Detection of an EGFR L858R mutation following prolonged sequential ALK-TKI therapy in ALK-rearranged NSCLC: a case report

Abstract Anaplastic lymphoma kinase ( ALK )-rearranged non-small cell lung cancer (NSCLC) typically exhibits profound sensitivity to ALK tyrosine kinase inhibitors (TKIs). While sequential therapy with next-generation inhibitors has significantly improved long-term outcomes, acquired resistance remains an eventual challenge. Whereas secondary ALK mutations or bypass signaling represent more common resistance mechanisms, the identification of a clinically actionable epidermal growth factor receptor ( EGFR ) alteration following prolonged ALK-TKI therapy remains rare. Here, we report a 60-year-old female with stage IV ALK -positive adenocarcinoma who has achieved exceptionally durable disease control for nearly nine years following sequential therapy with crizotinib, alectinib, lorlatinib, and brigatinib. Upon progression on multiple ALK-TKIs, next-generation sequencing (NGS) performed on pericardial effusion cell sediment identified a clinically actionable EGFR L858R mutation (VAF 12.05%). Retrospective NGS of the archival baseline lymph node specimen using the same DNA-based targeted sequencing panel did not identify EGFR L858R or an ALK fusion. Following detection of EGFR L858R mutation, treatment was switched to the third-generation EGFR-TKI osimertinib, resulting in a RECIST 1.1-defined partial response (PR), accompanied by a marked decline in serum carcinoembryonic antigen (CEA) levels. The patient has maintained ongoing disease control through Month 107. This case highlights the importance of repeat molecular profiling at clinically meaningful disease progression and supports the use of pericardial effusion-based molecular profiling when conventional tissue biopsy is difficult or infeasible.