1324MO - CNS outcomes of lazertinib vs gefitinib in EGFR-mutated advanced NSCLC: A LASER301 subset analysis

Background

Up to 50% of patients (pts) with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases (mets), which are a major source of mortality in NSCLC. Lazertinib (laz), a CNS-active 3^rd-generation (gen) tyrosine kinase inhibitor (TKI) targeting mutant epidermal growth factor receptor (EGFR), improved progression-free survival (PFS) vs the 1^st-gen TKI gefitinib (gef) in the LASER301 study. Here, we compared laz vs gef among LASER301 pts with CNS mets.

Methods

In the phase 3 LASER301 study (NCT04248829), treatment (tx)-naïve pts with EGFR-mutated advanced or metastatic NSCLC were randomized 1:1 to laz (240 mg/day) or gef (250 mg/day). Pts with symptomatic/unstable CNS mets were excluded. If tx was required for pts with asymptomatic/stable CNS mets, radiation and/or surgery, and steroids were completed >2 weeks before randomization. Magnetic resonance imaging was performed at screening, every 6 weeks for 18 months (mo), then every 12 weeks relative to randomization, using the same modality at each follow-up. Endpoints assessed by blinded independent central review and RECIST v1.1 included intracranial PFS (iPFS), intracranial objective response rate (iORR), intracranial duration of response (iDoR), and depth of intracranial response.

Results

Of 393 pts in LASER301, 45 (23%) receiving laz and 41 (21%) receiving gef had measurable and/or non-measurable baseline (BL) CNS mets. BL characteristics were balanced between groups, with most pts having 1–3 CNS lesions (laz: 91%, gef: 83%). Median BL target lesion size was 20.0 mm (laz) and 16.0 mm (gef). Median iPFS in the laz group was 28.2 mo (95% confidence interval [CI]: 14.8, 28.2) vs 8.4 mo (6.7, not reached [NR]) in the gef group (hazard ratio: 0.42; 95% CI: 0.20, 0.89; P=0.02). iORR was higher for the laz (n=17, 94%) vs gef (n=11, 73%) group. At data cutoff, median iDoR in the laz group was NR (8.3, NR) vs 6.3 mo (2.8, NR) in the gef group. The median best change from BL in CNS target lesion size was -57% and -47% for laz (n=17) and gef (n=14), respectively. No new safety signals were identified from LASER301.

Conclusions

In pts with BL CNS mets, laz significantly improved iPFS vs gef with more durable responses. Laz has the potential to improve CNS outcomes in NSCLC.

Clinical trial identification

NCT04248829.

Editorial acknowledgement

Dylan Mori of Lumanity Communications Inc.

Legal entity responsible for the study

Yuhan Corporation.

Funding

Yuhan Corporation.

Disclosure

R.A. Soo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Lily, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan, Janssen, Merck Serono, Puma Biotech, Thermo Fisher; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Janssen; Financial Interests, Personal, Advisory Board: Kanaph Therapeutic Inc, BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Other, Advisory role: Medpacto, Blueprint Medicines, RandBio, Hanmi; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, BridgeBio Therapeutics, Kanaph Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, BridgeBio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center; Other, Founder: Daan Biotherapeutics. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daiichi Sankyo, Merck, Boronoi. K.H. Lee: Financial Interests, Personal, Other, Consultant: BMS, Eli Lilly, Pfizer, AstraZeneca, MSD, Yuhan; Financial Interests, Personal, Research Funding: MSD. A. Zimina: Non-Financial Interests, Principal Investigator, Participation as PI in Yuhan LASER-301 trial: Yuhan. Y. Lee: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Boryung, Eli Lilly, Takeda; Financial Interests, Personal, Other, Consultant: Ono, Takeda, Yuhan, Guardant Health. L. Yueh Ni: Financial Interests, Personal, Other, Panel of Discussion for Hepatocellular Carcinoma: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Board Meeting for early breast cancer management in our current practice.: Roche; Financial Interests, Personal and Institutional, Local PI, Research Title: A multicentre, open-label, single-arm, molecular profiling study of patient with EGFR mutation-positive locally advanced or metastatic NSCLC treated with Osimertinib: AstraZeneca; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase 3 Double-blinded, Two-arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) versus Placebo as Adjuvant Therapy in Participants with Hepatocellular Carcinoma and Complete Radiological Response after Surgical Resection or Local Ablation (KEYNOTE-937): MSD; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase III, Randomized, Double-blind Study to Assess the Efficacy and Safety of Lazertinib versus Gefitinib as the First-line Treatment in Patients with Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer: Yuhan; Financial Interests, Personal and Institutional, Local PI, Research Title: A phase II randomized study of the combination of Ribociclib plus goserelin acetate with Hormonal Therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients with hormone receptor-positive/HER2-negative inoperable locally advanced or metastatic breast cancer - RIGHT Choice Study: Novartis; Financial Interests, Personal and Institutional, Local PI, Research Title: A Global, Randomized, Phase 3, Open-Label Study of REGN2810 (Anti-PD-1 Antibody) versus Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic PD-L1+ Non-Small Cell Lung Cancer: Regeneron; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase 3 study to Evaluate Zimberelimab (AB122) Monotherapy Compared to Standard Chemotherapy or Zimberelimab Combined with AB 154 in Front-Line, PD-L1 Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer: Arcus; Financial Interests, Personal and Institutional, Local PI, Research Title: A Prospective, Multicenter, Non-Interventional Genomic Profiling Study in Subjects with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) using Foundation Medicine: Roche; Financial Interests, Personal and Institutional, Local PI, Research Title: A Phase 3, randomize, double-blind trial of pembrolizumab (MK-3475) with or without lenvatinib (E7080/MK-7902) in participants with treatment naive, metastatic non-small cell lung cancer (NSCLC) whose tumors have a tumor proportion score (TPS) greater than or equal to 1% (LEAP-007): MSD. Y.K. Pang: Financial Interests, Personal, Research Funding: MSD, AstraZeneca, Sanofi.; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Specialised Therapeutics, MSD, Boehringer Ingelheim, Sanofi-Aventis, Orient Europharma, Eurodrug Laboratories.. C.H. Fong: Financial Interests, Personal, Local PI, Investigator fees: Yuhan Corporation, Janssen Research & Development, LLC, Arcus Biosciences, Inc., Novartis Pharmaceuticals, Hoffmann-La Roche. J.H. Kang: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Merck, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Boeringer Ingelheim, Roche, MSD, Ono, Yuhan, Takeda; Financial Interests, Personal, Research Grant: ONO, Daiichi Sankyo, Boeringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Yuhan. P. Danchaivijitr: Financial Interests, Personal, Speaker’s Bureau: MSD, Roche, AstraZeneca, BMS; Financial Interests, Personal, Advisory Board: MSD, Roche, AstraZeneca, BMS. H. Lee: Financial Interests, Personal, Full or part-time Employment: Yuhan. S. Park: Financial Interests, Personal, Full or part-time Employment: Yuhan Co. I. Cicin: Other, Principal investigator: Jounce Therapeutic. All other authors have declared no conflicts of interest.