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Clinical Trial
. 2025 Sep;20(9):1279-1288.
doi: 10.1016/j.jtho.2025.05.006. Epub 2025 May 9.

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

Sehhoon Park  1 , Hee Kyung Ahn  2 , Seoyoung Lee  3 , Young Joo Min  4 , Jinyong Kim  1 , Hyun Ae Jung  1 , Jong-Mu Sun  1 , Se-Hoon Lee  1 , Jin Seok Ahn  1 , Myung-Ju Ahn  1 , Jii Bum Lee  5 , Sun Min Lim  5 , Hye Ryun Kim  5 , Byoung Chul Cho  5 , Min Hee Hong  6
Affiliations
Free article
Clinical Trial

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

Sehhoon Park et al. J Thorac Oncol. 2025 Sep.
Free article

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.

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Conflict of interest statement

Disclosure Dr. Park reports research funding from Yuhan. Dr.Hee Kyung Ahn reports receiving consulting fees from Gilead, Amgen, Roche, Takeda, Daewoong, Bayer, Lilly, and Daiichi-Sankyo and payment or honoraria for lectures, presentations, speakers’ bureaus, or educational events from Eisai, Boryung, Lilly, LSK Korea, AstraZeneca, Yuhan, Pfizer, Novartis, Sanofi/Aventis, MSD, Boehringer Ingelheim, Celltrion, and Daiichi-Sankyo. Dr. Sun reports research funding from Yuhan. Dr. Se-Hoon Lee reports serving in a consulting or advisory role for Abion, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, IMBdx, ImmuneOncia, Janssen, Merck, MSD, Novartis, Pfizer, Roche, and Takeda; receiving honoraria from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, MSD, Roche, and Yuhan; and receiving research funding from AstraZeneca, Daiichi-Sankyo, Lunit, and MSD, outside the present work. Dr. Jin Seok Ahn reports receiving honoraria from Amgen Korea, Roche Korea, AstraZeneca Korea, Yuhan, BMS, Boryung, LG Chemical, Daiichi-Sankyo Korea, Menarini Korea, Nokwon Medical, BC World, Takeda Pharmaceuticals, Novartis Korea, Samyang, Pfizer, Lilly Korea, Boehringer Ingelheim, Kyowa Kirin, and Bayer Korea; serving on advisory boards for ImmuneOncia, Daiichi-Sankyo Korea, Pfizer, Yuhan, Pharmbio Korea, Roche, and Therapex; and holding a leadership role in the Korean Cancer Study Group. Dr. Myung-Ju Ahn reports receiving consulting fees and honoraria from AstraZeneca, Yuhan, Takeda, Genexin, Amgen, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Merck, Roche, and Pfizer; and serving on an advisory board for AstraZeneca. Dr. Jii Bum Lee reports receiving consulting fees from AstraZeneca, Boryung, Yuhan, AnHeart Therapeutics, Merck, Guardant Health, Daiichi Sankyo, and Takeda; reports honoraria from AstraZeneca, Guardant Health, Yuhan, Takeda, MSD, and Boryung; and holds unpaid leadership roles in the Korean Association for Lung Cancer (Public Relations Committee) and the Korean Society of Medical Oncology (International Affairs Committee). Dr. Lim reports receiving research funding from Yuhan, Johnson & Johnson, and MSD; serving in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Lilly, Takeda, J Ints Bio, Bristol Myers Squibb, Merck, MSD, Oscotec, and Therapex; receiving institutional research support from AstraZeneca, Boehringer Ingelheim, BioNTech, GSK, Roche, Hengrui, BridgeBio Therapeutics, Oscotec, Daiichi Sankyo, Johnson & Johnson, J Ints Bio, Therapex, and Yuhan. Dr. Kim reports clinical trial support to her institution from AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Pfizer, Beigene, Takeda, and Yuhan; participation in advisory boards for Bayer, AstraZeneca, Bristol Myers Squibb, Takeda, Daiichi, and Yuhan; and research funding from the Yonsei Lee Youn Jae Fellowship outside the present work. Dr. Cho reports receiving royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; research funding from GIInnovation, AstraZeneca, Champions Oncology, CJ Bioscience, Cyrus, Janssen, MSD, Dong-A ST, Yuhan, ImmuneOncia, Therapex, J INTS Bio, and Vertical Bio AG; serving in a consulting or advisory role for BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CJ, Cyrus Therapeutics, Ono Pharmaceuticals, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Gilead, Amgen, Daiichi Sankyo, Regeneron, Sanofi, AnHeart Therapeutics, Seagen, Harpoon Therapeutics, GSK, and ArriVent; serving on the advisory boards of KANAPH Therapeutics, BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, J INTS Bio, and Therapex; receiving honoraria for invited speaking engagements from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, the Chinese Thoracic Oncology Society, Pfizer, and Zailab; holding stock or shares in TheraCanVac Inc, Gencurix Inc, BridgeBio Therapeutics, KANAPH Therapeutics, Cyrus Therapeutics, Interpark Bio Convergence Corp., and J INTS Bio; being the founder of DAAN Biotherapeutics; and serving as a member of the board of directors of J INTS Bio. Dr. Hong reports receiving research funding from AstraZeneca, MSD, Novartis, and Yuhan; honoraria from AstraZeneca, Amgen, Bristol Myers Squibb, MSD, Ono Pharmaceutical, Takeda, Roche, Pfizer, and Yuhan; participation in clinical trials funded by AbbVie, IMPACT, Ignyta, Loxo Oncology, Novartis, Merck Serono, ORIC, AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Pfizer; and stock ownership in GI Cell, GI Biome, and Pfizer. The remaining authors declare no conflict of interest.

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