PO.CTP01.03 · 进行中的临床试验

Larotrectinib（L）治疗NTRK1/2/3扩增（amp）实体瘤患者（pts）：靶向药物与分析利用注册研究（TAPUR）的结果

Larotrectinib (L) in patients (pts) with solid tumors with NTRK1/2/3 amplification (amp): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

编号 CT206 展板 1 时间 4/21 09:00–12:00 区域 Section 51 主讲 Jordi Rodon, MD, PhD

分会场 Phase II and Phase III Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Jordi Rodon¹, Michael Rothe², Elizabeth Garrett-Mayer², Nithin Rohatgi³, Alvaro G. Menendez⁴, Leighton A. Elliott⁵, Andrew Gregory⁶, Abigail Gregory⁷, Dominique C. Hinshaw², Gina N. Grantham², Susan Halabi⁸, Richard L. Schilsky²

¹Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX,²American Society of Clinical Oncology, Alexandria, VA,³Sutter Cancer Research Consortium, Sacramento, CA,⁴Hartford HealthCare Cancer Institute, Hartford, CT,⁵UF Health Cancer Center, Gainesville, FL,⁶Advocate Aurora Healthcare, Milwaukee, WI,⁷American Society of Clinical Oncology (ASCO), Alexandria, VA,⁸Duke University Medical Center, Durham, NC

摘要 Abstract

中文摘要

背景：TAPUR是一项II期篮子研究，评估市售靶向药物在携带特定基因组改变的晚期癌症患者中的抗肿瘤活性。本文报告一个采用L治疗的NTRK1/2/3 amp实体瘤患者队列的结果。方法：符合条件的患者有可测量病灶、ECOG体能状态（PS）0-2、器官功能充足，且无剩余标准治疗（tx）选择。基因组检测在经CLIA认证、CAP认可的场所选定实验室进行。扩增临界值按NGS供应商定义。肿瘤不得携带NTRK融合。L给药方案为每次一粒100 mg胶囊或口服溶液，每日两次，直至疾病进展或不可接受的毒性。主要终点为研究者评估的疾病控制（DC），定义为按RECIST v1.1标准的客观缓解（OR）或持续至少16+周（wks）的疾病稳定（SD16+）。采用Simon两阶段设计检验无效DC率20%对45%（把握度=0.85，alpha=0.10）。若第1阶段8例患者中≥2例达到DC，则再入组13例；否则该队列因无效而关闭。次要终点为OR、无进展生存期（PFS）、总生存期（OS）、缓解和SD持续时间以及安全性。结果：共入组8例实体瘤患者（乳腺癌[n=3]、软组织肉瘤[n=2]、头颈部[n=1]、非小细胞肺癌（LC）[n=1]、小细胞LC[n=1]），携带NTRK1 amp（n=5）、NTRK2 amp（n=1）、NTRK1 amp及突变（mut）（n=1），以及NTRK1 amp及NTRK3 mut（n=1）。所有患者均可评估疗效。表格显示人口统计学特征和结局。1例携带NTRK1 amp的黏液脂肪肉瘤患者观察到SD16+，DC率为13%（单侧90% CI，1至100），OR率为0%（95% CI，0至37）。1例患者的SD持续时间为24周。无效DC率未被拒绝（p=0.83）。无患者发生3-5级tx相关不良事件或严重不良事件。结论：L未达到预设标准以宣布在NTRK amp实体瘤患者中存在活性信号。表格：人口统计学特征和疗效结局（N=8）中位（Med）年龄，岁（范围）52（37，67）女性，例数（%）5（63） ECOG PS，例数（%）0 3（38） 1 5（63）既往全身治疗方案，例数（%）1 1（13） 2 2（25） ≥3 5（63） DC率，%（OR或SD16+）（单侧90% CI），p值 13（1，100），（p=0.83） OR率，%（95% CI）0（0，37）中位PFS，周（95% CI）7（2，9）中位OS，周（95% CI）18（2，未报告） SD16+患者的SD持续时间，周 24 1 由于四舍五入，百分比之和可能不等于100%

查看英文原文 English abstract

Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with NTRK1/2/3 amp treated with L are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no remaining standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Amp cut-offs were defined per NGS providers. Tumors must not have had NTRK fusions. L dosing was one 100 mg capsule or oral solution twice daily until disease progression or unacceptable toxicity. Primary endpoint was disease control (DC) per investigator defined as objective response (OR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. Simon 2-stage design tested the null DC rate of 20% vs. 45% (power = 0.85, alpha=0.10). If ≥2 of 8 pts in stage 1 had DC, 13 more pts were enrolled; otherwise, the cohort was closed for futility. Secondary endpoints were OR, progression-free survival (PFS), overall survival (OS), duration of response and SD, and safety. Results: 8 pts with solid tumors (breast [n=3], soft tissue sarcoma [n=2], head and neck [n=1], non-small cell lung cancer (LC) [n=1], small cell LC [n=1]) with NTRK1 amp (n=5), NTRK2 amp (n=1), NTRK1 amp and mutation (mut) (n=1), and NTRK1 amp and NTRK3 mut (n=1) were enrolled. All pts were evaluable for efficacy. Table shows demographics and outcomes. SD16+ was observed in 1 pt with myxoliposarcoma and NTRK 1 amp for a DC rate of 13% (1-sided 90% CI, 1 to 100) and an OR rate of 0% (95% CI, 0 to 37). Duration of SD in 1 pt was 24 wks. The null DC rate was not rejected (p=0.83). No pts had grade 3-5 tx-related adverse or serious adverse events. Conclusions: L did not meet prespecified criteria to declare a signal of activity in pts with solid tumors with NTRK amp. Table: Demographics and Efficacy Outcomes (N=8) Median (Med) age, years (range) 52 (37, 67) Female, No. (%) 5 (63) ECOG PS, No. (%) 0 3 (38) 1 5 (63) Prior systemic regimens, No. (%) 1 1 (13) 2 2 (25) ≥3 5 (63) DC rate, % (OR or SD16+) (1-sided 90% CI), p-value 13 (1, 100), (p=0.83) OR rate, % (95% CI) 0 (0, 37) Med PFS, wks (95% CI) 7 (2, 9) Med OS, wks (95% CI) 18 (2, Not reported) Duration of SD in pt with SD16+, wks 24 1 Percentages may not sum to 100% due to rounding

利益披露 Disclosure

J. Rodon, 280 Bio, Adcentrix, Alnylam, Alterome, Beigene, Bicycle Therapeutics, Biohaven, Blueprint Medicines, Cancer Core Europe, Cogent, Eli Lilly, Ensem, ForeBio, Hummingbird, Ideaya, Immuneering Corp ). Incyte, Insilico Medicines, Ipsen, Kelun-Biotech, Merck Sharp & Dohme, Novartis, Nuvectis Pharma, Parabilis Pharmaceuticals, Pfizer, Relay, Roche Pharmaceuticals, Scorpion Therapeutics, Seed ). Tango Therapeutics, Tyra, Vividion, Zai Labs ). American Society of Medical Oncology (ASMO), Dava Oncology, European Society for Medical Oncology (ESMO), STOP Cancer Travel. Amgen ), Travel, Other, Consulting. AstraZeneca ), Other, Consulting. BioHybrid Solutions Travel, Other, Consulting, Scientific Advisory Board. Boxer Capital LLC Other, Consulting. Bridgebio ), Travel, Other, Consulting. Bristol Myers Squibb (BMS) ), Travel, Other, Consulting. Debio ), Travel, Other, Consulting. Ecor1 Other, Consulting. Guidepoint Other, Consulting. Ionctura Travel, Other, Consulting. Merus Travel, Other, Consulting. MonteRosa ), Travel, Other, Consulting. Tang Advisors, LLC Other, Consulting. Vall d'Hebron Institute of Oncology (VHIO) ), Other, Consulting. M. Rothe, None.. E. Garrett-Mayer, None. N. Rohatgi, Astra Zeneca Independent Contractor. Daiichi Sankyo Independent Contractor. Lilly Independent Contractor. Gilead Independent Contractor. BMS Independent Contractor. Stemline/Menarini Independent Contractor. Merck Independent Contractor. Natera Independent Contractor. Novartis Independent Contractor. Pfizer Independent Contractor. Astellas Independent Contractor. Agendia Independent Contractor. A. G. Menendez, None. L. A. Elliott, Deciphera Other, Advisory Board. EMD Serono Other, Advisory Board. A. Gregory, None. A. Gregory, Pfizer Other, Employment of immediate family member Stock options held by immediate family member. D. C. Hinshaw, None.. G. N. Grantham, None. S. Halabi, BMS Other, Member of DSMB. CG Oncology Other, Member of DSMB. Janssen Other, Member of DSMB. Sanofi Other, Member of DSMB. R. L. Schilsky, Clarified Precision Medicine Stock Option, Other, Leadership Position. Leap Therapeutics Stock, Other, Leadership Position. Cellworks Independent Contractor, Stock Option, Other, Consulting/Advisory Role. ZephyrAI Independent Contractor, Other, Consulting/Advisory Role. Flatiron Health Independent Contractor, Other, Consulting or Advisory Role. Toray Industries Other, Honoraria for service on a study for DSMB. AstraZeneca Other, Research Funding to ASCO in support of the TAPUR Study. Bayer Other, Research Funding to ASCO in support of the TAPUR Study. Bristol Myers Squibb Other, Research Funding to ASCO in support of the TAPUR Study. Genentech/Roche Other, Research Funding to ASCO in support of the TAPUR Study. Lilly Other, Research Funding to ASCO in support of the TAPUR Study. Merck Other, Research Funding to ASCO in support of the TAPUR Study. Pfizer Other, Research Funding to ASCO in support of the TAPUR Study. Boehringer Ingelheim Other, Research Funding to ASCO in support of the TAPUR Study. Taiho Oncology Other, Research Funding to ASCO in support of the TAPUR Study. WUGEN, Inc. Other, Honoraria for service as a DSMB Member. AbbVie Other, Honorarium for lecture. Sygnomics Independent Contractor, Other, consulting or advisory role.

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