Duke University Medical Center, Seeley G. Mudd Bldg, 10 Bryan Searle Drive, Box 3052, Durham, NC 27710, USA.
Cancer Chemother Pharmacol. 2011 Feb;67(2):465-74. doi: 10.1007/s00280-010-1507-6. Epub 2010 Nov 16.
VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination.
Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1.
Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020).
The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.
VEGF、mTOR 和 EGFR 抑制剂单独使用和联合使用均具有抗肿瘤和抗血管生成作用。本研究评估了贝伐单抗、依维莫司和厄洛替尼联合治疗的安全性、耐受性和药代动力学。
双联治疗方案为每 14 天给予贝伐单抗 10mg/kg，每日一次依维莫司 5mg，剂量逐渐增加至每日 10mg。厄洛替尼 75mg 每日一次加入贝伐单抗和依维莫司的推荐的 II 期剂量（RPTD）。在第 1 周期评估剂量限制性毒性（DLT）。
48 例晚期实体恶性肿瘤患者可评估 DLT 和疗效。在双联剂量递增中未观察到 DLT。加入厄洛替尼 75mg 每日一次后，出现 2 例 DLT（3 级黏膜炎和 3 级皮疹）。因此，调整了三联剂量，耐受性更好。4 例患者有部分缓解。双联治疗的中位无进展生存期（PFS）为 6.0 个月（0.5 至 32+个月），三联治疗为 5.5 个月（0.8 至 27+个月）。与单独使用时相比，与厄洛替尼联合使用时依维莫司的全身暴露显著增加（476±161ng h/mL 比 393±156ng h/mL；P=0.020）。
双联治疗的 RPTD 为贝伐单抗 10mg/kg 每 14 天一次，依维莫司 10mg 每日一次，三联治疗的 RPTD 为贝伐单抗 5mg/kg 每 14 天一次，依维莫司 5mg 和厄洛替尼 75mg 每日一次。在已知对 mTOR 抑制有反应且可能对 VEGF 阻断有耐药性的肿瘤中，疾病稳定时间延长。
