Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Korea.
Princess Margaret Cancer Center, Toronto, Ontario, Canada.
JAMA Oncol. 2023 Nov 1;9(11):1574-1582. doi: 10.1001/jamaoncol.2023.3867.
Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors.
To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors.
DESIGN, SETTING, AND PARTICIPANTS: The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022.
Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity.
The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables.
Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months).
In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC.
ClinicalTrials.gov Identifier: NCT02794571.
T 细胞免疫受体与 Ig 和 ITIM 结构域（TIGIT）/脊髓灰质炎病毒受体途径的抑制可能会增强在程序性死亡配体 1 选择的肿瘤中使用阿替利珠单抗的抗肿瘤免疫反应。
评估抗 TIGIT 抗体替利珠单抗及其与阿替利珠单抗联合用于晚期实体瘤患者的安全性和抗肿瘤活性。
设计、地点和参与者：这项开放性、首个人体 1a/1b 剂量递增和剂量扩展非随机对照试验在 6 个国家（澳大利亚、加拿大、法国、韩国、西班牙和美国）的 13 个地点进行。第 1a 阶段的开始日期为 2016 年 5 月 23 日，第 1b 阶段为 2016 年 10 月 11 日。患者年龄在 18 岁及以上，基线时有可测量的疾病。临床截止日期为 2021 年 10 月 1 日。数据分析于 2022 年 1 月 24 日进行。
患者在第 1a 阶段的每个 21 天周期（从 2mg 递增至 1200mg）的第 1 天接受固定剂量静脉内替利珠单抗，在第 1b 阶段接受固定剂量静脉内阿替利珠单抗（每 3 周 1200mg）。患者接受治疗，直到疾病进展、临床获益丧失或出现不可接受的毒性。
主要终点包括替利珠单抗或联合替利珠单抗加阿替利珠单抗的安全性、耐受性和推荐的 2 期剂量（RP2D）。次要终点包括研究者评估的客观缓解率（ORR）。计数和百分比用于分类变量，中位数和范围用于连续变量。
在第 1a 阶段（n=24）和第 1b 阶段（n=49）剂量递增队列中，中位年龄分别为 60 岁（范围为 40-77 岁）和 54 岁（范围为 25-81 岁）。超过一半的患者为女性（第 1a 阶段 14 例[58%]，第 1b 阶段 25 例[51%]），超过三分之一（第 1a 阶段 10 例[42%]，第 1b 阶段 18 例[37%]）接受过 4 次或更多的癌症治疗。未发生剂量限制毒性，替利珠单抗的最大耐受剂量未达到（NR）。最常见的治疗相关不良事件（AE）是第 1a 阶段的疲劳（24 例中的 5 例[21%]）和第 1b 阶段的瘙痒（49 例中的 5 例[10%]）；大多数 AE 为 1 级或 2 级。在第 1a 阶段和第 1b 阶段，分别有 4 例（17%）和 29 例（59%）患者发生免疫介导的 AE，主要为 1 级或 2 级。替利珠单抗的 RP2D 为每 3 周静脉注射 600mg，在第 1b 阶段剂量扩展中进行了测试。第 1a 阶段的确认客观缓解率为 0%，第 1b 阶段有 6%的患者（n=3）有抗肿瘤活性。第 1b 阶段替利珠单抗联合阿替利珠单抗的安全性与剂量递增和剂量扩展队列相似。非小细胞肺癌（NSCLC）队列的确认客观缓解率为 46%（13 例中的 6 例），中位缓解持续时间（DOR）为 NR；食管癌（EC）队列为 28%（18 例中的 5 例），中位 DOR 为 15.2 个月（95%CI，7.0 至 NR）。
在这项非随机对照试验中，替利珠单抗联合或不联合阿替利珠单抗耐受性良好；未观察到新的安全性信号。在免疫治疗初治转移性 NSCLC 或 EC 患者中，联合方案显示出初步抗肿瘤活性。
ClinicalTrials.gov 标识符：NCT02794571。
