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

IF 21 1区医学 Q1 ONCOLOGY

Journal of Thoracic Oncology Pub Date : 2024-10-10 DOI:10.1016/j.jtho.2024.10.004

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

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引用次数: 0

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.

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小细胞肺癌前瞻性大型基因组筛查的临床意义：基因分类和生物标记物驱动的吉达替尼 II 期试验。

简介小细胞肺癌（SCLC）一直被作为单一实体进行治疗，导致生存率改善有限。方法：通过基因组筛选平台对 1035 例小细胞肺癌进行了前瞻性分析：方法：通过基因组筛选平台 LC-SCRUM-Asia 对 1035 例 SCLC 进行了前瞻性分析。新鲜冷冻肿瘤样本通过新一代测序系统对癌症相关基因进行综合分析。在此基础上进行了吉达替尼治疗PI3K/AKT/mTOR通路突变SCLC的II期试验：根据治疗结果和治疗靶点，在SCLC中发现了5个不同的基因亚组：NSCLC亚组（与非小细胞肺癌相关的基因改变，占8.5%）、热点亚组（肿瘤中常见的可靶向热点突变，3.0%）、PI3K 亚组（PI3K/AKT/mTOR 通路突变，7.4%）、MYC 亚组（MYC 家族扩增，13.0%）和 HME 亚组（组蛋白修饰酶突变，17.6%）。NSCLC亚组（危险比为1.57；95% CI为1.22至2.03）和MYC亚组（危险比为1.56；95% CI为1.26至1.93）在一线铂类治疗后的无进展生存期明显较短。热点亚组和MYC亚组是新型靶向疗法的候选者。HME亚组显示，接受PD-（L）1抑制剂治疗的患者生存率较高（p = 0.005，log-rank检验），尽管与其他亚组有一些重叠。在PI3K亚组中，有15名患者加入了吉达替尼的II期试验，总反应率和疾病控制率分别为6.7%和20%。在该试验中，MYC亚组或NSCLC亚组与不利的临床结果相关：结论：通过基因方法对SCLC进行分子分类有利于预测治疗结果，并有效指导临床选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Thoracic Oncology 医学-呼吸系统

CiteScore

36.00

自引率

3.90%

发文量

1406

审稿时长

13 days

期刊介绍： Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.