A Phase II Trial of Bevacizumab plus Everolimus for Patients with Refractory Metastatic Colorectal Cancer

• Published in: The oncologist (Dayton, Ohio) Ohio), 2011-08, Vol.16 (8), p.1131-1137
• Main Authors: Altomare, Ivy, Bendell, Johanna C., Bullock, Karen E., Uronis, Hope E., Morse, Michael A., Hsu, S. David, Zafar, S. Yousuf, Blobe, Gerard C., Pang, Herbert, Honeycutt, Wanda, Sutton, Linda, Hurwitz, Herbert I.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - therapeutic use; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Colorectal Neoplasms - drug therapy; Disease-Free Survival; Everolimus; Gastrointestinal Cancer; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - therapeutic use; Middle Aged; Phase II; Refractory colorectal cancer; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - therapeutic use; Treatment Outcome
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2011-0078

Purpose. For patients with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5‐fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Preclinical data demonstrated that combined vascular endothelial growth factor and mammalian target of rapamycin inhibition has greater antiangiogenic and antitumor activity than either monotherapy. A phase I study of bevacizumab plus everolimus demonstrated that the combination is safe; activity was seen in several patients with refractory mCRC. Methods. Fifty patients with refractory mCRC were enrolled and received bevacizumab at 10 mg/kg every 2 weeks and everolimus at 10 mg orally daily. Results. Of the 50 patients enrolled, the median age was 56 years and the median number of prior regimens was four. Forty‐seven patients (96%) had prior bevacizumab exposure and 42 patients (84%) had documented progression on prior bevacizumab‐based therapy. Forty‐nine patients were evaluable for response; eight patients had minor responses (16%) and an additional 15 patients (30%) had stable disease (SD). No complete or partial responses were seen. The median progression‐free survival interval was 2.3 months; however, 26% of patients achieved prolonged SD for ≥6 months, and three patients (6%) were on study for >1 year. The median overall survival duration was 8.1 months. The most common grade 1–2 toxicities were mucositis (68%) and hyperlipidemia (64%). Clinically significant grade ≥3 toxicities included hypertension (14%), fistula/abscess/perforation (8%), mucositis (6%), and hemorrhage (2%). Conclusions. Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients. 摘要 目的就转移性结直肠癌（mCRC）患者而言，5氟尿嘧啶、奥沙利铂、伊立替康、贝伐珠单抗和西妥昔单抗或帕尼单抗治疗进展后，无标准治疗措施。临床前数据显示，联合抑制血管内皮生长因子与雷帕霉素哺乳类靶蛋白治疗的抗血管生成和抗肿瘤活性高于任一单药治疗。贝伐珠单抗+依维莫司的I期研究显示，联合方案是安全的，在部分难治性mCRC患者中可见抗瘤活性。 方法50例难治性mCRC入组研究，接受贝伐珠单抗（10mg/kg，每2周）和依维莫司（10 mg/天，口服）治疗。 结果50例入组患者的中位年龄为56岁，既往治疗方案的中位数为4。47例（96%）既往接受贝伐珠单抗治疗，42例（84%）在贝伐珠单抗为基础的治疗中有进展记载。49例患者可评估缓解，其中8例（16%）轻微缓解，另有15例（30%）疾病稳定（SD）。未见完全或部分缓解。中位无进展生存期为2.3个月，但26%的患者SD延长至³6个月，3例（6%）坚持研究>1年。中位总生存期为8.1个月，最常见的1~2级毒性为粘膜炎（68%）和高脂血症（64%）。有临床意义的³3级毒性有高血压（14%）、瘘/脓肿/穿孔（8%）、粘膜炎（6%）和出血（2%）。 结论贝伐珠单抗+依维莫司总体可耐受，但有粘膜损伤和/或伤口愈合风险。贝伐珠单抗+依维莫司似乎对难治性mCRC患者具有中等活性。 The results of a phase II study of bevacizumab and everolimus in patients with metastatic colorectal cancer ar