Emerging EGFR-Mutated Subclones in a Patient With Metastatic ALK-Rearranged Lung Adenocarcinoma Treated With ALK-Targeted Therapy: A Case Report.

We report a case of pathologically confirmed ALK-rearranged metastatic lung adenocarcinoma with emergence of EGFR L858R mutation on disease progression after two lines of treatment with ALK inhibitors. At initial diagnosis, tumoral ALK expression was detected without EGFR mutation by standard allele-specific polymerase chain reaction. There was sustained partial response to both first-line crizotinib and subsequent brigatinib. On disease progression to brigatinib, result of a liquid biopsy with circulating tumor DNA revealed only EGFR L858R, which was confirmed by tumor rebiopsy on the supraclavicular lymph node. The patient was then treated initially with pemetrexed and carboplatin, and erlotinib was subsequently added after two cycles of chemotherapy. The combination treatment has resulted in very good partial response and mild adverse effects. The overall clinical course would suggest the initial presence of two separate tumor clones, with ALK dominance at diagnosis. The subsequent breakthrough disease progression after initial response to brigatinib was related to uncontrolled growth of the EGFR-mutated tumor subpopulation. The implication on defining molecular mechanism of acquired resistance and treatment strategy would be discussed.