Clinical Significance of a Prospective Large Genomic Screening for SCLC: The Genetic Classification and a Biomarker-Driven Phase 2 Trial of Gedatolisib.

Introduction: SCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial.
Methods: A total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening.
Results: On the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22-2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26-1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial.
Conclusions: Molecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices.
Competing Interests: Disclosure Dr. Umemura reports receiving grants from Taiho Pharmaceutical and honoraria from Merck Sharp & Dohme and Chugai Pharmaceutical. Dr. Udagawa reports receiving grants from Takeda and Boehringer Ingelheim. Dr. Murakami reports receiving grants from Chugai Pharma, AstraZeneca, Takeda, Daiichi Sankyo, AbbVie, IQVIA, Taiho Pharmaceutical, and Bayer; receiving honoraria from Pfizer, Chugai Pharma, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Merck Sharp & Dohme, Novartis, Lilly Japan, Taiho Pharmaceutical, Eisai, and Nihonkayaku; and having participation on a data safety monitoring board or advisory board for Chugai Pharma, GAIA BioMedicine, Daiichi Sankyo, and Amgen. Dr. Daga reports receiving honoraria from AstraZeneca and Chugai Pharmaceutical. Dr. Toyozawa reports receiving grants from Pfizer, AbbVie, Amgen, AnHeart Therapeutics, Daiichi Sankyo, Eli Lilly Japan, Novartis Pharma, and Takeda Pharmaceutical and honoraria from Pfizer, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. Dr. Kozuki reports receiving grants from Pfizer, Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., Merck Sharp & Dohme, Kyowa Hakko Kirin, Merck Biopharma, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, LabCorp Development Japan, IQVIA Services Japan, Gilead Sciences, and Bayer; consulting fees from Pfizer, Chugai Pharmaceutical Co., AstraZeneca, Ono Pharmaceutical Co., Daiichi Sankyo, Bayer, and AbbVie; and honoraria from Pfizer, Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., Merck Sharp & Dohme, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck Biopharma, Nippon Kayaku, Novartis, Daiichi Sankyo, Takeda Pharmaceutical Co., Bayer, Sawai, and Amgen. Dr. Sakakibara-Konishi reports receiving grants from Lilly. Dr. Ohe reports receiving grants from Pfizer, AstraZeneca, Chugai, Lilly, ONO, Bristol-Myers Squibb, Kyorin, Dainippon-Sumitomo, Taiho, Novartis, Takeda, Kissei, Daiichi Sankyo, Janssen, and Loxo; receiving payment for expert testimony from AstraZeneca, Chugai, ONO, Bristol-Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, and AnHeart Therapeutics Inc., and having leadership roles with JSMO, JLCS, and JCOG. Dr. Morise reports receiving grants from Boehringer Ingelheim and Eli Lilly; honoraria from Pfizer, Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme, Ono Pharmaceutical, and Taiho Pharmaceutical; and other financial or nonfinancial interests from Pfizer, Chugai, AstraZeneca, Ono, Merck Serono, Kissei, Taiho, and Novartis. Dr. Kato reports receiving grants from Pfizer, AbbVie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai, Daiichi Sankyo, Eli Lilly, Haihe, Merck KGaA, Merck Sharp & Dohme, Novartis, Regeneron, Takeda, and TurningPoint; receiving honoraria from Pfizer, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono, Taiho, and Takeda; having participation on a data safety monitoring board or advisory board from Pfizer, AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck KGaA, Merck Sharp & Dohme, and Novartis; and receiving other financial or nonfinancial interests for Eli Lilly. Dr. Furuya reports receiving honoraria from Pfizer, Eli Lilly Japan, AstraZeneca, Boehringer Ingelheim Japan, Chugai, Bristol-Myers Squibb, Taiho, and Novartis. Dr. Nakachi reports receiving honoraria from AstraZeneca, Chugai Pharmaceutical, and Novartis Pharma. Dr. Nomura reports receiving grants from AstraZeneca and Amgen and honoraria from AstraZeneca, Chugai, Kyowa Hakko, JMDC, Byer, and Asahi-Kasei Pharma. Dr. Sato reports receiving grants from Taiho Pharmaceutical, Boehringer Ingelheim, Bayer, Chugai Pharma, Eisai, Ono Pharmaceutical, Takeda, Aspyrian Therapeutics, Pentax Medical Devices, and Daiichi Sankyo/UCB Japan. Dr. Ishii reports receiving grants from Daiichi Sankyo, Inc., Ono Pharmaceutical Co., Ltd., Noile-Immune Biotech, Takeda Pharmaceutical Company Limited, Sumitomo Dainippon Pharma Co., Ltd., Nihon Medi-Physics Co., Ltd., Indivumed GmbH, and H.U. Group Research Institute; consulting fees from Takeda Pharmaceutical Company Limited; and honoraria from Roche Diagnostics K.K., Chugai Pharmaceutical Co., Ltd., Novartis International AG, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AstraZeneca, Riken Genesis Co., Ltd., and Merck Biopharma Japan. Dr. Kirita reports receiving consulting fees from Eli Lilly and honoraria from Pfizer, Merck Sharp & Dohme Oncology, Boehringer Ingelheim, Novartis, Takeda Pharmaceuticals, Boston Scientific, Chugai Pharma, ONO Pharma, Merk BioPharma, Thermo Fisher Scientific, AstraZeneca, Taiho Pharmaceuticals, Amgen, and Bristol-Myers Squibb. Dr. Sakai reports receiving grants from Amgen and Daiichi Sankyo and honoraria from AstraZeneca, Chugai, Novartis, Merck Sharp & Dohme, Thermo Fisher Scientific, and Merck. Dr. Shibata reports receiving grants from Merck Sharp & Dohme and Blueprint Medicines Corporation and honoraria from Pfizer, Chugai, Bristol-Myers Squibb, Takeda, AstraZeneca, Merck, Ono Pharmaceutical Co., Ltd., and Eli Lilly Japan. Dr. Izumi reports receiving grants from AbbVie, AstraZeneca, Amgen, Takeda, Eisai, and Ono Pharmaceutical; receiving honoraria from Takeda, Merck, Ono Pharmaceutical, Merck Sharp & Dohme, Chugai, and Bristol-Myers Squibb Japan; and having participation on a data safety monitoring board or advisory board for Amgen. Dr. Nosaki reports receiving grants from AbbVie, AnHeart Therapeutics, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Merck Sharp & Dohme, and Takeda; receiving honoraria from Pfizer, AstraZeneca, Chugai Pharma, Lilly, Merck Sharp & Dohme, Taiho Pharmaceutical, Yansen Pharma, Ono, Takeda, Novartis, and Merck; and having participation on a data safety monitoring board or advisory board for Daiichi Sankyo/UCB/Japan and AbbVie. Dr. Zenke reports receiving grants from AstraZeneca, Merck Sharp & Dohme, Daiichi Sankyo, Amgen, GlaxoSmithKline, Roche, and Merck and honoraria from Pfizer, AstraZeneca, Lilly, Chugai, Ono, Bristol-Myers Squibb, Takeda, Boehringer Ingelheim, Taiho, Merck Sharp & Dohme, Novartis, Nihon Kayaku, Kyowa Kirin, and Amgen. Dr. Matsumoto reports receiving grants from Chugai Pharma, Janssen Pharmaceutical, and Merck Sharp & Dohme and honoraria from Eli Lilly, Merck Biopharma, Chugai Pharma, Novartis Pharma, Guardant Health, and AstraZeneca. Dr. Yoh reports receiving grants from Pfizer, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Taiho, and Takeda; receiving honoraria from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono, Otsuka, Taiho, and Takeda; and having participation on a data safety monitoring board or advisory board for Boehringer Ingelheim. Dr. Niho reports receiving grants from Chugai, Eli Lilly, Daiichi Sankyo, Boehringer Ingelheim, GlaxoSmithKline, Kyowa Kirin, Kyorin, Taiho, Nippon Kayaku, and Teijin; receiving consulting fees from Pfizer, AstraZeneca, and Daiichi Sankyo; and receiving honoraria from Pfizer, AstraZeneca, Amgen, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyorin, Kyowa Kirin, Merck Biopharma, Merck Sharp & Dohme, Nippon Kayaku, Novartis, Ono, and Takeda. Dr. Goto reports receiving grants from Pfizer, Amgen Inc., Amgen K.K., Amgen Astellas BioPharma K.K., AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Blueprint Medicines Corporation, Craif Inc., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Loxo Oncology, Inc., LSI Medience Corporation, Medical & Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., Merck Sharp & Dohme K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Precision Medicine Asia Co., Ltd., Riken Genesis Co., Ltd., Sumitomo Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics, Inc., and Xcoo, Inc.; receiving honoraria from Amgen Inc., Amgen K.K., Amoy Diagnostics Co., Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Blueprint Medicines Corporation, Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Haihe Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Medpace Japan K.K., Merck Biopharma Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Riken Genesis Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Xcoo, Inc.; and having participation on a data safety monitoring board or advisory board for Amgen Inc., Amgen K.K., Daiichi Sankyo Co., Ltd., and Eli Lilly Japan K.K. The remaining authors declare no conflict of interest.
(Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)