Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.

IF 42.1 1区医学 Q1 ONCOLOGY

Journal of Clinical Oncology Pub Date : 2024-10-30 DOI:10.1200/JCO-24-01266

Daniel H Ahn, Maya Ridinger, Timothy L Cannon, Lawrence Mendelsohn, Jason S Starr, Joleen M Hubbard, Anup Kasi, Afsaneh Barzi, Errin Samuëlsz, Anju Karki, Ramanand A Subramanian, Divora Yemane, Roy Kim, Chu-Chiao Wu, Peter J P Croucher, Tod Smeal, Fairooz F Kabbinavar, Heinz-Josef Lenz

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引用次数: 0

Abstract

Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC).

Patients and methods: This multicenter, open-label, single-arm study enrolled patients with KRAS-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m² once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC.

Results: Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.

Conclusion: Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).

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Onvansertib 联合化疗和贝伐单抗二线治疗 KRAS 突变转移性结直肠癌：单臂 II 期试验。

目的：这项II期研究评估了onvansertib（一种多聚样激酶1（PLK1）抑制剂）与氟尿嘧啶、亮菌素和伊立替康（FOLFIRI）+贝伐单抗联合用于KRAS突变转移性结直肠癌（mCRC）二线治疗的疗效和耐受性：这项多中心、开放标签、单臂研究招募了曾接受奥沙利铂和氟尿嘧啶联合或不联合贝伐珠单抗治疗的KRAS突变mCRC患者。患者接受安万斯替布（15 mg/m2，每天一次，28 天为一个周期，第 1-5 天和第 15-19 天）和 FOLFIRI + 贝伐珠单抗（第 1 天和第 15 天）治疗。主要终点是客观反应率（ORR），次要终点包括无进展生存期（PFS）、反应持续时间（DOR）和耐受性。在 KRAS 突变的 CRC 中进行了转化和临床前研究：在接受治疗的 53 名患者中，确诊 ORR 为 26.4%（95% CI，15.3 至 40.3）。中位DOR为11.7个月（95% CI，9.4至未达到）。62%的患者出现了3/4级不良反应。一项事后分析显示，与既往接受过贝伐珠单抗治疗的患者相比，既往未接受过贝伐珠单抗治疗的患者的ORR明显更高，PFS也更长：ORR为76.9%对10.0%（几率比为30.0，P < .001），中位PFS为14.9个月对6.6个月（危险比为0.16，P < .001）。我们的转化研究结果支持先前贝伐珠单抗暴露会导致昂万舍替耐药。临床前研究表明，onvansertib可抑制缺氧通路，并通过抑制血管生成与贝伐珠单抗联用显示出强大的抗肿瘤活性：结论：onvansertib联合FOLFIRI+贝伐珠单抗在KRAS突变mCRC患者的二线治疗中表现出显著的活性，尤其是在既往未接受过贝伐珠单抗治疗的患者中。这些研究结果促成了在一线治疗中对联合用药的评估（ClinicalTrails.gov 标识符：NCT06106308）。

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

Journal of Clinical Oncology 医学-肿瘤学

CiteScore

41.20

自引率

2.20%

发文量

8215

审稿时长

2 months

期刊介绍： The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.