Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.
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DOI：
10.1016/s1470-2045(14)70189-5
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发表时间：
2014-06
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通讯作者：
CA184-043 Investigators
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作者：
Kwon ED;Drake CG;Scher HI;Fizazi K;Bossi A;van den Eertwegh AJ;Krainer M;Houede N;Santos R;Mahammedi H;Ng S;Maio M;Franke FA;Sundar S;Agarwal N;Bergman AM;Ciuleanu TE;Korbenfeld E;Sengeløv L;Hansen S;Logothetis C;Beer TM;McHenry MB;Gagnier P;Liu D;Gerritsen WR;CA184-043 Investigators
Ipilimumab是一种完全人源单克隆抗体，结合细胞毒性t淋巴细胞抗原4增强抗肿瘤免疫。我们的目的是评估多西紫杉醇化疗后进展的转移性去势抵抗性前列腺癌患者放疗后伊匹单抗的使用情况。我们进行了一项多中心，随机，双盲，3期试验，在多西他赛治疗后进展的至少有一个阉割抵抗性前列腺癌骨转移的男性以1:1的比例随机分配接受骨定向放疗（8 Gy / 1），随后每3周接受伊匹单抗10 mg/kg或安慰剂，最多4次剂量。无进展患者可继续接受ipilimumab 10mg /kg或安慰剂作为维持治疗，每3个月一次，直到疾病进展、不可接受的毒性作用或死亡。通过最小化算法将患者随机分配到两个治疗组，并根据东部肿瘤合作组的工作状态、碱性磷酸酶浓度、血红蛋白浓度和研究者地点进行分层。患者和调查人员对治疗分配不知情。主要终点是在意向治疗人群中评估的总生存期。该试验已在ClinicalTrials.gov注册，注册号为NCT00861614。从2009年5月26日到2012年2月15日，799名患者被随机分配（399名接受伊匹单抗治疗，400名接受安慰剂治疗），所有患者都被纳入意向治疗分析。伊匹单抗组的中位总生存期为11.2个月（95% CI为9.5 ~ 12.7），安慰剂组的中位总生存期为10.0个月（8.3 ~ 11.0）（风险比[HR] 0.85, 0.72 ~ 1.00; p= 0.053）。然而，对比例风险假设的评估显示不符合（p= 0.0031）。分段风险模型显示，HR随时间变化：0 - 5个月的HR为1.46 (95% CI为1.10 - 1.95)，5-12个月的HR为0.65(0.50 - 0.85)，12个月以上的HR为0.60（0.43 - 0.86）。最常见的3-4级不良事件与免疫相关，易普利姆单抗组发生101例（26%）患者，安慰剂组发生11例（3%）患者。最常见的3-4级不良事件包括腹泻（ipilimumab组393例患者中64例[16%]vs安慰剂组396例患者中7例[2%]），疲劳（40例[11%]vs 35例[9%]），贫血（40例[10%]vs 43例[11%]）和结肠炎（18例[5%]vs 0）。4例（1%）死亡是由于研究药物的毒性作用，全部发生在伊匹单抗组。虽然在初步分析中，易普利姆单抗组和安慰剂组在总生存率方面没有显著差异，但有迹象表明易普利姆单抗具有活性，值得进一步研究。百时美施贵宝。
Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio [HR] 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Bristol-Myers Squibb.