Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore & Mater Hospitals, Sydney, NSW, Australia.
Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Lancet Oncol. 2022 Nov;23(11):1378-1388. doi: 10.1016/S1470-2045(22)00559-9. Epub 2022 Oct 18.
Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up.
KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment.
Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported.
Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting.
Merck Sharp & Dohme, a subsidiary of Merck & Co.
接受单独手术治疗的 IIB 期或 IIC 期黑色素瘤患者有很大的疾病复发风险。在 KEYNOTE-716 试验的首次中期分析中，与安慰剂相比，辅助 pembrolizumab 显著改善了 IIB 期或 IIC 期黑色素瘤的无复发生存率。在此，我们报告了远处无转移生存期（预先指定的第三次中期分析）的次要终点结果，以及随着随访时间的延长，无复发生存率的结果。
KEYNOTE-716 是一项多中心、双盲、安慰剂对照、交叉或再挑战、随机、III 期试验，在 16 个国家的 160 个学术医疗中心和医院进行。符合条件的患者为年龄在 12 岁及以上、新诊断为完全切除且组织学确认的 IIB（T3b 或 T4a）或 IIC（T4b）皮肤黑色素瘤、前哨淋巴结活检阴性、东部合作肿瘤学组表现状态为 0-1。患者随机分配（1:1）接受 200mg 的 pembrolizumab（2mg/kg，最大剂量为 200mg，适用于儿科患者）或安慰剂，均为静脉注射，每 3 周一次，共 17 个周期（第 1 部分），直至疾病复发或不可接受的毒性。有疾病复发的合格患者可在第 2 部分交叉或再挑战阶段接受进一步的 pembrolizumab 治疗。随机分组使用交互式响应技术系统进行，并按 T 分类和儿科状况分层。主要终点为研究者评估的无复发生存率（在此报告了随着随访时间的延长的结果），我们报告了预先指定的第三次中期分析的远处无转移生存期（次要终点）。疗效分析在按意向治疗人群（所有根据分配组随机分配的患者）进行，安全性根据接受的治疗在所有随机分配并接受至少一剂试验治疗的患者中进行评估。KEYNOTE-716 在 ClinicalTrials.gov 上注册，NCT03553836，现已完成招募。
在 2018 年 9 月 23 日至 2020 年 11 月 4 日期间，976 名患者被随机分配接受 pembrolizumab（n=487）或安慰剂（n=489）。在中位随访 27.4 个月（IQR 23.1-31.7）时，两组均未达到中位远处无转移生存期。与安慰剂相比，pembrolizumab 显著改善了远处无转移生存期（风险比[HR]0.64，95%CI 0.47-0.88，p=0.0029）。pembrolizumab 组的中位无复发生存期为 37.2 个月（95%CI NR-NR），安慰剂组未达到（95%CI NR-NR）。与安慰剂相比，pembrolizumab 组的复发风险仍然较低（HR 0.64，95%CI 0.50-0.84）。最常见的 3 级或更高级别的不良事件是高血压（pembrolizumab 组 483 名患者中有 16 名[3%]，安慰剂组 486 名患者中有 17 名[4%]）、腹泻（8 名[2%]vs 1 名[<1%]）、皮疹（7 名[1%]vs 2 名[<1%]）、自身免疫性肝炎（7 名[1%]vs 2 名[<1%]）和脂肪酶升高（6 名[1%]vs 8 名[2%]）。pembrolizumab 组有 49 名（10%）患者发生与治疗相关的严重不良事件，安慰剂组有 11 名（2%）患者发生与治疗相关的严重不良事件。没有报告与治疗相关的死亡事件。
辅助 pembrolizumab 是一种有效的 IIB 期和 IIC 期黑色素瘤治疗选择，与安慰剂相比，远处无转移生存期显著改善，并且随着复发风险的降低，与 pembrolizumab 先前研究一致的不良反应谱。在辅助治疗环境中，pembrolizumab 的总体获益风险仍然为正。
默克公司的子公司默沙东 Sharp & Dohme，Merck & Co.
