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

Shigeki Umemura; Hibiki Udagawa; Takaya Ikeda; Haruyasu Murakami; Haruko Daga; Ryo Toyozawa; Toshiyuki Kozuki; Jun Sakakibara-Konishi; Yuichiro Ohe; Masahiro Morise; Terufumi Kato; Masato Shingyoji; Satoshi Hara; Naoki Furuya; Shuhei Teranishi; Saori Takata; Shingo Miyamoto; Ichiro Nakachi; Masashi Wakabayashi; Shogo Nomura; Akihiro Sato; Genichiro Ishii; Katsuya Tsuchihara; Eri Sugiyama; Keisuke Kirita; Tetsuya Sakai; Yuji Shibata; Hiroki Izumi; Kaname Nosaki; Yoshitaka Zenke; Shingo Matsumoto; Kiyotaka Yoh; Seiji Niho; Koichi Goto

doi:10.1016/j.jtho.2024.10.004

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

J Thorac Oncol. 2024 Oct 10:S1556-0864(24)02378-5. doi: 10.1016/j.jtho.2024.10.004. Online ahead of print.

Authors

Shigeki Umemura¹, Hibiki Udagawa¹, Takaya Ikeda¹, Haruyasu Murakami², Haruko Daga³, Ryo Toyozawa⁴, Toshiyuki Kozuki⁵, Jun Sakakibara-Konishi⁶, Yuichiro Ohe⁷, Masahiro Morise⁸, Terufumi Kato⁹, Masato Shingyoji¹⁰, Satoshi Hara¹¹, Naoki Furuya¹², Shuhei Teranishi¹³, Saori Takata¹⁴, Shingo Miyamoto¹⁵, Ichiro Nakachi¹⁶, Masashi Wakabayashi¹⁷, Shogo Nomura¹⁸, Akihiro Sato¹⁷, Genichiro Ishii¹⁹, Katsuya Tsuchihara²⁰, Eri Sugiyama¹, Keisuke Kirita¹, Tetsuya Sakai¹, Yuji Shibata¹, Hiroki Izumi¹, Kaname Nosaki¹, Yoshitaka Zenke¹, Shingo Matsumoto¹, Kiyotaka Yoh¹, Seiji Niho¹, Koichi Goto²¹

Affiliations

¹ Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
² Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
³ Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.
⁴ Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
⁵ Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
⁶ Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
⁷ Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁸ Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹ Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan.
¹⁰ Division of Respirology, Chiba Cancer Center, Chiba, Japan.
¹¹ Department of Respiratory Medicine, Itami City Hospital, Itami, Japan.
¹² Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
¹³ Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan.
¹⁴ Department of Respiratory Medicine, Kyorin University School of Medicine, Mitaka, Japan.
¹⁵ Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.
¹⁶ Department of Internal Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan.
¹⁷ Clinical Research Support Office, National Cancer Center Hospital East, Chiba, Japan.
¹⁸ Clinical Research Support Office, National Cancer Center Hospital East, Chiba, Japan; Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁹ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan.
²⁰ Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
²¹ Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kgoto@east.ncc.go.jp.

PMID: 39395663
DOI: 10.1016/j.jtho.2024.10.004

Abstract

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.

Keywords: Clinical outcome; Genetic classification; Genomic screening; Lung cancer; Small cell.