Lazertinib in EGFR-Variant Non–Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors

Importance EGFR -variant non–small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Objective To investigate CNS activity with lazertinib, a third-generation EGFR TKI. Design, Setting, and Participants This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR -variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Exposure Lazertinib, 240 mg, once daily. Main Outcomes and Measures The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Results Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. Conclusions and Relevance In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR -variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR -variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. Trial Registration ClinicalTrials.gov Identifier: NCT05326425