Standard dose osimertinib for erlotinib refractory T790M-negative -mutant non-small cell lung cancer with leptomeningeal disease.

BACKGROUND

Leptomeningeal spread in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor () mutations who experience disease progression on TKIs portends a poor prognosis. Mutation profiling of tumour DNA in cerebrospinal fluid (CSF) samples can be used to determine the presence of the T790M resistance mutation, indicating that osimertinib, a CNS-penetrating 3 generation TKI may be efficacious.

METHODS

Eight patients on EGFR TKIs who progressed with cytology-proven leptomeningeal disease at our institution were studied. mutations were profiled in CSF using droplet digital PCR (ddPCR) and compared to matched plasma samples. Clinical characteristics and survival outcomes on subsequent therapies tailored to ddPCR analysis were reported.

RESULTS

None of the four patients who developed leptomeningeal disease while receiving 1st generation EGFR TKIs developed the T790M mutation in CSF. One patient who did not have extra-cranial disease and was T790M-negative in both plasma and CSF was nevertheless treated with standard-dose osimertinib, and achieved a rapid and durable response lasting 9 months to date. Three patients developed leptomeningeal disease on osimertinib, with one patient developing the C797S mutation in a cis-allelic conformation with the T790M mutation in plasma.

CONCLUSIONS

Standard-dose osimertinib resulted in a clinically meaningful response in a patient with T790M-negative 1st generation EGFR TKI refractory leptomeningeal disease. Next generation sequencing and ddPCR has a role at identifying the C797S mutation and its allelic conformation with the T790M mutation with clinical implications.