Lazertinib for Patients with NSCLC Harboring Uncommon EGFR Mutations: A Phase II Multicenter Trial

Sehhoon Park; Hee Kyung Ahn; Seoyoung Lee; Young Joo Min; Jinyong Kim; Hyun Ae Jung; Jong-Mu Sun; Se-Hoon Lee; Jin Seok Ahn; Myung-Ju Ahn; Jii Bum Lee; Sun Min Lim; Hye Ryun Kim; Byoung Chul Cho; Min Hee Hong

doi:10.1016/j.jtho.2025.05.006

Lazertinib for Patients with NSCLC Harboring Uncommon EGFR Mutations: A Phase II Multicenter Trial

J Thorac Oncol. 2025 May 9:S1556-0864(25)00713-0. doi: 10.1016/j.jtho.2025.05.006. Online ahead of print.

Authors

Sehhoon Park¹, Hee Kyung Ahn², Seoyoung Lee³, Young Joo Min⁴, Jinyong Kim¹, Hyun Ae Jung¹, Jong-Mu Sun¹, Se-Hoon Lee¹, Jin Seok Ahn¹, Myung-Ju Ahn¹, Jii Bum Lee⁵, Sun Min Lim⁵, Hye Ryun Kim⁵, Byoung Chul Cho⁵, Min Hee Hong⁶

Affiliations

¹ Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
² Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea.
³ Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁴ Division of Hematology and Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
⁵ Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
⁶ Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: minhee_hong@yuhs.ac.

PMID: 40350080
DOI: 10.1016/j.jtho.2025.05.006

Abstract

Introduction: Uncommon EGFR mutations comprise 10% to 20% of all EGFR mutations in NSCLC and generally report reduced responsiveness to EGFR tyrosine kinase inhibitors (TKIs). Lazertinib, a third-generation EGFR-TKI, has found efficacy in common EGFR mutations, but its potential in uncommon mutations remains unexplored. This study investigated the efficacy and safety of lazertinib in patients with NSCLC with uncommon EGFR mutations.

Method: 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 end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety.

Results: Among 36 patients enrolled, the ORR was 50.0% (95% confidence interval [CI]: 34.5%-65.5%), with 18 partial responses, meeting the primary end point. Disease control rate was 88.9% (95% CI: 74.1%-96.2%). Patients with major uncommon mutations (G719X, L861Q, S768I) reported 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 reported 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 or higher events in 33.3%; most common were rash (47.2%), pruritus (36.1%), and muscle spasms (33.3%).

Conclusions: Lazertinib reported promising efficacy and a manageable safety profile in patients with NSCLC 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.

Keywords: Lazertinib; NSCLC; Tyrosine kinase inhibitors; Uncommon EGFR mutations.