1 protein (PD-1) in L-LCNEC and their use in association with radiotherapy and in the neoadjuvant setting.