1348P Management of paresthesia in patients treated with lazertinib: Integrated analysis of LASER201 and LASER301 studies

Lazertinib, a third generation, highly mutant-selective, irreversible EGFR TKI, has demonstrated efficacy in locally advanced or metastatic EGFR-mutated NSCLC as front line and later line treatment with a manageable safety profile at the dose of 240 mg/day. Paresthesia, an uncommon adverse event (AE) for EGFR TKIs, was reported in 33% and 39% of patients receiving lazertinib in the LASER201 (NCT03046992) and LASER301 (NCT04248829) studies. We performed an integrated analysis of these studies to characterize the clinical features of paresthesia and related AEs, and examined the effect of lazertinib dose reduction (DR) on drug exposure, safety and clinical efficacy. Patients treated with lazertinib 240 mg/day in the LASER201 and LASER301 studies were included in the analysis (332 patients). Lazertinib plasma trough concentrations at steady state (Ctrough) were measured at doses of 240 mg/day and 160 mg/day (post-DR). Efficacy outcomes including PFS were compared in patients with and without DR for any reason in LASER301. Paresthesia and related AEs including hypoesthesia and neuropathy were reported in 160 (48%) of 332 patients. Most AEs were of CTCAE grade 1 or 2 without serious AEs. Paresthesia leading to DR was infrequent (22 patients; 7%). Median time to paresthesia onset was 105 days (range: 2–799); time to DR due to paresthesia was 252.5 days (range: 64–1135). Median post-DR Ctrough levels in DR patients were similar to those in non-DR patients (post-DR: 168.5 ng/mL; non-DR: 177.9 ng/mL). In the LASER301 study, DR occurred in 42 of 196 patients assigned to 240mg/day lazertinib. Median PFS was similar in patients with and without DR: 18.0 months (95% CI: 14.8–not reached) for DR patients vs 23.3 months (95% CI: 16.7–26.1) for non-DR patients. In the LASER201 study, 12 of 76 T790M-positive patients experienced DR due to any cause. Of 13 patients in the LASER301 study with paresthesia leading to DR, AE severity decreased in 9 patients (63%) after DR to 160mg/day, including complete AE resolution in 1 patient. Most paresthesia and related AEs were grade 1 or 2 and DR due to paresthesia was infrequent. Lazertinib DR to 160 mg/day may alleviate paresthesia severity without compromising clinical outcomes.