Novel LZTR1 germline mutation as a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma: a case report.

Abstract

Background: Tyrosine kinase inhibitors (TKIs) are now the standard of care first-line therapy for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) patients. Despite positive outcomes in most patients, with extended progression-free survival (PFS), a small population of patients respond poorly to these drugs. Complex genetic and non-genetic resistance mechanisms may be the drivers of disease in cancer, but further research is required to identify these mechanisms in the clinic. Germline molecular testing alongside broad-panel somatic next-generation sequencing (NGS) has allowed for detection of resistance mutations in EGFR-mutated NSCLC patients that may be linked with poor response on TKIs.

Case description: Here, we present a case of an NSCLC patient harboring an EGFR somatic mutation and a concomitant leucine-zipper-like transcriptional regulator-1 (LZTR1) germline mutation. The patient experienced rapid disease progression on first-line EGFR TKI, osimertinib-chemotherapy, combination therapy with a PFS of only 4 months as compared to the median PFS of 27.9 months in the FLAURA2 study.

Conclusions: This case report indicates that identification of germline resistance mutations such as LZTR1 may be associated with poor response to EGFR TKIs. Furthermore, further characterization of these resistance mutations beyond somatic mutations can aid in development of future therapeutic options, which currently do not exist. It is recommended that germline testing be performed as part of the initial patient workup, if available.