BOS172738, a selective RET inhibitor, for the treatment of patients with RET-altered tumors including RET-fusion-positive non-small-cell lung cancer and RET-mutant medullary thyroid cancer: a phase I dose-escalation/expansion multicenter study

IF 8.3 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2025-09-24 DOI:10.1016/j.esmoop.2025.105543

P. Schöffski , A. Gazzah , J. Trigo , A. Italiano , P. Gougis , V. Subbiah , J.-Y. Shih , H.H. Loong , B. Doger , M. Keegan , B. Jeglinski , K. Andreas , B.C. Cho

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引用次数: 0

Abstract

Background

This phase I dose-escalation (part A)/dose-expansion (part B) study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of BOS172738 [a selective rearranged during transfection (RET) inhibitor] in patients with RET-altered tumors including RET-fusion-positive non-small-cell lung cancer (NSCLC) and RET-mutant medullary thyroid cancer (MTC).

Patients and methods

Adult patients with advanced solid tumors with RET gene alteration received BOS172738 10-150 mg orally once daily in part A, and the recommended phase II dose (RP2D) in part B. Primary endpoints included safety (Common Terminology Criteria for Adverse Event v.4.03) and tolerability, and in part A, determining the maximum tolerated dose (MTD) and RP2D. Secondary endpoints included objective response rate (ORR; RECIST v.1.1), disease control rate (DCR), progression-free survival, duration of response (DoR), and pharmacokinetic assessments. Exploratory endpoints involved pharmacodynamic biomarkers.

Results

A total of 117 patients were enrolled (67 part A, 50 part B). Patients had advanced disease, were heavily pretreated, and 21% had brain metastases. In part A, three patients had dose-limiting toxicities, but MTD was not reached, with 75 mg recommended for part B. At final cut-off (November 2023), 85% had BOS172738-related treatment-emergent adverse events [54% grade ≥3, most common: blood creatine phosphokinase increased (25%), neutrophil count decreased (10%), and anemia (9%)]. In RET-fusion-positive NSCLC, 28% had an objective response and 59% disease control, with a median DoR (mDoR) of 10.17 months. In RET-mutant MTC, 30% had an objective response, and DCR was 74%, with a mDoR of 19.15 months.

Conclusions

BOS172738 showed preliminary efficacy and a manageable safety profile in RET-altered tumors, including those resistant to prior therapies and in patients with brain metastases.

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选择性RET抑制剂BOS172738用于治疗RET改变的肿瘤患者，包括RET融合阳性的非小细胞肺癌和RET突变的甲状腺髓样癌：一项I期剂量递增/扩展多中心研究

这项I期剂量递增（A部分）/剂量扩大（B部分）研究评估了BOS172738[一种转染期间选择性重排（RET）抑制剂]在RET改变肿瘤患者中的安全性、药代动力学、药效学和初步疗效，包括RET融合阳性的非小细胞肺癌（NSCLC）和RET突变的甲状腺髓样癌（MTC）。患者和方法伴有RET基因改变的成年晚期实体瘤患者在A部分接受BOS172738 10- 150mg每日一次口服，在b部分接受推荐的II期剂量（RP2D）。主要终点包括安全性（不良事件通用术语标准v.4.03）和耐受性，在A部分确定最大耐受剂量（MTD）和RP2D。次要终点包括客观缓解率（ORR; RECIST v.1.1）、疾病控制率（DCR）、无进展生存期、缓解持续时间（DoR）和药代动力学评估。探索性终点包括药效学生物标志物。结果共纳入117例患者（A组67例，B组50例）。患者病情晚期，接受了大量的预处理，21%的患者有脑转移。在A部分，3名患者有剂量限制性毒性，但未达到MTD， b部分推荐75mg。在最终截止日期（2023年11月），85%的患者出现与bos172738相关的治疗不良事件[54%分级≥3，最常见：血肌酸磷酸激酶增加（25%），中性粒细胞计数减少（10%）和贫血（9%）]。在ret融合阳性的NSCLC中，28%的患者客观缓解，59%的患者疾病控制，中位DoR （mDoR）为10.17个月。在ret突变型MTC中，30%的患者客观缓解，DCR为74%，mDoR为19.15个月。结论bos172738在ret改变的肿瘤中显示出初步的疗效和可管理的安全性，包括那些对既往治疗有耐药性的肿瘤和脑转移患者。

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来源期刊

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.