Lazertinib Plus Pemetrexed and Carboplatin in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer after Progression on Lazertinib

Background Therapeutic strategies after progression on third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) remain suboptimal in EGFR -mutant non-small cell lung cancer (NSCLC). We investigated whether continuing EGFR inhibition with lazertinib combined with platinum-pemetrexed chemotherapy could extend clinical benefit after progression on prior lazertinib. Methods In the multicenter, single-arm, phase II LUCAS study (NCT05786430), patients with advanced EGFR -mutant NSCLC who had progressed on lazertinib received lazertinib 240 mg daily plus pemetrexed-carboplatin for four cycles, followed by maintenance lazertinib and pemetrexed. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), intracranial PFS, safety, and exploratory ctDNA analyses. Results Of 86 patients, 46.5% had a history of brain metastases. Among 81 response-evaluable patients, median PFS was 9.5 months (95% CI: 6.3-9.6; one-sided p=0.017 against a null median of 6.0 months). In the safety population, median OS was 15.9 months (95% CI: 12.4-20.0) and ORR was 36.0% (95% CI: 26.0-47.1). Outcomes were similar irrespective of prior lazertinib line or EGFR subtype. Baseline ctDNA-detected EGFR amplification was associated with inferior survival. Among 36 patients with radiologically evident baseline brain metastases, median intracranial PFS was 9.9 months (95% CI: 7.8-16.4) with infrequent isolated intracranial progression. Grade ≥3 adverse events occurred in 69.8%, predominantly hematologic, without new safety signals. Conclusions Continuation of lazertinib with platinum-pemetrexed chemotherapy after progression on prior lazertinib was associated with meaningful systemic and intracranial activity and manageable toxicity. Randomized evaluation is required to establish the incremental benefit of lazertinib continuation.