近日，美国纪念斯隆-凯特琳癌症中心Alison M. Schram团队研究了p53再激活剂Rezatapopt治疗TP53 y220c突变肿瘤的1期研究。相关论文发表在2026年2月26日出版的《新英格兰医学杂志》上。

Rezatapopt是一种研究性、首创的、口服、选择性p53再激活剂，它能特异性结合Y220C突变的p53，从而稳定p53使其呈现野生型构象，并恢复其功能。

在这项1期、单组、剂量递增和剂量优化研究中，研究组分配携带TP53 Y220C突变的局部晚期或转移性实体瘤且经过大量预治疗的患者，在连续21天的治疗周期内接受rezatapopt治疗。主要目标是确定最大耐受剂量和推荐的2期剂量。主要终点包括剂量限制性毒性反应和不良事件。次要终点包括初步疗效和药代动力学特征。

共有77名患者接受了八种递增剂量之一的rezatapopt治疗：每日一次150 mg、300 mg、600 mg、1150 mg、1500 mg、2000 mg或2500 mg，或每日两次1500 mg。最大耐受剂量为每日两次1500 mg。基于安全性、疗效和药代动力学数据，选择每日一次2000 mg随餐服用作为推荐的2期剂量。在治疗期间，76名患者（99%）至少发生一次不良事件，29名患者（38%）发生1级或2级不良事件。最常见的不良事件为恶心（占患者的58%）、呕吐（44%）、血肌酐升高（39%）、疲劳（39%）和贫血（36%）。治疗相关不良事件发生于67名患者（87%），其中1级或2级者48名（62%）；2名患者（3%）因治疗相关不良事件停止使用rezatapopt。大多数胃肠道不良事件经对症治疗后缓解，且随餐服用rezatapopt时发生频率较低。治疗期间，贫血是3级或以上最常见的不良事件，发生于16%的患者。在所有患者中，总缓解率（完全或部分缓解）为20%；在携带KRAS野生型肿瘤且接受至少每日一次1150 mg剂量的患者中，总缓解率为30%。在多种肿瘤类型中观察到经确认的缓解，包括卵巢癌和乳腺癌。所有获得缓解的患者均携带TP53 Y220C和野生型KRAS的实体瘤。

研究结果表明，在这项涉及经过大量预治疗患者的1期研究中，与rezatapopt相关的最常见不良事件是恶心和呕吐。在多种肿瘤类型中观察到抗肿瘤活性，为p53再激活提供了概念验证。

附：英文原文

Title: Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C–Mutated Tumors

Author: Ecaterina E. Dumbrava, Geoffrey I. Shapiro, Aparna R. Parikh, Melissa L. Johnson, Anthony W. Tolcher, John A. Thompson, Anthony B. El-Khoueiry, Andrae L. Vandross, Shivaani Kummar, Dale R. Shepard, Kim LeDuke, Lisa Sheehan, Leila Alland, Arshad Haque, Deepika Jalota, Marc Fellous, Alison M. Schram

Issue&Volume: 2026-02-26

Abstract:

Background

Rezatapopt is an investigational, first-in-class, oral, selective p53 reactivator that specifically binds to Y220C-mutated p53, which stabilizes p53 in its wild-type conformation and restores its functionality.

Methods

In this phase 1, single-group, dose-escalation and dose-optimization study, we assigned heavily pretreated patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation to receive rezatapopt during continuous 21-day treatment cycles. The primary objectives were to determine the maximum tolerated dose and recommended phase 2 dose. Primary end points included dose-limiting toxic effects and adverse events. Secondary end points included preliminary efficacy and pharmacokinetic features.

Results

A total of 77 patients received rezatapopt at one of eight escalating doses: 150 mg, 300 mg, 600 mg, 1150 mg, 1500 mg, 2000 mg, or 2500 mg once daily or 1500 mg twice daily. The maximum tolerated dose was 1500 mg twice daily. On the basis of safety, efficacy, and pharmacokinetic data, 2000 mg once daily with food was selected as the recommended phase 2 dose. During the treatment period, 76 patients (99%) had at least one adverse event and 29 (38%) had an adverse event of grade 1 or 2. The most common adverse events were nausea (in 58% of patients), vomiting (in 44%), an increased blood creatinine level (in 39%), fatigue (in 39%), and anemia (in 36%). Treatment-related adverse events occurred in 67 patients (87%) and those of grade 1 or 2 in 48 (62%); 2 patients (3%) discontinued rezatapopt because of a treatment-related adverse event. Most gastrointestinal adverse events resolved with the treatment of symptoms and were less frequent when rezatapopt was given with food. Anemia was the most common adverse event of grade 3 or higher during the treatment period, occurring in 16% of patients. The overall response (complete or partial response) was 20% among all patients and 30% among those who had a KRAS wild-type tumor and received a dose of at least 1150 mg once daily. Confirmed responses were seen across multiple tumor types, including ovarian and breast cancers. All patients with a response had a solid tumor that harbored TP53 Y220C and wild-type KRAS.

Conclusions

In this phase 1 study involving heavily pretreated patients, the most common adverse events associated with rezatapopt were nausea and vomiting. Antitumor activity occurred across multiple tumor types, providing proof of concept for p53 reactivation.

DOI: NJ202602263940909

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2508820