PD-1/PD-L1和TGF-β途径的双重抑制是恶性肿瘤的合理治疗策略。SHR-1701是一种新的双功能融合蛋白,由与TGF-β受体II胞外域融合的抗PD-L1单克隆抗体组成。这项首次人体试验旨在评估SHR-1701在预处理的晚期实体瘤中的应用,并找到可以从SHR-1701中受益的人群。
这是剂量递增,剂量膨胀,和临床扩展1期研究。通过加速滴定(1mg/kgq3w;静脉输注)开始剂量递增,然后切换到3+3方案(3、10、20和30mg/kgq3w和30mg/kgq2w),然后在10、20和30mg/kgq3w和30mg/kgq2w下进行剂量扩展。剂量递增和剂量扩展部分的主要终点是最大耐受剂量和推荐的2期剂量。在临床扩展部分,选定的肿瘤以推荐剂量接受SHR-1701,主要终点为确认客观缓解率(ORR)。
总共,纳入171例患者(剂量递增:n=17;剂量扩大,n=33;临床扩展,n=121)。在剂量递增部分,未观察到剂量限制性毒性,未达到最大耐受剂量。SHR-1701显示出线性剂量-暴露关系,每3周30mg/kg时ORR最高,在剂量递增和剂量扩展部分的剂量之间没有明显加重的毒性。合并,每3周30mg/kg作为推荐的2期剂量。在临床扩展部分,SHR-1701在胃癌队列中显示出最有利的疗效,ORR为20.0%(7/35;95%CI,8.4-36.9),12个月总生存率为54.5%(95%CI,29.5-73.9)。171例患者中有37例(22%)发生≥3级治疗相关不良事件,主要包括增加的γ-谷氨酰转移酶(4%),天冬氨酸转氨酶增加(3%),贫血(3%),低钠血症(3%),皮疹(2%)。一般来说,PD-L1CPS≥1或pSMAD2组织化学评分≥235的患者的ORR数值较高.
SHR-1701在预处理的晚期实体瘤中显示出可接受的安全性和令人鼓舞的抗肿瘤活性,尤其是胃癌,为进一步探索奠定基础。
ClinicalTrials.gov,NCT03710265。
Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human
trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701.
This was a dose-escalation, dose-expansion, and clinical-expansion phase 1
study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR).
In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR.
SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration.
ClinicalTrials.gov , NCT03710265.