Rodrigues Heloisa Veasey, Ke Danxia, Lim JoAnn, Stephen Bettzy, Bellido Jorge, Janku Filip, Zinner Ralph, Tsimberidou Apostolia, Hong David, Piha-Paul Sarina, Fu Siqing, Naing Aung, Subbiah Vivek, Karp Daniel, Falchook Gerald, Kurzrock Razelle, Wheler Jennifer
Centro de Oncologia e Hematologia do Hospital Israelita Albert Einstein, São Paulo, Brazil.
Invest New Drugs. 2015 Jun;33(3):700-9. doi: 10.1007/s10637-015-0238-2. Epub 2015 Apr 24.
Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors.
Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway.
Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration (p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive.
Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted.
联合使用阻断VEGF和PI3K/AKT/mTOR通路的药物可能具有协同作用。我们探索了一种新的给药方案，以评估晚期实体瘤患者的安全性、毒性和活性。
难治性实体瘤患者参加一项改良的3+3一期剂量递增研究，以确定依维莫司（mTOR抑制剂）和帕唑帕尼（具有抗VEGF活性的酪氨酸激酶抑制剂）联合用药的剂量限制毒性（DLT）和最大耐受剂量（MTD）。为PI3K/AKT/mTOR通路存在分子改变的患者选择了一个扩大队列。
共纳入62例患者；中位年龄为60岁；29例为女性。MTD为帕唑帕尼600mg隔日一次（QOD），与依维莫司10mg口服QOD交替使用。DLT为3级血小板减少和肌酐升高。任何级别的最常见毒性为血小板减少、转氨酶升高、白细胞减少/中性粒细胞减少和血脂异常。在52例可评估疗效的患者中，临床获益率（CBR）为27%（14/52），包括4例部分缓解（PR）和10例疾病稳定（SD）≥6个月。在45例接受分子改变评估的患者中，26例在PI3K/AKT/mTOR通路中至少有一处改变。有匹配改变的患者CBR为27%（7/26），无改变的患者为26%（5/19）（p=0.764）。然而，在进行PI3K/AKT/mTOR通路改变的CBR和分子检测的患者中，64%为阳性。
帕唑帕尼和依维莫司联合治疗耐受性良好，并在实体瘤中显示出活性。有必要进一步探索这种联合治疗及其与治疗结果的分子相关性。
