Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
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DOI：
10.1016/s1470-2045(15)00083-2
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发表时间：
2015-08
期刊：
影响因子：
51.1
通讯作者：
Daud, Adil
中科院分区：
文献类型：
--
作者：
Ribas, Antoni;Puzanov, Igor;Dummer, Reinhard;Schadendorf, Dirk;Hamid, Omid;Robert, Caroline;Hodi, F. Stephen;Schachter, Jacob;Pavlick, Anna C.;Lewis, Karl D.;Cranmer, Lee D.;Blank, Christian U.;O'Day, Steven J.;Ascierto, Paolo A.;Salama, April K. S.;Margolin, Kim A.;Loquai, Carmen;Eigentler, Thomas K.;Gangadhar, Tara C.;Carlino, Matteo S.;Agarwala, Sanjiv S.;Moschos, Stergios J.;Sosman, Jeffrey A.;Goldinger, Simone M.;Shapira-Frommer, Ronnie;Gonzalez, Rene;Kirkwood, John M.;Wolchok, Jedd D.;Eggermont, Alexander;Li, Xiaoyun Nicole;Zhou, Wei;Zernhelt, Adriane M.;Lis, Joy;Ebbinghaus, Scot;Kang, S. Peter;Daud, Adil
接受伊匹单抗治疗进展的黑色素瘤患者，如果BRAFV 600 muplatin阳性，则接受BRAF或MEK抑制剂或两者，则几乎没有治疗选择。我们评估了两种帕博利珠单抗剂量与选择性化疗在伊匹单抗难治性黑色素瘤患者中的疗效和安全性。我们对来自12个国家的73家医院、诊所和学术医疗中心的18岁或以上患者进行了一项随机2期试验，这些患者在接受两次或更多次伊匹单抗给药后24周内确诊疾病进展，如果BRAFV 600 muR阳性，则既往接受过BRAF或MEK抑制剂或两者联合治疗。患者必须将所有伊匹单抗相关不良事件缓解至0-1级，泼尼松10 mg/天或更低，持续至少2周，东部肿瘤协作组（ECOG）体力状态为0或1，并且至少有一个可测量的病变才有资格。使用集中式交互式语音应答系统，我们将患者随机分配（1：1：1）到6个区组中，接受静脉注射帕博利珠单抗2 mg/kg或10 mg/kg，每3周一次或选择性化疗（紫杉醇加卡铂、紫杉醇、卡铂、达卡巴嗪或口服替莫唑胺）。根据ECOG体力状态、乳酸脱氢酶浓度和BRAFV 600突变状态对随机化进行分层。帕博利珠单抗和化疗之间的个体治疗分配是开放标签的，但研究者和患者对帕博利珠单抗的剂量分配不知情。我们在预先规定的第二次中期分析中提出了意向治疗人群的无进展生存期的主要终点。本研究注册于ClinicalTrials.gov，编号NCT 01704287。该研究已停止招募，但仍在继续随访和治疗患者。在2012年11月30日至2013年11月13日期间，我们招募了540例患者：180例患者随机分配接受帕博利珠单抗2 mg/kg，181例接受帕博利珠单抗10 mg/kg，179例接受化疗。基于410例无进展生存期事件，与分配到化疗组的患者相比，分配到派姆单抗2 mg/kg组（HR 0.57，95% CI 0.45 - 0.73; p<0.0001）和分配到派姆单抗10 mg/kg组（0.50，0.39 - 0.64; p<0.0001）的患者的无进展生存期有所改善。6-在帕博利珠单抗2 mg/kg组、10 mg/kg组和化疗组中，3个月无进展生存率分别为34%（95% CI 27-41）、38%（31-45）和16%（10-22）。Pembrolizumab 2 mg/kg组20例（11%）患者、Pembrolizumab 10 mg/kg组25例（14%）患者和化疗组45例（26%）患者发生了治疗相关的3-4级不良事件。帕博利珠单抗组中最常见的治疗相关3-4级不良事件是疲劳（2 mg/kg组178例患者中有2例[1%]，10 mg/kg组179例患者中有1例[<1%]，而化疗组171例患者中有8例[5%]）。其他治疗相关的3-4级不良事件包括全身水肿和肌痛（各2例[1%]患者）;垂体功能减退、结肠炎、腹泻、食欲减退、低钠血症和肺炎（每2例[1%]），给予pembrolizumab 10 mg/kg;化疗组中有贫血（9例[5%]）、疲劳（8例[5%]）、中性粒细胞减少（6例[4%]）和白细胞减少（6例[4%]）。这些发现确立了派姆单抗作为治疗伊匹单抗难治性黑色素瘤的新标准治疗。
Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39–0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27–41) in the pembrolizumab 2 mg/kg group, 38% (31–45) in the 10 mg/kg group, and 16% (10–22) in the chemotherapy group. Treatment-related grade 3–4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3–4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3–4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.