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

Background

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.

Methods

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 (C_trough) 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.

Results

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 C_trough 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.

Conclusions

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.

Clinical trial identification

LASER 201 study, phase 1/2 NCT03046992; LASER 301 study, phase 3 NCT04248829.

Editorial acknowledgement

Editorial assistance by Tay Sen Kwan, Tech Observer Asia Pacific.

Legal entity responsible for the study

Yuhan.

Funding

Yuhan.

Disclosure

Y. Lee: Financial Interests, Personal, Advisory Board, Honoraria: Yuhan, Takeda; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Ono Pharma, Astellas Seagen, Guardant Health; Financial Interests, Personal, Other, Honoraria: MSD, Pfizer. J.S. Ahn: Financial Interests, Personal, Other, Honoraria: Boryung, BW World, Takeda Phar, Roche Korea, Menarini Korea, Pfizer, Lilly Korea, Boehringer Ingelheim, Kyowa Kirin, Amgen Korea, AstraZeneca Korea, Novartis Korea, Hanmi; Financial Interests, Personal, Advisory Role, Honoraria: Yuhan, Bayer Korea; Financial Interests, Personal, Advisory Role: Therapex, Guardant, Immueoncia, Pharmbio Korea, Yooyoung, Vifor Pharma, Bixink. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daiichi Sankyo, Merck, Boronoi. J.H. Kang: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Merck, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Roche, MSD, Ono, Yuhan, Takeda; Financial Interests, Personal, Research Grant: Ono, Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Yuhan. 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. T. Reungwetwattana: Financial Interests, Personal, Advisory Board, Clinical research & speaker: AstraZeneca, Boehringer Ingelheim, Roche, Novartis, MSD, Yuhan; Financial Interests, Personal, Advisory Board, speaker: BMS, Amgen; Financial Interests, Personal, Advisory Board: Johnson & Johnson; Financial Interests, Personal, Speaker, Consultant, Advisor: Zuellig. J.C. Yang: Financial Interests, Personal, Other: Amgen, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eli Lilly, Merck KGaA, Darmstadt, Germany, Merck Sharp & Dohme, Novartis, Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, JNJ, Puma Technology, Gilead, GSK; Financial Interests, Personal, Research Grant: AstraZeneca. I. Cicin: Financial Interests, Personal, Speaker’s Bureau: Abdi Ibrahim, BMS, Novartis, Pfizer, Roche; Financial Interests, Personal, Advisory Role: AbbVie, Abdi Ibrahim, Astellas, Takeda, BMS, Deva, Gilead Janssen Oncology, Lilly, MSD Oncology, Nobel Pharma, Novartis/Ispen, Pfizer, Roche, Sandoz, Servier, Teva. D. Kim: Financial Interests, Institutional, Research Funding: Yuhan; Financial Interests, Institutional, Research Grant: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, BMS, Boehringer Ingelheim, BridgeBioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GSK, Hanmi, Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan; Non-Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS/ONO Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, GSK, Janssen, Merck, MSD, Pfizer, SK Biopharm, Takeda; Financial Interests, Personal, Member of Board of Directors: Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology; Financial Interests, Personal, Advisory Role: Health Insurance Review and Assessment Service, Republic of Korea; Financial Interests, Personal, Writing Engagement: Amgen, AstraZeneca, Boehringer Ingelheim, BridgeBio Therapeutics, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Personal, Other, Travel support for attending meeting: International Association for the Study of Lung Cancer, Asian Thoracic Oncology Research Group, Taiwan Lung Cancer Society; Financial Interests, Personal, Other, Honorarium: Korean Association for Lung Cancer , Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society, Asian Thoracic Oncology Research Group. H. Go, K.C. Jahng, S. Kim, Y. Lim: Financial Interests, Personal, Other, Employee: Wuhan Corporation. K.H. Lee: Financial Interests, Personal, Advisory Board: BMS, MSD, Eli Lilly, Yuhan, Pfizer, AstraZeneca; Financial Interests, Funding: Merck. B.C. Cho: Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Stocks/Shares: J Ints Bio, Interpark Bio Convergence Corp., Cyrus Therapeutics, Kanaph Therapeutic Inc, BridgeBio Therapeutics, Gencurix Inc, TheraCanVac Inc; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Personal, Research Funding: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Boehringer Ingelheim, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, 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, CHA Bundang Medical Center, Hanmi; Financial Interests, Personal, Advisory Board: Kanaph Therapeutics Inc., BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc; Financial Interests, Personal, Advisory 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, Medpacto, Blueprint Medicines, RandBio, Hanmi; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Personal, Other, Founder: Daan Biotherapeutics. All other authors have declared no conflicts of interest.