Survival benefit of combinatorial osimertinib rechallenge and entrectinib in an EGFR-mutant NSCLC patient with acquired LMNA-NTRK1 fusion following osimertinib resistance.

Acquired resistance to osimertinib is inevitable and heterogeneous despite its documented efficacy against EGFR-mutated non-small cell lung cancer (NSCLC). Subsequent therapeutic options assume the dominant form of the resistance mechanism; however, the more rare oncogenic driver, NTRK1 fusion, has also reportedly conferred osimertinib resistance. Nevertheless, clear-cut options when NSCLCs are driven by EGFR mutation and the subsequent NTRK fusion are lacking. This is a case of NSCLC wherein exon 19 deletion in EGFR (19del) and acquired LMNA-NTRK1 fusion were accompanied by the persistence of EGFR T790M. The patient underwent peritoneal metastasis after multiple targeted therapies: gefitinib, osimertinib, chemotherapy, and anlotinib plus docetaxel (in clinical trials). Osimertinib was subsequently re-administered with the NTRK fusion inhibitor entrectinib, resulting in remission of peritoneal metastases even after slow progression of pancreatic metastasis over the following 5 months. An extensive literature review to identify the efficacies of therapies for NTRK fusion as the means to acquired resistance to EGFR TKIs revealed that blocking both the EGFR mutation and the subsequent NTRK fusion can provide clinical benefits following EGFR TKIs resistance; however, the efficacy and safety of combination therapies must be further investigated. To precisely manage EGFR-mutated NSCLCs, it is also essential to identify the resistance mechanisms by repeating biopsies.