美国UPMC希尔曼癌症中心Jason J Luke团队研究了派姆单抗与安慰剂作为完全切除的IIB或IIC期黑色素瘤辅助治疗的疗效和安全性。相关论文于2022年3月31日发表在《柳叶刀》杂志上。
派姆单抗可延长晚期黑色素瘤患者的无进展生存期和总生存期，并延长切除的III期疾病患者的无复发生存期。KEYNOTE-716评估了派姆单抗作为完全切除的高危II期黑色素瘤患者辅助治疗的疗效。该研究报道了第一次和第二次无复发生存期中期分析的结果。
在这项双盲、随机、安慰剂对照的3期临床研究中，研究组在16个国家（澳大利亚、比利时、巴西、加拿大、智利、法国、德国、以色列、意大利、日本、波兰、南非、西班牙、瑞士、英国和美国）的160家学术医疗中心和医院中招募年龄在12岁及以上、完全切除的IIB期或IIC期黑色素瘤（TNM T3b期或T4期，前哨淋巴结活检阴性）的新诊断患者。
将符合条件的患者按1:1随机分配，按T类（3b、4a和4b）和儿科状况（年龄12-17岁与≥18岁）进行分层，使用交互式反应技术系统，每3周静脉注射200 mg派姆单抗（儿科患者为2 mg/kg）或安慰剂，持续17个周期，或直到疾病复发或出现不可接受的毒性。所有患者、临床研究人员和分析人员均双盲接受治疗任务。
主要终点是研究者评估的意向治疗（ITT）人群（即随机分配给治疗的所有患者）的无复发生存率（定义为从随机分组到复发或死亡的时间）。在多重控制下，如果在第一次中期分析（约128名患者发生事件后）或第二次中期分析（179名患者发生事件后），与安慰剂相比，派姆单抗的无复发生存率显著提高，则达到主要终点。对所有随机分配至少接受一剂研究治疗的患者进行安全性评估。
2018年9月23日至2020年11月4日，研究组共筛查了1182名患者，其中976名患者接受随机分组，派姆单抗组487例，安慰剂组489例。中位年龄为61岁，387名（40%）为女性，589名（60%）为男性。976名患者中有874名（90%）白人，799名（82%）非西班牙裔或拉丁裔。派姆单抗组487名患者中有483名（99%）接受了指定治疗，安慰剂组489名患者中有486名（99%）。
在第一次中期分析中（数据截止于2020年12月4日；派姆单抗组中位随访14.4个月，安慰剂组中位随访14.3个月），派姆单抗组487名患者中有54名（11%）首次复发或死亡，显著低于安慰剂组（489名患者中有82名[17%]）。第二次中期分析中（数据截止于2021年6月21日；两组均中位随访20.9个月），派姆单抗组有72名（15%）首次复发或死亡，显著低于安慰剂组（115名[24%]）。
在两个评估时间点，两组均未达到中位无复发生存率。在第一次中期分析中，派姆单抗组483名患者中有78名（16%）发生3-4级治疗相关不良事件，而安慰剂组486名患者中有21名（4%）。在第一次中期分析中，安慰剂组有4名患者死于不良事件（分别死于肺炎、新冠肺炎、自杀和复发性癌症），在第二次中期分析中，派姆单抗组有1名患者死于不良事件（新冠肺炎）。未发生因研究治疗导致的死亡。
研究结果表明，派姆单抗作为IIB或IIC期黑色素瘤的辅助治疗长达约1年，与安慰剂相比，其疾病复发或死亡风险显著降低，且安全性可控。
附：英文原文
Title: Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial
Author: Jason J Luke, Piotr Rutkowski, Paola Queirolo, Michele Del Vecchio, Jacek Mackiewicz, Vanna Chiarion-Sileni, Luis de la Cruz Merino, Muhammad A Khattak, Dirk Schadendorf, Georgina V Long, Paolo A Ascierto, Mario Mandala, Federica De Galitiis, Andrew Haydon, Reinhard Dummer, Jean-Jacques Grob, Caroline Robert, Matteo S Carlino, Peter Mohr, Andrew Poklepovic, Vernon K Sondak, Richard A Scolyer, John M Kirkwood, Ke Chen, Scott J Diede, Sama Ahsan, Nageatte Ibrahim, Alexander M M Eggermont
Issue&Volume: 2022-03-31
Abstract:
Background
Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival.
Methods
In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12–17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual.
Findings
Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52–69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2–18·7] in the pembrolizumab group and 14·3 months [10·1–18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46–0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7–25·3] in the pembrolizumab group and 20·9 months [16·6–25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45–0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3–4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred.
Interpretation
Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile.
DOI: 10.1016/S0140-6736(22)00562-1
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00562-1/fulltext
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