Lessons learned: Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.
Background: Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC.
Methods: We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination.
Results: The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%).
Conclusion: The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.
经验总结
• 尽管对已有治疗的长期反应不足, 但肾细胞癌试验的招募仍具有挑战性。
• 在30例中位无进展生存期和总生存期分别为8.3个月和15个月的患者中观察到三种缓解, 表明联合治疗具有部分效果, 但不足以进行进一步开发。
摘要
背景.转移性肾细胞癌（mRCC）的治疗效果不佳。既往临床前数据显示, 伊沙匹隆（一种获批用于治疗乳腺癌的微管稳定剂）在紫杉烷敏感和耐药性细胞中具有活性。在本项单组、II期试验中, 在难治性mRCC患者中考察了贝伐珠单抗联合伊沙匹隆的治疗效果。
方法.研究入组了30例经组织学证实的mRCC的患者, 这些患者具有透明细胞亚型, 此前未接受过伊沙匹隆或贝伐珠单抗治疗, 但至少接受过一次经美国食品药品监督管理局（FDA）批准的肾细胞癌（RCC）药物治疗。治疗方案为：伊沙匹隆6 mg/m2/天, 共5天, 以及每21天接受贝伐珠单抗15 mg/kg。6个周期后, 治疗间隔可延长至每28天一个周期。主要终点是根据实体瘤疗效评价标准（RECIST）评估的客观缓解率。次要终点为无进展生存期（PFS）、总生存期（OS）和联合用药的毒性。
结果.中位既往治疗数为2（每名患者的范围为1‐5）。患者接受伊沙匹隆联合贝伐珠单抗治疗的中位周期数为8（范围为2‐54）。中位随访时间为36.4个月（范围为23.5‐96.5）。19名患者（63.3％）的疾病稳定为最佳缓解。3名患者（10%）为部分缓解。中位PFS为8.3个月 [95％置信区间（CI）, 4.9‐10.6], 中位OS为15.0个月（95％CI, 11.3‐28.8）。安全性评价的总周期数为289。3级或4级不良事件（发生率>5％）包括淋巴细胞减少症（16.7％）、高血压（6.7％）和白细胞减少症（6.7％）。
结论.伊沙匹隆与贝伐珠单抗联合给药的耐受性良好, 在二线或二线以上的mRCC治疗中具有中度效果, 但在未进行进一步临床开发的情况下, 不推荐将其作为治疗方案。在未来的研究中可以探索与这些药物联用的替代方案。
Trial registration: ClinicalTrials.gov NCT00923130.
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