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

Uncommon EGFR mutations comprise 10-20% of all EGFR mutations in non-small cell lung cancer (NSCLC) and generally show reduced responsiveness to EGFR tyrosine kinase inhibitors (TKIs). Lazertinib, a third-generation EGFR-TKI, has demonstrated efficacy in common EGFR mutations, but its potential in uncommon mutations remains unexplored. This study investigated the efficacy and safety of lazertinib in NSCLC patients with uncommon EGFR mutations. This single-arm, multicenter phase II trial enrolled patients with advanced NSCLC harboring uncommon EGFR mutations excluding exon 20 insertions. Patients received lazertinib 240 mg daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Among 36 enrolled patients, the ORR was 50.0% (95% CI: 34.5-65.5%), with 18 partial responses, meeting the primary endpoint. Disease control rate was 88.9% (95% CI: 74.1-96.2%). Patients with major uncommon mutations (G719X, L861Q, S768I) showed an ORR of 54.8% (17/31). Median PFS was 10.8 months (95% CI: 4.4-19.2) and median DoR was 15.1 months. G719X mutations showed the highest response (ORR 61%, median PFS 20.3 months), followed by S768I (ORR 60%) and L861Q (ORR 58%, median PFS 9.5 months). Treatment-emergent adverse events occurred in all patients, with grade ≥3 events in 33.3%; most common were rash (47.2%), pruritus (36.1%), and muscle spasms (33.3%). Lazertinib demonstrated promising efficacy and a manageable safety profile in NSCLC patients with uncommon EGFR mutations, particularly for G719X, S768I, and L861Q subtypes. These results suggest lazertinib could be an effective treatment option for this heterogeneous patient population with limited therapeutic alternatives.