Banerjee Susana, Krebs Matthew G, Greystoke Alastair, Garces Alvaro Ingles, Perez Vicky Sanchez, Terbuch Angelika, Shinde Rajiv, Caldwell Reece, Grochot Rafael, Rouhifard Mahtab, Ruddle Ruth, Gurel Bora, Swales Karen, Tunariu Nina, Prout Toby, Parmar Mona, Symeonides Stefan, Rekowski Jan, Yap Christina, Sharp Adam, Paschalis Alec, Lopez Juanita, Minchom Anna, de Bono Johann Sebastian, Banerji Udai
Gynecological Oncology Unit and Division of Clinical Studies, The Royal Marsden Hospital Foundation Trust and The Institute of Cancer Research, London, UK.
Division of Cancer Sciences, The University of Manchester and Christie NHS Foundation Trust, Manchester, UK.
Nat Med. 2025 Jun 27. doi: 10.1038/s41591-025-03763-y.
Use of signal transduction inhibitors as single agents to treat cancer leads to resistance because of the plasticity of intracellular signaling, and combination therapy can overcome this. We describe the first-in-human trial of avutometinib (RAF-MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors. The trial met its primary endpoint and recommended a phase 2 dose and schedule. The recommended phase 2 dose and schedule for a 28-day cycle was determined to be avutometinib 3.2 mg once a day, twice weekly (Monday and Thursday or Tuesday and Friday), and defactinib 200 mg twice a day, seven days a week. Both drugs were administered orally on a 3 weeks 'on' and 1 week 'off' basis. The pharmacokinetics and pharmacodynamics were consistent with previous reports of avutometinib and defactinib used as single agents. Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4-63.1) and a median progression-free survival of 20.1 months (95% confidence interval 11.2-43.9) in patients with low-grade serous ovarian cancer. This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820 .
由于细胞内信号传导的可塑性，使用信号转导抑制剂作为单一药物治疗癌症会导致耐药性，而联合治疗可以克服这一问题。我们描述了阿武替尼（RAF-MEK钳制）和地法替尼（粘着斑激酶抑制剂）在实体瘤患者中的首例人体试验。该试验达到了其主要终点，并推荐了2期剂量和给药方案。确定的28天周期的推荐2期剂量和给药方案为：阿武替尼3.2毫克，每天一次，每周两次（周一和周四或周二和周五）；地法替尼200毫克，每天两次，每周七天。两种药物均按3周“用药”和1周“停药”的方案口服给药。药代动力学和药效学与之前关于阿武替尼和地法替尼作为单一药物的报道一致。主要发现包括：低级别浆液性卵巢癌患者的客观缓解率为42.3%（26例中的11例；95%置信区间23.4-63.1），无进展生存期的中位数为20.1个月（95%置信区间11.2-43.9）。这项研究证明了间歇给药方案在联合靶向丝裂原活化蛋白激酶和粘着斑激酶途径以提高耐受性方面的重要性，并获得了针对低级别浆液性卵巢癌（一种对化疗相对耐药的肿瘤）的抗肿瘤活性的概念验证。ClinicalTrials.gov标识符：NCT03875820 。
