Baljevic Muhamed, Zaman Shadia, Baladandayuthapani Veerabhadran, Lin Yan Heather, de Partovi Claudia Morales, Berkova Zuzana, Amini Behrang, Thomas Sheeba K, Shah Jatin J, Weber Donna M, Fu Min, Cleeland Charles S, Wang Xin Shelley, Stellrecht Christine M, Davis Richard E, Gandhi Varsha, Orlowski Robert Z
Division of Hematology & Oncology, The University of Nebraska Medical Center, Omaha, NE, USA.
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ann Hematol. 2017 Jun;96(6):977-985. doi: 10.1007/s00277-017-2980-3. Epub 2017 Mar 23.
The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest.
肝细胞生长因子/c-MET通路已被证实与多发性骨髓瘤的病理生物学相关，且c-MET抑制剂可诱导骨髓瘤细胞凋亡，这表明它们在临床上可能具有应用价值。我们对复发或复发难治性骨髓瘤患者开展了一项关于c-MET抑制剂替万替尼的II期研究，这些患者在接受1至4线前期治疗后病情进展。替万替尼剂量为每剂口服360 mg，在4周的治疗周期内每日给药2次，持续给药，允许的治疗周期数不限，但出现过度毒性或疾病进展者除外。主要目的是确定替万替尼在该患者群体中的总缓解率和毒性。16例患者采用两阶段设计入组。显著的3级和4级血液学不良事件分别仅限于5例患者的中性粒细胞减少和4例患者的中性粒细胞减少。3级或更高等级的非血液学不良事件包括高血压（4例患者）；晕厥、感染和疼痛（各2例）；以及疲劳、咳嗽和肺栓塞（各1例）。11例可评估患者中有4例（36%）的最佳反应为疾病稳定，其余患者则显示疾病进展。总体而言，替万替尼作为单一药物对未经选择的复发/难治性骨髓瘤患者未显示出应用前景。然而，实现疾病稳定的能力确实表明，在c-MET通路激活的患者中纳入靶向抑制剂的联合治疗方案可能值得关注。
