PO.ET09.08 · 实验与分子治疗

VS-7375：一种口服、选择性 KRAS G12D 双 ON/OFF 抑制剂，作为单药及与其他药物联用时具有强效抗肿瘤活性

VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents

编号 7100 展板 20 时间 4/22 09:00–12:00 区域 Section 13 主讲 Jonathan Pachter, PhD

分会场 Novel Antitumor Agents 3

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作者与单位 Authors & Affiliations

Silvia Coma¹, Ian Smith², Cristina Caffarra Malvezzi³, Clint A. Stalnecker⁴, Emilia Berardelli³, Enrico Patrucco³, Fusheng Zhou⁵, Channing Der⁴, Chiara Ambrogio³, David G. DeNardo², Jonathan A. Pachter¹

¹Verastem Oncology, Needham, MA,²Department of Medicine, Washington University School of Medicine, st louis, MO,³Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy,⁴University of North Carolina at Chapel Hill, Chapel Hill, NC,⁵Genfleet Therapeutics, Shanghai, China

摘要 Abstract

中文摘要

KRAS G12D 是人类癌症中最常见的 KRAS 突变，分别见于 40%、15% 和 5% 的胰腺癌、结直肠癌和肺癌。目前，尚无 FDA 批准的 RAS 抑制剂用于 KRAS G12D 突变（mt）癌症患者。VS-7375（GFH375）是一种口服、选择性 KRAS G12D 双 ON/OFF 抑制剂，对人 KRAS G12D 的 ON 和 OFF 状态均表现出极高的亲和力（K D = 12-18 pM）和长驻留时间（18-24 小时）。VS-7375 在代表胰腺癌、结直肠癌和肺癌的多个 KRAS G12D mt 异种移植模型中，经口服给药显示出强效的单药抗肿瘤疗效。为评估双 ON/OFF 抑制相对于仅 ON 型 RAS 抑制剂的潜在获益，我们在 KRAS G12D mt 体内模型中，将其疗效与 KRAS G12D 仅 ON 型抑制剂 zoldonrasib（RMC-9805）及泛 RAS 仅 ON 型抑制剂 daraxonrasib（RMC-6236）进行了比较。在 KP4 KRAS G12D 胰腺癌模型中，VS-7375（50 mg/kg 每日两次口服）相较 zoldonrasib（100 mg/kg 每日一次口服）和 daraxonrasib（25 mg/kg 每日一次口服）显示出相似的初始肿瘤消退（至第 9 天）。然而，在给药约 20 天时，zoldonrasib 和 daraxonrasib 逐渐丧失其抗肿瘤活性并伴随肿瘤再生长（至第 30 天平均肿瘤体积 >850 mm 3），而接受 VS-7375 治疗者则显示出持续的肿瘤消退（至第 30 天平均肿瘤体积约 80 mm 3）。相应地，采用通路特异性基因特征的药效学分析显示，虽然三种 KRAS 抑制剂在第 6 天均抑制了 MAPK、MYC 和 PI3K 信号传导，但只有 G12D ON/OFF 抑制剂 VS-7375 在第 20 天仍维持对这些信号通路的抑制。VS-7375 在 KRAS G12D mt 肺癌和结直肠癌异种移植模型中也表现出比这些仅 ON 型 RAS 抑制剂更深的肿瘤消退。目前，我们正在评估 VS-7375 与其他抗癌药物（包括 EGFR、PRMT5 和 FAK 抑制剂）联用的抗肿瘤疗效。简而言之，抗 EGFR 抗体西妥昔单抗与 VS-7375 联用在 KRAS G12D mt 癌症模型中诱导了强效的肿瘤生长抑制。此外，PRMT5 抑制剂与 VS-7375 联用在 KRAS G12D mt；MTAP 缺失的胰腺癌模型中延长了肿瘤消退的持续时间。最后，FAK 抑制剂与 VS-7375 联用在 KRAS G12D mt 癌症模型中延长了肿瘤消退的持续时间，这些结果共同支持对 VS-7375 的新型联合策略进行潜在的临床评估，以在 KRAS G12D mt 癌症患者中实现最大的抗肿瘤疗效和持久性。VS-7375 目前正在美国进行 1/2 期临床评估（VS-7375-101；NCT07020221），并在中国进行高级临床评估（NCT06500676），作为单药疗法以及与西妥昔单抗或化疗 ± 帕博利珠单抗联用，用于治疗 KRAS G12D mt 癌症患者。

查看英文原文 English abstract

KRAS G12D is the most prevalent KRAS mutation in human cancers, present in 40%, 15%, and 5% of pancreatic, colorectal and lung cancers, respectively. Currently, there are no FDA-approved RAS inhibitors for patients with KRAS G12D-mutated (mt) cancers. VS-7375 (GFH375) is an oral, selective KRAS G12D dual ON/OFF inhibitor exhibiting extremely high affinity (K D = 12-18 pM) and long residence time (18-24 hours) for the ON and OFF states of human KRAS G12D. VS-7375 has shown potent single agent anti-tumor efficacy with oral dosing across multiple KRAS G12D mt xenograft models representing pancreatic, colorectal and lung cancers. To assess potential benefits of dual ON/OFF inhibition relative to ON-only RAS inhibitors, we compared efficacy in KRAS G12D mt in vivo models relative to the KRAS G12D ON-only inhibitor zoldonrasib (RMC-9805) and the pan-RAS ON-only inhibitor daraxonrasib (RMC-6236). In the KP4 KRAS G12D pancreatic cancer model, VS-7375 (50 mg/kg twice daily orally) showed similar initial tumor regression (through day 9) relative to zoldonrasib (100 mg/kg once daily orally) and daraxonrasib (25 mg/kg once daily orally). However, by approximately 20 days of dosing, zoldonrasib and daraxonrasib progressively lose their anti-tumor activity with associated tumor outgrowth (mean tumor volume >850 mm 3 by day 30) in contrast to those treated with VS-7375 which showed sustained tumor regression (mean tumor volume ~80 mm 3 by day 30). Accordingly, pharmacodynamic analysis with pathway-specific gene signatures showed that whereas all three KRAS inhibitors inhibited MAPK, MYC and PI3K signaling at day 6, only the G12D ON/OFF inhibitor VS-7375 maintained inhibition of these signaling pathways by day 20. VS-7375 also showed deeper tumor regression compared to these RAS ON-only inhibitors in KRAS G12D mt lung and colorectal xenograft models. Currently, we are assessing the anti-tumor efficacy of VS-7375 in combination with other anti-cancer agents including EGFR, PRMT5 and FAK inhibitors. Briefly, the combination of the anti-EGFR antibody cetuximab with VS-7375 induced strong tumor growth inhibition in KRAS G12D mt cancer models. Furthermore, addition of a PRMT5 inhibitor with VS-7375 increased duration of tumor regression in KRAS G12D mt;MTAP-deleted pancreatic cancer models. Lastly, addition of a FAK inhibitor with VS-7375 increased duration of tumor regression in KRAS G12D mt cancer models, altogether supporting the potential clinical evaluation of novel combination strategies with VS-7375 in patients with KRAS G12D mt cancers for maximal anti-tumor efficacy and durability. VS-7375 is currently in phase 1/2 clinical evaluation in the US (VS-7375-101; NCT07020221) and in advanced clinical evaluation in China (NCT06500676) as monotherapy and in combination with cetuximab or chemotherapy ± pembrolizumab for patients with KRAS G12D mt cancers.

利益披露 Disclosure

S. Coma, Verastem Oncology Employment, Stock, Stock Option. I. Smith, None.. C. Caffarra Malvezzi, None.. C. A. Stalnecker, None.. E. Berardelli, None.. E. Patrucco, None. F. Zhou, GenFleet Employment. C. Der, None.. C. Ambrogio, None.. D. G. DeNardo, None. J. A. Pachter, Verastem Oncology Employment, Stock, Stock Option.

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