A phase 2 basket study of talabostat, a small-molecule inhibitor of dipeptidyl peptidases, administered in combination with pembrolizumab in patients with advanced solid cancers

IF 5.1 2区医学 Q1 ONCOLOGY Cancer Pub Date : 2025-01-23 DOI:10.1002/cncr.35728

Jibran Ahmed MD, Filip Janku MD, PhD, Daniel D. Karp MD, Sarina A. Piha-Paul MD, Apostolia M. Tsimberidou MD, PhD, Timothy Anthony Yap MD, PhD, Bettzy Stephen MBBS, Yali Yang PhD, Serdar Gurses PhD, Qian Liu PhD, Juhee Song PhD, Funda Meric-Bernstam MD, Aung Naing MD

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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talabostat是一种二肽基肽酶的小分子抑制剂，在晚期实体癌患者中与派姆单抗联合使用。

背景：Talabostat是一种口服二肽基肽酶（DPP4和DPP8/9）的小分子抑制剂，在临床前研究中显示出与免疫检查点抑制剂的协同作用。这项开放标签的2期篮子试验评估了talabostat和pembrolizumab（抗程序性死亡-1抗体）联合治疗晚期实体瘤患者的抗肿瘤活性。方法：主要目的是评估前6例患者（引入期）的剂量限制性毒性（DLT）率和缓解率(疗效期；采用实体瘤应答评价标准（RECIST） v1.1和免疫RECIST （iRECIST）进行治疗的研究包括队列A[检查点抑制剂（ICI） naive]和队列B [ICI预处理]。疗效评估采用贝叶斯最优二期设计。结果：共有31例患者入组（A队列14例，B队列17例），中位年龄61岁；男性17例（55%），白人21例（68%）。在19例（61%）可评估缓解的患者中，基于iRECIST，最佳缓解是9例患者病情稳定，7例患者病情未确诊进展，3例患者病情临床进展。疾病控制率为47%。1例程序性死亡-配体1阴性、微卫星稳定型子宫内膜癌患者出现未证实的部分反应。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）经历了4级低血压，作为DLT并停止治疗。最常见的毒性是低血压（22.6%）、疲劳（9.7%）、腹泻、皮疹、血小板减少症、呕吐、晕厥、全身疾病和给药部位疾病（其他）以及皮肤和皮下组织疾病（其他），各占6.5%的患者。结论：在晚期实体瘤患者中联合使用他博他和派姆单抗的研究显示出可预测的不良事件和有限的活性。这种组合被证明是安全的。疗效数据显示19例可评估患者中有9例免疫稳定，1例子宫内膜癌患者出现未经证实的免疫部分反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer 医学-肿瘤学

CiteScore

13.10

自引率

3.20%

发文量

480

审稿时长

2-3 weeks

期刊介绍： The CANCER site is a full-text, electronic implementation of CANCER, an Interdisciplinary International Journal of the American Cancer Society, and CANCER CYTOPATHOLOGY, a Journal of the American Cancer Society. CANCER publishes interdisciplinary oncologic information according to, but not limited to, the following disease sites and disciplines: blood/bone marrow; breast disease; endocrine disorders; epidemiology; gastrointestinal tract; genitourinary disease; gynecologic oncology; head and neck disease; hepatobiliary tract; integrated medicine; lung disease; medical oncology; neuro-oncology; pathology radiation oncology; translational research