The transformation of lung adenocarcinoma into large cell neuroendocrine carcinoma (LCNEC) in terms of genotype and histology has been described as a mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, this phenomenon is exceedingly rare in anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. Here, we report a case of an ALK-positive lung adenocarcinoma patient who developed resistance following sequential treatment with the ALK-TKI alectinib and lorlatinib, accompanied by histological transformation to LCNEC and concurrent genetic alterations including TP53 deletion, CDKN2A deletion, and MYC amplification. This case expands the spectrum of ALK-TKI resistance mechanisms and highlights the potential value of exploring combinatorial approaches incorporating immunotherapy, antiangiogenic therapy, and chemotherapy for the management of such cases.
Zhong et al. (Wed,) studied this question.