PO.ET03.03 · 实验与分子治疗

利用MTAP缺失非小细胞肺癌和间皮瘤的患者来源异种移植模型，开发与新型MTA协同性PRMT5抑制剂AMG 193的药物联合方案

Developing drug combinations with AMG 193, a novel MTA-cooperative PRMT5 inhibitor, using patient-derived xenograft models of MTAP -deleted non-small cell lung cancer and mesothelioma

编号 7134 展板 23 时间 4/22 09:00–12:00 区域 Section 14 主讲 Florence Wu, BS;MD;MS;PhD

分会场 Novel Strategies to Reverse Drug Resistance

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作者与单位 Authors & Affiliations

Florence T. H. Wu¹, Nhu-An Pham¹, Yu-Hui Wang¹, Ming Li¹, Nikolina Radulovich¹, Katrina Hueniken¹, Quan Li¹, Siyuan (Claret) Liu², Brian Belmontes², Paul Hughes², Ming-Sound Tsao³, Adrian Sacher⁴

¹Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada,²Amgen Research, Thousand Oaks, CA,³Princess Margaret Cancer Centre, University Health Network; Departments of Laboratory Medicine & Pathobiology and Medical Biophysics, University of Toronto, Toronto, ON, Canada,⁴Princess Margaret Cancer Centre, University Health Network; Departments of Medicine and Immunology, University of Toronto, Toronto, ON, Canada

摘要 Abstract

中文摘要

背景：AMG 193是一种MTA协同性PRMT5抑制剂，旨在对MTAP缺失肿瘤细胞具有优先选择性。AMG 193目前正在MTAP缺失实体瘤中进行I-II期临床试验(MTAPESTRY-101,104, 201)。在患者来源异种移植(PDX)模型中的体内检验，具有指导AMG 193聚焦性临床开发的重要潜力。目的：利用来自我们机构生物库的MTAP缺失PDX模型，我们试图：(i)在肺腺癌(LUAD)、肺鳞状细胞癌(LUSC)和间皮瘤(MESO)中识别AMG 193有前景的药物联合伙伴；以及(ii)研究对AMG 193原发或获得性耐药的机制。方法：我们通过SNP阵列识别出21个MTAP深度缺失或经免疫组化识别出MTAP缺失的PDX模型——包括7个LUAD（含2个KRAS G12C；1个EGFR L858R + MET扩增）、10个LUSC和6个MESO。在皮下植入NOD SCID或NSG小鼠(每组n=5-7)的7个模型中表征了AMG 193的体内活性。结果：四个模型(2个KRAS G12C LUAD；1个LUSC；1个MESO)显示出对AMG 193的持续敏感性。两个模型(1个KRAS野生型LUAD；1个MESO)表现出对AMG 193的原发耐药。一个LUSC模型在初始敏感后表现出对AMG 193的获得性耐药。有趣的是，两个KRAS G12C LUAD模型尽管对sotorasib单药耐药，却与AMG 193+sotorasib表现出相加/协同活性。结论：在MTAP缺失的LUAD、LUSC、MESO PDX模型中展现出AMG 193活性的谱系，重现了临床中所见的应答与耐药范围。与AMG 193的联合治疗在KRAS G12C LUAD模型中克服了sotorasib耐药。其他药物联合将在原发或获得性耐药模型中进行评估。急性给药研究正在进行中，以进一步表征这些模型对AMG 193的应答。 7个MTAP缺失PDX模型汇总 PDX模型药物活性† 倍增时间（周），基于线性混合效应模型（N.R.=因完全缓解而未达到） KRAS G12C LUAD#239 Sotorasib单药：耐药。AMG 193单药：敏感。Sotorasib + AMG 193：敏感且加速深度应答治疗中(d10-21)，Vehicle 2.3 vs. Sotorasib 3.6 P=0.20，AMG 193 N.R. P<0.001 ***，联合 N.R. P<0.001 ***。KRAS G12C LUAD#256 Sotorasib单药：耐药。AMG 193单药：部分敏感。Sotorasib + AMG 193：敏感且加速深度应答治疗中(d0-45)，联合 N.R. vs. Sotorasib 5.9 P=0.04*，AMG 193 5.3 P=0.04*。KRAS WT LUAD#196 AMG 193：部分耐药治疗中(d0-24)，Vehicle 1.8 vs. AMG 193 2.3 P=0.04* LUSC#410 AMG 193：敏感(d0-48)并最终获得性耐药(d49-91) 治疗中(d0-15)，Vehicle 0.9 vs. AMG 193 19.3 P<0.001 *** LUSC#470 AMG 193：敏感治疗中(d0-20)，Vehicle 1.1 vs. AMG 193 2.8 P<0.001 *** MESO#7 AMG 193：敏感治疗中(d0-49)，Vehicle 3.4 vs. AMG 193 N.R. P<0.001 *** MESO#18 AMG 193：部分耐药治疗中(d0-24)，Vehicle 1.8 vs. AMG 193 2.9 P=0.003 ** † 药物活性基于肿瘤生长曲线动力学和倍增时间评估。

查看英文原文 English abstract

BACKGROUND: AMG 193 is an MTA-cooperative PRMT5 inhibitor designed for preferential selectivity against MTAP -del tumor cells. AMG 193 is currently being investigated in phase I-II clinical trials in MTAP -del solid tumors (MTAPESTRY-101,104, 201). In vivo testing in patient-derived xenograft (PDX) models has significant potential to inform focused clinical development of AMG 193. OBJECTIVES: Using MTAP -del PDX models from our institutional biobank, we sought to: (i) identify promising drug combination partners for AMG 193 across lung adenocarcinomas (LUAD), lung squamous cell carcinomas (LUSC), and mesotheliomas (MESO); and (ii) investigate mechanisms of primary or acquired resistance to AMG 193. METHODS: We identified 21 PDX models with MTAP deep deletion by SNP array or MTAP loss by immunohistochemistry - including 7 LUAD (including 2 KRAS G12C; 1 EGFR L858R + MET amp), 10 LUSC, and 6 MESO. In vivo AMG 193 activity was characterized in 7 models subcutaneously implanted in NOD SCID or NSG mice (n=5-7 per group). RESULTS: Four models (2 KRAS G12C LUAD; 1 LUSC; 1 MESO) showed sustained sensitivity to AMG 193. Two models (1 KRAS -wildtype LUAD; 1 MESO) exhibited primary resistance to AMG 193. One LUSC model showed acquired resistance to AMG 193 after initial sensitivity. Interestingly, the two KRAS G12C LUAD models demonstrated additive/synergistic activity with AMG 193+sotorasib despite exhibiting resistance to sotorasib monotherapy. CONCLUSIONS: A spectrum of AMG 193 activity was demonstrated across MTAP -del LUAD, LUSC, MESO PDX models, recapitulating the range of response & resistance seen clinically. Combination therapy with AMG 193 overcame sotorasib resistance in KRAS G12C LUAD models. Other drug combinations will be evaluated in primary or acquired resistance models. Acute dosing studies are underway to further characterize response to AMG 193 in these models. Summary of 7 MTAP-deleted PDX models PDX model Drug Activity† Doubling time in weeks, from linear mixed-effects modeling (N.R. = not reached due to complete response) KRAS G12C LUAD#239 Sotorasib monotherapy: resistant. AMG 193 monotherapy: sensitive. Sotorasib + AMG 193: sensitive with accelerated deep response On-treatment (d10-21) , Vehicle 2.3 vs. Sotorasib 3.6 P =0.20, AMG 193 N.R. P< 0.001 ***, Combo N.R. P< 0.001 ***. KRAS G12C LUAD#256 Sotorasib monotherapy: resistant. AMG 193 monotherapy: partial sensitivity. Sotorasib + AMG 193: sensitive with accelerated deep response On-treatment (d0-45) , Combo N.R. vs. Sotorasib 5.9 P =0.04*, AMG 193 5.3 P= 0.04 *. KRAS WT LUAD#196 AMG 193: partial resistance On-treatment (d0-24) , Vehicle 1.8 vs. AMG 193 2.3 P= 0.04 * LUSC#410 AMG 193: sensitive (d0-48) with eventual acquired resistance (d49-91) On-treatment (d0-15) , Vehicle 0.9 vs. AMG 193 19.3 P< 0.001 *** LUSC#470 AMG 193: sensitive On-treatment (d0-20) , Vehicle 1.1 vs. AMG 193 2.8 P< 0.001 *** MESO#7 AMG 193: sensitive On-treatment (d0-49) , Vehicle 3.4 vs. AMG 193 N.R. P< 0.001 *** MESO#18 AMG 193: partial resistance On-treatment (d0-24) , Vehicle 1.8 vs. AMG 193 2.9 P =0.003 ** † Drug activity assessed based upon tumor growth curve kinetics and doubling time.

利益披露 Disclosure

F. T. H. Wu, None.. N. Pham, None.. Y. Wang, None.. M. Li, None.. N. Radulovich, None.. K. Hueniken, None.. Q. Li, None. S. Liu, Amgen Employment. B. Belmontes, Amgen Employment. P. Hughes, Amgen Employment. M. Tsao, AstraZeneca ), Other, research grant (to institution); consultancy honoraria. Sanofi ), Other, research grant (to institution); consultancy honoraria. Daiichi-Sankyo Other, consultancy honoraria. Abbvie Other, consultancy honoraria. Boehringer-Ingelheim Other, consultancy honoraria. A. Sacher, Amgen ), Other, Institutional Research & Clinical Trial PI; Advisory committee (no personal fees); Travel expenses for clinical trial investigator meetings. AstraZeneca ), Other, Institutional Research & Clinical Trial PI. Genentech-Roche ), Other, Institutional Research & Clinical Trial PI; Advisory committee (no personal fees); Travel expenses for clinical trial investigator meetings. Merck ), Other, Institutional Research & Clinical Trial PI; Advisory committee (no personal fees); Travel expenses for clinical trial investigator meetings. Lilly ), Other, Institutional Research & Clinical Trial PI. Pfizer ), Other, Institutional Research & Clinical Trial PI. Bristol Myers Squibb ), Other, Institutional Research & Clinical Trial PI. Spectrum ), Other, Institutional Research & Clinical Trial PI. GSK ), Other, Institutional Research & Clinical Trial PI. Iovance ), Other, Institutional Research & Clinical Trial PI. CRISPR Therapeutics ), Other, Institutional Research & Clinical Trial PI. BridgeBio ), Other, Institutional Research & Clinical Trial PI. HotSpot Therapeutics ), Other, Institutional Research & Clinical Trial PI. AdaptImmune ), Other, Institutional Research & Clinical Trial PI.

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