Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Hunan Cancer Hospital, Changsha, China.
Eur J Cancer. 2024 Nov;212:114337. doi: 10.1016/j.ejca.2024.114337. Epub 2024 Sep 26.
IBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation.
In phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated.
As of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months.
IBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation.
IBI351 是一种不可逆和共价的 KRAS G12C 抑制剂。尽管 FDA 批准了两种 KRAS G12C 抑制剂，但中国患者仍存在显著的未满足的临床需求，并且对最佳剂量的担忧仍在持续。在此，我们报告了 IBI351 单药治疗携带 KRAS G12C 突变的晚期实体瘤患者的 Ia/Ib 期研究。
在 Ia 期剂量递增中，评估了 IBI351 每天一次 250/450/700/900mg 和每天两次 450/600/750mg（BID）。在 Ia 期剂量扩展和 Ib 期进一步评估了在晚期非小细胞肺癌（NSCLC）患者中具有潜在疗效的剂量和最佳推荐的 II 期剂量（RP2D）。评估了安全性、药代动力学和研究者评估的肿瘤反应。
截至 2023 年 6 月 13 日，共招募了 176 名患者。在所有评估剂量中，IBI351 耐受性良好，未报告剂量限制毒性。考虑到安全性、疗效和药代动力学，确定了 600mg BID 为 RP2D。共有 168 名（95.5%）患者至少发生了一次与治疗相关的不良事件（TRAEs），64 名（36.4%）患者发生了 3 级或更高级别的 TRAEs，最常见的是γ-谷氨酰转移酶升高（10.2%）和贫血（6.8%）。对于 NSCLC 患者，所有剂量的确认客观缓解率（ORR）为 45.5%。在 600mg BID 时，确认的 ORR 为 46.8%，中位无进展生存期为 9.6 个月，中位随访时间为 6.9 个月。
IBI351 在晚期实体瘤患者中具有良好的耐受性，并在携带 KRAS G12C 突变的晚期 NSCLC 患者中显示出有希望的抗肿瘤活性。
