LBPO.CL03 · 临床研究 · Late-Breaking

Daraxonrasib单药作为转移性胰腺腺癌（mPDAC）患者的一线（1L）治疗

Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC)

编号 LB337 展板 18 时间 4/21 02:00–05:00 区域 Section 52 主讲 Eileen O'Reilly, MD

分会场 Late-Breaking Research: Clinical Research 3

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作者与单位 Authors & Affiliations

Eileen M. O'Reilly¹, Brian Wolpin², Shubham Pant³, Joel Randolph Hecht⁴, Jennifer Valerin⁵, Dae Won Kim⁶, Nilofer Azad⁷, Kyaw Aung⁸, Lin Tao⁹, Sumit Kar⁹, Hina Patel⁹, Rashmi Vora⁹, Aparna Hegde⁹, Alexander Spira¹⁰, Alexander Starodub¹¹, Benjamin Herzberg¹², Ignacio Garrido-Laguna¹³

¹Memorial Sloan Kettering Cancer Center, New York, NY,²Dana-Farber Cancer Institute, Boston, MA,³MD Anderson Cancer Center, Houston, TX,⁴David Geffen School of Medicine at UCLA, Los Angeles, CA,⁵University of California Irvine, Orange, CA,⁶Moffitt Cancer Center, Tampa, FL,⁷Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD,⁸University of Texas Health Austin, Austin, TX,⁹Revolution Medicines, Redwood City, CA,¹⁰NEXT Oncology Virgina, Virgina Cancer Specialists Research Institute, Fairfax, VA,¹¹The Christ Hospital, Cincinnati, OH,¹²Columbia University, New York, NY,¹³Huntsman Cancer Institute, Salt Lake City, UT

摘要 Abstract

中文摘要

背景：mPDAC是一种具有挑战性的RAS驱动疾病，5年生存率约为3%。标准的一线化疗具有相当大的毒性且获益有限（ORR：23-43%；6个月时PFS：40%-50%；mOS：8.5-11.7个月）。致癌性RAS突变发生于超过90%的病例。Daraxonrasib是一种强效的口服RAS(ON)多选择性抑制剂，靶向GTP结合的突变型（包括G12、G13和Q61突变）和WT RAS。在一项1/2期研究（NCT05379985）中，二线daraxonrasib在RAS突变型mPDAC患者中表现出可控的安全性和令人鼓舞的早期疗效。在此，我们呈现daraxonrasib作为RAS突变型mPDAC患者一线治疗的安全性和疗效（NCT05379985）。方法：RAS突变型mPDAC患者接受一线daraxonrasib 300 mg QD，并按治疗患者和可评估患者评估安全性、耐受性、抗肿瘤活性和ctDNA反应。结果：截至2025年12月1日（中位随访：13.7个月），40例患者接受了daraxonrasib治疗。全级别TRAE（≥20%）为皮疹（88%）、腹泻（63%）、口炎/黏膜炎（63%）、恶心（53%）、呕吐（50%）、疲乏（35%）和甲沟炎（20%）。≥3级TRAE（≥10%）为皮疹、腹泻和口炎/黏膜炎（各10%）。未发生4/5级TRAE。TRAE导致70%的患者进行剂量调整，1例（3%）患者停药。平均相对剂量强度为84%。daraxonrasib治疗的抗肿瘤和ctDNA反应见表。结论：Daraxonrasib单药一线治疗mPDAC显示出可控的安全性（与既往研究一致）和引人注目的初步疗效，支持启动一项全球3臂3期研究（RASolute 303），评估daraxonrasib联合或不联合化疗一线治疗mPDAC。表抗肿瘤活性治疗患者可评估患者疗效指标 n=38 b n=35 c ORR d，%（95% CI）47%（31-64）51%（34-69）疾病控制率（DCR），%（95% CI）92%（79-98）97%（85-100）6个月时PFS e %（95% CI）71%（53-83）_ 6个月时OS e，%（95% CI）83%（67-92）_ ctDNA反应 f _ n=28 f >50% RAS VAF g 下降，% _ 100% 100% RAS VAF g 清除，% _ 57% C，周期；D，天；VAF，变异等位基因频率。 a TRAE包括任何研究药物相关的治疗中出现的AE。 b 2例患者因不符合既往未经治疗mPDAC的定义而被排除在疗效分析之外。 c 基线时具有可测量疾病，且有≥1次基线后肿瘤评估，或在此类评估前发生临床进展或死亡的患者。 d 包括确认的完全缓解（CR）和部分缓解（PR）。 e 基于Kaplan-Meier法的估计。 f 在基线（C1D1）和至少一次治疗中（C2D1或C3D1）进行ctDNA测序的患者。 g VAF 变异等位基因频率在C2D1/C3D1相对于基线（C1D1）的下降。

查看英文原文 English abstract

Background: mPDAC is a challenging, RAS-driven disease with 5-y survival of ~3%. Standard 1L chemotherapy has substantial toxicity and limited benefit (ORR: 23-43%; PFS at 6 mo: 40%-50%; mOS: 8.5-11.7 months). Oncogenic RAS mutations occur in >90% of cases. Daraxonrasib is a potent, oral, RAS(ON) multi-selective inhibitor targeting GTP-bound mutant (incl. G12, G13, and Q61 mutations) and WT RAS. In a phase 1/2 study (NCT05379985), second-line daraxonrasib demonstrated manageable safety and encouraging early efficacy in pts with RAS-mutant mPDAC. Here, we present the safety and efficacy of daraxonrasib as 1L therapy for pts with RAS-mutant mPDAC (NCT05379985). Methods: Pts with RAS-mutant mPDAC received 1L daraxonrasib 300 mg QD and were evaluated for safety, tolerability, antitumor activity, and ctDNA response per treated and evaluable pts. Results: As of Dec 1, 2025 (median follow-up: 13.7 mo), 40 pts received daraxonrasib. All-grade TRAEs a (≥20%) were rash (88%), diarrhea (63%), stomatitis/mucositis (63%), nausea (53%), vomiting (50%), fatigue (35%), and paronychia (20%). Grade ≥3 TRAEs (≥10%) were rash, diarrhea, and stomatitis/mucositis (10% each). No Grade 4/5 TRAEs occurred. TRAEs led to dose modifications in 70% of pts and discontinuation in 1 (3%) pt. The mean relative dose intensity was 84%. Antitumor and ctDNA responses to daraxonrasib treatment are shown in the table. Conclusions: Daraxonrasib monotherapy in 1L mPDAC showed manageable safety, consistent with prior studies, and compelling preliminary efficacy supporting the initiation of a global 3-arm phase 3 study (RASolute 303) of daraxonrasib with or without chemotherapy in 1L mPDAC. Table Antitumor activity Treated pts Evaluable pts Efficacy measures n=38 b n=35 c ORR d , % (95% CI) 47% (31-64) 51% (34-69) Disease control rate (DCR), % (95% CI) 92% (79-98) 97% (85-100) PFS at 6 mo e % (95% CI) 71% (53-83) _ OS at 6 mo e , % (95% CI) 83% (67-92) _ ctDNA Response f _ n=28 f >50% RAS VAF g reduction, % _ 100% 100% RAS VAF g clearance, % _ 57% C, Cycle; D, Day; VAF, variant allele frequency. a TRAEs include any study drug-related treatment-emergent AE. b 2 pts were excluded from the efficacy analysis as they did not meet the definition of previously untreated mPDAC. c Pts with measurable disease at baseline and either had ≥ 1 post-baseline tumor assessment or had clinical progression or death prior to such assessment. d Includes confirmed complete responses (CR) and partial responses (PR). e Estimate based on Kaplan-Meier method. f Patients who had ctDNA sequenced at baseline (C1D1) and at least one on-tx (C2D1 or C3D1). g VAF variant allele frequency reduction at C2D1/C3D1 from baseline (C1D1).

利益披露 Disclosure

E. M. O'Reilly, Arcus ), Travel, Other, Consulting/DSMB. Genentech/Roche ). BioNTech ), Travel, Other, Consulting/DSMB. AstraZeneca ), Other, Consulting/DSMB. Elicio Therapeutics ). Digestive Care ). Agenus ), Other, Consulting/DSMB. Amgen ), Other, Consulting/DSMB. Revolution Medicines ), Other, Consulting/DSMB. Tango Therapeutics ). Ability Pharma; Alligator BioSciences; Pfizer; Ipsen; lkena; Merck; lmmuneering; Moma Therapeutics; Novartis; Astellas; BMS; Regeneron Other, Consulting/DSMB. American Association of Cancer Research (AACR) Other. American Society of Clinical Oncology (ASCO) Other. lmedex Other. Research To Practice Other. Stand Up To Cancer (SU2C) Other. NIH/NCI Other. Break Through Cancer Other. Cancer Center Support Grant/Core Grant P30 CA008748 Other. NCI/NIH P50 CA257881-01A1 Other. B. Wolpin, Amgen ). AstraZeneca ). Eli Lilly ). Harbinger Health ), Other, Advisory boards/consulting. Novartis ). Revolution Medicines ), Other, Advisory boards/consulting. Agenus Other, Advisory boards/consulting. BeiGene Other, Advisory boards/consulting. BMS/Mirati Other, Advisory boards/consulting. Cancer Panels Other, Advisory boards/consulting. Diaceutics Other, Advisory boards/consulting. EcoR1 Capital Other, Advisory boards/consulting. GRAIL Other, Advisory boards/consulting. lmmuneering Other, Advisory boards/consulting. Ipsen Other, Advisory boards/consulting. Takeda Other, Advisory boards/consulting. Tango Therapeutics Other, Advisory boards/consulting. Third Rock Ventures Other, Advisory boards/consulting. S. Pant, Ipsen; Novartis; Daiichi Sankyo; Janssen; Jazz Pharmaceuticals; AstraZeneca; Boehringer Ingelheim; USWorldmeds; Alligator Bioscience; Revolution Medicines; Arcus; BMS; Merck; Pfizer; Immuneering Other, Consulting or advisory Role. EMD Serono Other, Consulting or advisory Role. Incyte; CG Pharmaceuticals; Bristol-Myers Squibb; Boehringer Ingelheim; Janssen; Arcus; Elicio; Pfizer; ImmunoMET; Immuneering; Amal Therapeutics; Jazz Therapeutics; Revolution medicines; AstraZeneca ). Oncomed LLC, Telperian Stock, Stock Option. J. R. Hecht, A2 Bio ), Travel. Affini-T ). Agenus ). AstraZeneca ). Bold ). Camurus ). Crinetics ). Exelixis ), Other, Consulting. Gilead ), Other, Consulting. GSK ). Gritstone ). IGM ). Janssen ). Mirati; NGM; Pfizer; Regeneron; Tizona ). Triumvira; Actym Stock, Stock Option. NCCN Colorectal Committee g., Board of Directors, non-salaried role). Revolution Medicines ), Other, Consulting. Scripps; Research To Practice; MLJ Other, Honoraria. Astellas; BeiGene; Novartis; Hexagon; Corcept; Deciphera; BMS; Parabilis; Taiho; Urogen Other, Consulting. Xilio ), Other, Consulting. J. Valerin, Astra Zeneca ), Other, Speaker Bureau. Dragonfly ). Revolution Medicine ). Pfizer ). Ikena ). Bioatla ). Incyte Other, Speaker bureau. Tempus Other, Consulting. D. Kim, Ipsen Other, Honorarium. N. Azad, Johns Hopkins University Employment. Haystack Oncology/Quest Stock, Stock Option. Cage Pharma Stock, Stock Option. Irazu Stock, Stock Option. AstraZeneca ), Other, Honoraria/Consulting. Revolution Medicine ), Other, Honoraria/Consulting. Beigene ), Other, Honoraria/Consulting. Atlas ). Mirati/BMS ). Inctye ), Other, Honoraria/Consulting. Taiho ). Syndax ). Bayer ). Pfizer/Seagen ). Compass ). Agenus Other, Honoraria/Consulting. GlaxoSmithKline Other, Honoraria/Consulting. Astellas Other, Honoraria/Consulting. Eli Lilly Other, Honoraria/Consulting. Tempus Other, Honoraria/Consulting. K. Aung, None. L. Tao, Revolution Medicines Employment. S. Kar, Revolution Medicines Employment. H. Patel, Revolution Medicines Employment. R. Vora, Revolution Medicines Employment. A. Hegde, Revolution Medicines Employment, Stock, Stock Option. A. Spira, CytomX Therapeutics; AstraZeneca/MedImmune; Merck; Takeda; Amgen; Janssen Oncology; Novartis; Bristol-Myers Squibb; Bayer; Prelude Therapeutics; Abbvie; Astellas Pharma; Lilly Other, Honoraria. Incyte; Amgen; Novartis; Mirati Therapeutics; Gritstone Oncology; Jazz Pharmaceuticals; Takeda; Janssen Research & Development; Mersana; Gritstone Bio; Daiichi Sankyo; Astra Zeneca; Regeneron; Lilly Independent Contractor. Black Diamond Therapeutics; Sanofi; ArriVent Biopharma; Synthekine; GSK; Crisp Therapeutics; Revolution Medicines; AstraZeneca/MedImmune; Merck; Bristol-Myers Squibb; Blueprint Medicines Independent Contractor. LAM Therapeutics; Roche; AstraZeneca; Boehringer Ingelheim; Astellas Pharma; MedImmune; Novartis; Incyte; Abbvie; Ignyta; Takeda; Macrogenics; CytomX Therapeutics; Astex Pharmaceuticals ). Bristol-Myers Squibb; Loxo; Gritstone; Plexxikon; Amgen; Daiichi Sankyo; ADCT; Janssen Oncology; Rubius; Synthekine; Mersana; Blueprint Medicines; Regeneron; Alkermes; Revolution Medicines; Medikine ). Synthekine; Black Diamond Therapeutics; BluPrint Oncology; Nalo Therapeutics; Scorpion Therapeutics; ArriVent Biopharma; Prelude Therapeutics; Lilly; Lepu Biopharma; Tango Therapeutics ). NEXT Oncology Virginia g., Board of Directors, non-salaried role). A. Starodub, None. B. Herzberg, Amgen ), Other, Consulting. Repare ). Ideaya ), Other, Consulting. Astellas ), Other, Consulting. Revolution Medicines ), Other, Consulting. AstraZeneca ), Other, Consulting. Seagen ). Genentech ). Monte Rosa Therapeutics ). Eli Lilly ), Other, Consulting. Prelude ). DAVA Oncology Travel. Arvinas Travel. Boxer Capital Other, Consulting. Johnson and Johnson Other, Consulting. Guidepoint Other, Consulting. Onclive Other, Consulting. Ideology Health Other, Consulting. Curio Health Other, Consulting. Abbvie Other, Consulting. I. Garrido-Laguna, SOTIO; Abbvie; Revolution Medicines; Lilly; Quanta Therapeutics; Kestrel Therapeutics; Fortvita; EcoR1 Capital; Guidepoint Global; KeyQuest Health Other, Consulting. EcoRl; Guidepoint Inc; Novartis; Bayer; Bristol-Myers Squibb; Pfizer; Medimmune; Lilly; Incyte; GlaxoSmithKline; Tolero Pharmaceuticals; BridgeBio Pharma; Jacobio; Repare Therapeutics ). Sumitomo Dainippon Pharma Oncology; Revolution Medicines; Yingli Pharma; Quanta Therapeutics; 280 BIO; ABM Therapeutics; Tango; Kumquat Biosciences ).

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