Abstract RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node regulating RAS signaling. Consistent with preclinical observations, initial data from a phase 1 trial of RMC-4630 showed anti-tumor activity in tumors harboring diverse mutations in the RAS pathway including KRASG12C, KRASG12D, NF1LOF, and BRAF Class 3. Here we report data from the dose-escalation phase of this study. A total of 104 patients were dosed across three schedules: daily dosing (n = 49) and two intermittent dosing schedules, twice weekly on D1D4 (n = 31) or D1D2 (n = 24). Based on PK and tolerability, the recommended phase 2 dose and schedule (RP2DS) was determined to be 200 mg D1D2, delivering a 400 mg weekly dose intensity. Of the 80 efficacy evaluable patients, there was 1 CR (NF1LOF uterine carcinosarcoma), 1 PR (KRASG12C NSCLC), and 1 unconfirmed PR (KRASG12D NSCLC). Tumor regressions were observed in another 11 patients (-2.4% to -27.1%). Disease control rate was 61% (23/38) in patients with KRASMUT NSCLC and 80% (12/15) in KRASG12C NSCLC specifically. The safety and tolerability profile of RMC-4630 were consistent with the mechanism of action and RAS pathway inhibition. The most frequent adverse events (AEs) were edema (48%), diarrhea (47%), fatigue (36%), anemia (34%), and thrombocytopenia (33%). Most AEs were grade 1 or 2 and were manageable. Intermittent dosing with either D1D2 or D1D4 weekly was generally better tolerated than daily dosing at an equivalent weekly dose intensity. Plasma concentrations of RMC-4630 after dosing with 200 mg D1D2 were above those predicted to be clinically active based on preclinical models. Cmax reached and often exceeded the ‘apoptotic threshold' defined as plasma exposures that were associated with induction of tumor regressions in preclinical models. Trough concentrations at the end of each week were at or around the EC50 for RAS pathway inhibition in tumor which is predicted to be sufficient to allow normal tissue recovery and therefore maintain tolerability with sustained dosing up to 6 months. Sequential analysis of pERK levels in peripheral blood cells and paired pre- and on-treatment tumor biopsies showed evidence of RAS pathway inhibition. Tumor and blood-based immune-oncology biomarkers showed preliminary evidence of anti-tumor immune activation. Longitudinal analysis of circulating tumor DNA indicated molecular responses consistent with anti-tumor activity in tumors carrying specific driver mutations in the RAS signaling pathway. An expansion cohort of patients with gynecologic cancers with NF1LOF is underway with monotherapy at the RP2DS. RMC-4630 continues to be evaluated in combination with the MEK inhibitor cobimetinib (Cotellic), the KRASG12C(OFF) inhibitor sotorasib, the PD1 inhibitor pembrolizumab (Keytruda) and the EGFR inhibitor osimertinib (Tagrisso). Additional combination studies are also planned. Citation Format: Marianna Koczywas, Eric Haura, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Richa Dua, Zhengping Wang, Ariel Chen, Josie Hayes, Luxi Yang, Serena Masciari, Xiaolin Wang, S Ignatius Ou. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB001.

中文翻译：

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摘要 LB001：SHP2 抑制剂 RMC-4630 作为单药治疗 RAS 成瘾实体癌患者的抗肿瘤活性和耐受性

摘要 RMC-4630 是一种有效的、选择性的、口服生物可利用的 SHP2 变构抑制剂，SHP2 是调节 RAS 信号传导的中心节点。与临床前观察一致，来自 RMC-4630 1 期试验的初步数据显示，在 RAS 通路中存在多种突变的肿瘤中具有抗肿瘤活性，包括 KRASG12C、KRASG12D、NF1LOF 和 BRAF 3 类。这里我们报告来自剂量-本研究的升级阶段。共有 104 名患者在三个方案中给药：每日给药 (n = 49) 和两个间歇给药方案，在 D1D4 (n = 31) 或 D1D2 (n = 24) 每周两次。根据 PK 和耐受性，推荐的第 2 阶段剂量和时间表 (RP2DS) 确定为 200 mg D1D2，每周提供 400 mg 剂量强度。80 例疗效可评价患者中，1 例 CR（NF1LOF 子宫癌肉瘤），1 名 PR（KRASG12C NSCLC）和 1 名未确诊 PR（KRASG12D NSCLC）。在另外 11 名患者中观察到肿瘤消退（-2.4% 至 -27.1%）。KRASMUT NSCLC 患者的疾病控制率为 61% (23/38)，而 KRASG12C NSCLC 患者的疾病控制率为 80% (12/15)。RMC-4630 的安全性和耐受性与作用机制和 RAS 通路抑制一致。最常见的不良事件 (AE) 是水肿 (48%)、腹泻 (47%)、疲劳 (36%)、贫血 (34%) 和血小板减少症 (33%)。大多数 AE 为 1 级或 2 级并且是可控的。每周间歇给药 D1D2 或 D1D4 的耐受性通常优于以相同的每周剂量强度每日给药。服用 200 mg D1D2 后 RMC-4630 的血浆浓度高于基于临床前模型预测的具有临床活性的浓度。在临床前模型中，Cmax 达到并经常超过定义为与诱导肿瘤消退相关的血浆暴露量的“凋亡阈值”。每周结束时的谷浓度处于或接近肿瘤中 RAS 通路抑制的 EC50，预计这足以使正常组织恢复并因此在持续给药长达 6 个月时保持耐受性。外周血细胞中 pERK 水平的顺序分析和配对的治疗前和治疗中的肿瘤活检显示了 RAS 通路抑制的证据。肿瘤和基于血液的免疫肿瘤生物标志物显示出抗肿瘤免疫激活的初步证据。循环肿瘤 DNA 的纵向分析表明，分子反应与在 RAS 信号通路中携带特定驱动突变的肿瘤中的抗肿瘤活性一致。一个扩大的 NF1LOF 妇科癌症患者队列正在 RP2DS 进行单药治疗。RMC-4630 继续与 MEK 抑制剂 cobimetinib (Cotellic)、KRASG12C(OFF) 抑制剂 sotorasib、PD1 抑制剂 pembrolizumab (Keytruda) 和 EGFR 抑制剂 osimertinib (Tagrisso) 联合进行评估。还计划进行其他组合研究。引文格式： Marianna Koczywas、Eric Haura、Pasi A. Janne、Jose M. Pacheco、Susanna Ulahannan、Judy S. Wang、Howard A. Burris、Jonathan W. Riess、Caroline McCoach、Michael S. Gordon、Anna Capasso、Richa Dua , 王正平, Ariel Chen, Josie Hayes, Luxi Yang, Serena Masciari、王晓琳、S Ignatius Ou。SHP2 抑制剂 RMC-4630 作为单药治疗 RAS 成瘾实体癌患者的抗肿瘤活性和耐受性[摘要]。在：美国癌症研究协会 2021 年年会论文集；2021 年 4 月 10 日至 15 日和 5 月 17 日至 21 日。费城 (PA)：AACR；癌症研究 2021；81(13_Suppl)：摘要 nr LB001。