PO.CL01.01 · 临床研究

KRAS G12C抑制剂MK-1084对携带KRAS G12突变肿瘤参与者循环肿瘤DNA水平的影响

Effect of the KRAS G12C inhibitor MK-1084 on circulating tumor DNA levels in participants with KRAS G12-mutated tumors

编号 1008 展板 2 时间 4/19 02:00–05:00 区域 Section 40 主讲 Carlos Rojas, MD

分会场 Biomarkers Predictive of Therapeutic Benefit 1

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作者与单位 Authors & Affiliations

Carlos Rojas¹, Matteo Simonelli², Adrian Sacher³, Mehmet Ali Sendur⁴, Rafal Dziadziuszko⁵, Joon Oh Park⁶, Victor Moreno Garcia⁷, Jair Bar⁸, Yun Fan⁹, Mustafa Erman¹⁰, Shun Lu¹¹, Jenny H. Lee¹², Rosalyn A. Juergens¹³, Bangwei Cao¹⁴, Cai Chen¹⁵, Razvan Cristescu¹⁵, Thomas Jemielita¹⁵, Yewon Sofia Choi¹⁵, Mark D. Ayers¹⁵, Iwona Lugowska¹⁶

¹Bradford Hill Clinical Cancer Research Center, Santiago, Chile,²IRCCS Humanitas Research Hospital, Rozzano MI and Humanitas University, Pieve Emanuele MI, Italy,³Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada,⁴Ankara Yıldırım Beyazıt University and Ankara Bilkent City Hospital, Ankara, Turkey,⁵Medical University of Gdánsk, Gdánsk, Poland,⁶Associate Professor, Dept. of Hem./Onc., Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea, Republic of,⁷START Madrid, Madrid, Spain,⁸Jusidman Cancer Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel,⁹Zhejiang Cancer Hospital, Hangzhou, China,¹⁰Hacettepe University Cancer Institute, Ankara, Turkey,¹¹Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China,¹²Chris O’Brien Lifehouse Research Institute, Camperdown, Australia,¹³Hamilton Health Sciences-Juravinski Cancer Centre, Hamilton, ON, Canada,¹⁴Beijing Friendship Hospital, Capital Medical University, Beijing, China,¹⁵Merck & Co., Inc., Rahway, NJ,¹⁶Maria Sklodowska-Curie National Research Institute and Oncology Centre, Warsaw, Poland

摘要 Abstract

中文摘要

背景：1期KANDLELIT-001试验（NCT05067283）的初步数据显示，MK-1084（一种下一代、选择性的KRAS G12C-GDP共价抑制剂）在既往接受过治疗的KRAS G12C突变实体瘤参与者（pts）中具有可控的安全性特征和初步的抗肿瘤活性。在此，我们研究了在KANDLELIT-001单药剂量递增阶段，MK-1084单药治疗对晚期KRAS G12C突变实体瘤患者中KRAS G12C变异等位基因频率（VAF）和最大体细胞等位基因频率（MSAF）ctDNA水平的影响。方法：KANDLELIT-001纳入携带任何KRAS G12C突变的晚期实体瘤患者，接受MK-1084单药或各种联合治疗。任何晚期实体瘤且既往接受过≥1种系统性治疗的患者在第1组接受MK-1084单药口服QD或BID（每日总剂量25-800 mg）。使用Guardant Health OMNI panel，对第1组入组患者采集的系列血样在基线、第1周期开始前和第3周期开始前评估ctDNA KRAS-G12C VAF和MSAF水平的变化。使用描述性统计评估ctDNA水平的差异。结果：在第1组中，23例患者中有22例可评估ctDNA水平的变化。从第1周期（给药前，第0天）到第3周期（治疗第42天），KRAS G12C VAF和MSAF ctDNA中位水平各下降≥90%，分别从14%降至0.9%和从25%降至2%；6例（26%）患者实现了KRAS G12C VAF ctDNA的完全清除。在实现KRAS G12C ctDNA完全清除的患者中观察到更大的肿瘤缩小。与无应答者相比，完全或部分应答（应答者）的患者中观察到更大的ctDNA水平下降。基线时检测到PI3KCA、KEAP1以及KRAS G12D、Q61H和BRAF的共存突变。结论：在23例接受MK-1084单药治疗的KRAS G12C突变患者队列中，肿瘤应答与KRAS G12C VAF和MSAF ctDNA水平的下降相关。这可能反映了MK-1084在KRAS G12C突变肿瘤中的分子活性和治疗效应。本分析的样本量较小，限制了对这些发现的解读。

查看英文原文 English abstract

Background: Preliminary data from the phase 1 KANDLELIT-001 trial (NCT05067283) showed a manageable safety profile and preliminary antitumor activity for MK-1084, a next-generation, selective KRAS G12C-GDP covalent inhibitor, in participants (pts) with previously treated, KRAS G12C-mutant solid tumors. Here, we examine the effect of MK-1084 monotherapy on KRAS G12C variant allele frequency (VAF) and maximum somatic allele frequency (MSAF) ctDNA levels in pts with advanced KRAS G12C-mutant solid tumors during the monotherapy dose escalation phase of KANDLELIT-001. Methods: KANDLELIT-001 enrolled pts with any KRAS G12C-mutated advanced solid tumor to receive MK-1084 alone or in various combination therapies. Pts with any advanced solid tumor and ≥1 prior systemic therapy received MK-1084 monotherapy PO QD or BID in Arm 1 (total daily dose, 25-800 mg). Serial blood samples collected from pts enrolled in Arm 1 were evaluated for changes in ctDNA KRAS-G12C VAF and MSAF levels at baseline, and before beginning cycle 1 and cycle 3 using the Guardant Health OMNI panel. Differences in ctDNA levels were assessed using descriptive statistics. Results: In Arm 1, 22 of 23 pts were evaluable for changes in ctDNA levels. Median KRAS G12C VAF and MSAF ctDNA levels decreased ≥90% each from 14% to 0.9% and from 25% to 2%, respectively, from cycle 1 (pre-dose, day 0) to cycle 3 (day 42 on treatment); 6 (26%) pts achieved complete clearance of KRAS G12C VAF ctDNA. Greater reductions in tumor size were observed in pts who achieved complete clearance of KRAS G12C ctDNA. Larger reductions in ctDNA levels were seen in pts with a complete or partial response (responders) vs those with no response. Co-occurring mutations in PI3KCA, KEAP1, and KRAS G12D, Q61H, and BRAF were detected at baseline. Conclusions: In a cohort of 23 patients with KRAS G12C mutations receiving MK-1084 monotherapy, tumor response was associated with reductions in KRAS G12C VAF and MSAF ctDNA levels. This potentially reflects the molecular activity and therapeutic effect of MK-1084 in KRAS G12C-mutated tumors. The small sample size of this analysis limits interpretation of these findings.

利益披露 Disclosure

C. Rojas, MSD ), Other, Invited Speaker. AstraZeneca Other, Invited Speaker, Advisory Board. BMS Other, Invited Speaker, Advisory Board. Knight Other, Invited Speaker. Pfizer Other, Invited Speaker, Advisory Board. Roche Other, Advisory Board. Sanofi Other, Advisory Board. Bradford Hill g., Board of Directors, non-salaried role). M. Simonelli, MSD ). GSK Other, Consulting, Advisory Board. Pfizer Travel, Other, Advisory Board. Sanofi Travel, Other, Advisory Board. Roche Travel, Other, Advisory Board. Incyte Other, Advisory Board. Servier Other, Advisory Board. BMS/Celgene Other, Advisory Board. A. Sacher, MSD ), Travel, Other, Advisory Committee. Amgen Travel, Other, Consultant, Advisory Committee. Iovance Other, Consultant. CRISPR Therapeutics Other, Consultant. Pfizer Other, Consultant. GSK Other, Consultant. Spectrum Other, Consultant. Lilly Other, Consultant. BridgeBio Other, Consultant. Hotspot Therapeutics Other, Consultant. Genentech-Roche Travel, Other, Advisory role. M. A. Sendur, MSD ), Other, consultant. Roche ), Other, consultant. AstraZeneca ), Other, consultant. Pfizer ), Other, consultant. Novartis ), Other, consultant. Astellas ), Other, consultant. BMS ), Other, consultant. Eli Lilly ), Other, consultant. Gilead ), Other, consultant. Takeda ), Other, consultant. Janssen Other, consultant. R. Dziadziuszko, MSD ), Other, Advisory Board. Roche Other, Advisory Board. AstraZeneca Other, Advisory Board. Pfizer Other, Advisory Board. Novartis Other, Advisory Board. BMS Other, Advisory Board. Amgen Other, Advisory Board. J. Park, MSD ). Servier Other, Advisory Board. MediRama Other, Advisory Board. Adicet Bio Other, Advisory Board. AstraZeneca Other, Advisory Board. Merck Serono Other, Advisory Board. ImmuneOncia Other, Advisory Board. Arcus biosciences Other, Advisory Board. Servier Travel. BMS/Celgene Travel. V. Moreno Garcia, MSD ). BMS Other, Advisory Board. Janssen Other, Advisory Board. Roche Other, Advisory Board. Basilea Other, Advisory Board. Bayer Other, Advisory Board. AstraZeneca Other, Advisory Board. START Employment. Abbvie ). AceaBio ). Adaptimmune ). ADC Therapeutics ). Boehringer ). Boston ). Celgene ). Daichii Sankyo, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith ). Debiopharm, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncol, Synthon, Taiho, Takeda ). Eisai, Nektar, Novartis, Odonate Ther, PFizer, Pharma Mar, Principia, PsiOxus, Puma ). e-Therapeutics, Exelisis, Forma Ther, Genmab, GSK, Harpoon, Hutchinson ). Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merus, Millennium, Nanobiotix ). J. Bar, MSD ), Other, Advisory Role. Abbvie ), Other, Advisory Role. Amgen Other, Advisory Role. AstraZeneca ), Other, Advisory Role. Bayer Other, Advisory Role. Beigene Other, Advisory Role. Janssen Other, Advisory Role. Merck Serono Other, Advisory Role. Medison Other, Advisory Role, Speaker/Writing engagement. Roche ), Other, Advisory Role. Takeda Other, Advisory Role. BMS Other, Speaker/Writing engagement. Pfizer Other, Speaker/Writing engagement. Immunai ). OncoHost ). Y. Fan, MSD ). M. Erman, MSD ). S. Lu, MSD ). J. H. Lee, MSD ), Other, Advisory Board, Speaker. AstraZeneca Other, Speaker. Pfizer Other, Conference support. Novartis Other, Conference support. Gilead ). Merus ). Exelixis ). R. Juergens, Merck & Co., Inc., Rahway, NJ, USA ). B. Cao, MSD ). C. Chen, Merck & Co., Inc., Rahway, NJ, USA Employment, Stock, Stock Option. R. Cristescu, Merck & Co., Inc.., Rahway, NJ, USA Employment, Stock, Stock Option. T. Jemielita, Merck & Co., Inc., Rahway, NJ, USA Employment, Stock, Stock Option. Y. S. Choi, Merck & Co., Inc., Rahway, NJ, USA Employment, Stock, Stock Option. M. D. Ayers, Merck & Co., Inc., Rahway, NJ, USA Employment, Stock, Stock Option. I. Lugowska, MSD ), Other, medical writing support. Agenus ). Roche ), Other, consultant. European Society of Medical Oncology Other, consultant. BMS Other, consultant. Janssen Other, consultant. AstraZeneca Other, consultant. Amgen Other, consultant. RyVu Other, consultant. Incyte Other, consultant. Siropa Other, consultant. Mennarini Other, consultant. Celon Other, consultant. Pfizer Other, consultant. Rhizen Other, consultant. Morgan Stanley Capital International (MSCI) Other, consultant. Organization of European Cancer Institutes (OECI) Other, consultant. Clininote Other, consultant.

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