Lazertinib for patients with NSCLC harboring uncommon EGFR mutations: A single-arm, phase II multi-center trial

BackgroundLazertinib has demonstrated significant clinical efficacy as both monotherapy and in combination with amivantamab for treatment-naïve patients with activating EGFR mutations. Previous preclinical trials have indicated a comparably low IC50 for uncommon EGFR mutations. Consequently, we initiated a prospective phase II study to assess the effectiveness of lazertinib at a dosage of 240mg in treatment-naïve NSCLC patients harboring these rare mutations.MethodsWe enrolled confirmed NSCLC patients exhibiting uncommon EGFR mutations (e.g., G719X, S768I, L861Q, combinations of G719X + S768I, G719X + L861Q, L861Q + S768I, and others such as L747S, S720A, E709A, Exon 18 deletion), without common EGFR mutations (Exon 19 deletion, L858R, T790M, and Exon 20 insertion). Participants received a daily dose of 240mg lazertinib until disease progression or the onset of unacceptable toxicities.ResultsWe enrolled a total of 36 patients from five different institutions across South Korea between April 2022 and May 2023, with the data cut-off date being February 29, 2024. The median age of the study cohort was 67 years (range: 37-82), comprising 58.3% males and 44.4% never smokers. At enrollment, 41.7% of patients presented with brain metastases. The median follow-up duration was 9.4 months (95% CI: 4.4-11.1), with a median progression-free survival of 10.8 months (95% CI: 4.4-19.2). The overall response rate (ORR) was 50.0%, and the disease control rate stood at 91.7%. ORR by mutation subtype was as follows: G719X (69.2%), L861Q (54.6%), exon 18 deletion (0%), G719X/S768I (66.7%), S768I (50.0%), and Other (0%). Adverse events led to dose reductions in 47.2% of the patients and one patient discontinued treatment due to grade 2 pneumonitis.ConclusionsThis study underscores the clinical benefits of 240mg lazertinib for treating naïve patients with uncommon EGFR mutations. Notably, the two most prevalent mutations, G719X and L861Q, demonstrated promising outcomes, consistent with preclinical expectations. The safety profile aligns with previous registry trials, reinforcing the need for further investigations to substantiate the clinical efficacy of lazertinib in treating uncommon EGFR mutations on larger population.Clinical trial identificationNCT05277701.Legal entity responsible for the studyThe authors.FundingYuhan.DisclosureAll authors have declared no conflicts of interest.