Banerjee Susana N, Van Nieuwenhuysen Els, Aghajanian Carol, D'Hondt Véronique, Monk Bradley J, Clamp Andrew, Prendergast Emily, Oaknin Ana, Ring Kari, Colombo Nicoletta, Holloway Robert W, Rodrigues Manuel, Chon Hye Sook, Gourley Charlie, Santin Alessandro D, Thaker Premal H, Gennigens Christine, Newman Gregg, Salinas Erin, Youssoufian Hagop, Moore Kathleen N, Lustgarten Stephanie, O'Malley David M, Van Gorp Toon, Grisham Rachel N
The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, GTG-UK, London, United Kingdom.
University Hospitals Leuven, Leuven Cancer Institute, BGOG, Leuven, Belgium.
J Clin Oncol. 2025 Sep;43(25):2782-2792. doi: 10.1200/JCO-25-00112. Epub 2025 Jul 11.
This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK] clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor) in patients with recurrent low-grade serous ovarian cancer (LGSOC).
In this phase II, open-label study, patients with recurrent, measurable LGSOC after ≥1 line of platinum chemotherapy were stratified by tumor Kirsten rat sarcoma virus homolog () mutation status and randomly assigned to oral avutometinib 4.0 mg two times per week monotherapy or avutometinib 3.2 mg two times per week in combination with oral defactinib 200 mg two times per day. The combination was selected as the go-forward regimen for expansion. The primary end point was objective response rate (ORR) by blinded independent central review.
A total of 115 patients received the go-forward combination regimen. Patients had a median of 3 (range, 1-9) prior lines of therapy, including hormonal (86%), bevacizumab (51%), and MEK inhibitor (22%). Confirmed ORR was 31% (95% CI, 23% to 41%) with a median duration of response of 31.1 months (95% CI, 14.8 to 31.1). ORR was 44% in mutant and 17% in wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) overall and 22.0 months (95% CI, 11.1 to 36.6) and 12.8 months (95% CI, 7.4 to 18.4) in mutant and wild-type cohorts, respectively. The most frequent grade ≥3 treatment-related adverse events (AEs) were elevated creatine phosphokinase (24%), diarrhea (8%), and anemia (5%). Ten percent of patients discontinued because of AEs.
The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781).
本研究评估了阿伐替尼（快速加速纤维肉瘤/丝裂原活化细胞外信号调节激酶[MEK]钳制）单药或与地法替尼（粘着斑激酶抑制剂）联合用于复发性低级别浆液性卵巢癌（LGSOC）患者的疗效和安全性。
在这项II期开放标签研究中，铂类化疗≥1线后出现复发性、可测量LGSOC的患者按肿瘤Kirsten大鼠肉瘤病毒同源物（）突变状态分层，并随机分配至口服阿伐替尼4.0 mg每周两次单药治疗或阿伐替尼3.2 mg每周两次联合口服地法替尼200 mg每日两次。联合治疗方案被选为进一步扩大研究的方案。主要终点是由盲法独立中央审查评估的客观缓解率（ORR）。
共有115例患者接受了进一步扩大研究的联合治疗方案。患者既往治疗的中位数为3（范围1 - 9）线，包括激素治疗（86%）、贝伐单抗治疗（51%）和MEK抑制剂治疗（22%）。确认的ORR为31%（95%CI，23%至41%），中位缓解持续时间为31.1个月（95%CI，14.8至31.1）。突变型队列的ORR为44%，野生型队列的ORR为17%。总体中位无进展生存期为12.9个月（95%CI，10.9至20.2），突变型和野生型队列分别为22.0个月（95%CI，11.1至36.6）和12.8个月（95%CI，7.4至18.4）。最常见的≥3级治疗相关不良事件（AE）为肌酸磷酸激酶升高（24%）、腹泻（8%）和贫血（5%）。10%的患者因AE停药。
阿伐替尼联合地法替尼的疗效和安全性概况支持该联合方案作为复发性LGSOC潜在的标准治疗方案。一项关于阿伐替尼和地法替尼与研究者选择的治疗方案对比用于复发性LGSOC女性患者的随机3期研究目前正在入组（RAMP301；ClinicalTrials.gov标识符：NCT06072781）。
