Ahmed Jibran, Janku Filip, Karp Daniel D, Piha-Paul Sarina A, Tsimberidou Apostolia M, Yap Timothy Anthony, Stephen Bettzy, Yang Yali, Gurses Serdar, Liu Qian, Song Juhee, Meric-Bernstam Funda, Naing Aung
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer. 2025 Feb 1;131(3):e35728. doi: 10.1002/cncr.35728.
Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients.
The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST (iRECIST). Efficacy was assessed using a Bayesian optimal phase 2 design.
A total of 31 patients enrolled in this trial (14 in cohort A, 17 in cohort B). The median age was 61 years; 17 (55%) patients were male and 21 (68%) patients were White. Among 19 (61%) patients evaluable for response, the best response was stable disease in nine patients, unconfirmed progressive disease in seven patients, and clinical progressive disease in three patients based on iRECIST. Disease control rate was 47%. One patient with programmed death-ligand 1 negative, microsatellite stable endometrial cancer had unconfirmed partial response. Median progression-free survival was 2.7 months; median overall survival was 20.5 months. One patient (cohort A) experienced a grade 4 hypotension as a DLT and treatment discontinuation. The most common toxicities were hypotension (22.6%), fatigue (9.7%), diarrhea, rash, thrombocytopenia, vomiting, syncope, general disorders and administration site conditions-other, and skin and subcutaneous tissue disorders-other, each in 6.5% of patients.
This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer.
他拉泊司他是一种口服的二肽基肽酶（DPP4和DPP8/9）小分子抑制剂，在临床前研究中已显示出与免疫检查点抑制剂的协同活性。这项开放标签的2期篮子试验评估了他拉泊司他与帕博利珠单抗（抗程序性死亡-1抗体）联合用于晚期实体瘤患者的抗肿瘤活性。
主要目标是使用实体瘤疗效评价标准（RECIST）v1.1和免疫RECIST（iRECIST）评估前六名患者（导入期）的剂量限制性毒性（DLT）率以及研究治疗的缓解率（疗效期；包括队列A[初治检查点抑制剂（ICI）]和队列B[经ICI治疗]）。疗效采用贝叶斯最优2期设计进行评估。
共有31名患者入组本试验（队列A中有14名，队列B中有17名）。中位年龄为61岁；17名（55%）患者为男性，21名（68%）患者为白人。在19名（61%）可评估缓解的患者中，根据iRECIST，最佳缓解为9名患者病情稳定，7名患者未确认疾病进展，3名患者临床疾病进展。疾病控制率为47%。一名程序性死亡配体1阴性、微卫星稳定的子宫内膜癌患者出现未确认的部分缓解。中位无进展生存期为2.7个月；中位总生存期为20.5个月。一名患者（队列A）出现4级低血压作为DLT并停止治疗。最常见的毒性反应为低血压（22.6%）、疲劳（9.7%）、腹泻、皮疹、血小板减少、呕吐、晕厥、全身性疾病和给药部位情况-其他，以及皮肤和皮下组织疾病-其他，各占患者的6.5%。
这项关于他拉泊司他与帕博利珠单抗联合用于晚期实体瘤患者的研究显示了可预测的不良事件和有限的活性。该联合用药显示是安全的。疗效数据显示，19名可评估患者中有9名免疫病情稳定，一名子宫内膜癌患者出现未确认的免疫部分缓解。
