Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial.
Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial.
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DOI：
10.1016/s1470-2045(17)30421-7
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发表时间：
2017-08
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通讯作者：
Guigay J
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作者：
Harrington KJ;Ferris RL;Blumenschein G Jr;Colevas AD;Fayette J;Licitra L;Kasper S;Even C;Vokes EE;Worden F;Saba NF;Kiyota N;Haddad R;Tahara M;Grünwald V;Shaw JW;Monga M;Lynch M;Taylor F;DeRosa M;Morrissey L;Cocks K;Gillison ML;Guigay J
铂难治性复发或转移（R/M）头颈部鳞状细胞癌（SCCHN）患者的治疗选择有限，预后较差。在Checkmate 141中，与研究者选择的标准单药治疗（IC）相比，Nivolumab显著提高了该患者群体的生存率；在这里，我们报告了纳武单抗对患者报告结局（PROs）的影响。CheckMate 141 （NCT02105636）是一项随机、开放标签的3期临床试验，在铂类化疗后6个月内进展的R/M SCCHN患者中进行。患者按2:1随机分配至每2周纳武单抗3mg /kg组（n=240）或甲氨蝶呤组（体表面积40 - 60mg /m2）、多西他赛组（30 - 40mg /m2）或西妥昔单抗组（负荷剂量400mg /m2后250mg /m2）组（n=121）。2016年1月26日，独立数据监测委员会审查了计划中期分析的数据，并宣布nivolumab优于IC治疗的总生存期（主要终点，如上文所述）。该方案经过修改，允许IC组的患者交叉使用纳武单抗。所有未接受积极治疗的患者均被跟踪观察生存情况。作为探索性终点，使用欧洲癌症研究与治疗组织（EORTC）生活质量问卷-核心30 （QLQ-C30）、EORTC头颈部癌症特异性模块（EORTC QLQ-H&N35）和三级欧洲生活质量5维度（EQ-5D）问卷，在基线、第9周和之后每6周对PROs进行评估。采用协方差分析（ANCOVA）对基线和≥1项其他评估的患者（n=129）进行pro治疗组内部和治疗组之间的差异分析。在所有随机分组的患者（N=361）中，采用Kaplan-Meier方法分析出现临床意义恶化的中位时间。nivolumab治疗导致EORTC QLQ-C30测量的功能和症状域从基线到第15周的调整平均变化范围为- 2.1至+ 5.4，没有域表明有临床意义的恶化。相比之下，IC组15个结构域中的8个（53%）在第15周表现出临床意义上的恶化（10分或更多）（从基线范围变化，−24.5到+ 2.4）。同样，在EORTC QLQ-H&N35中，在第15周时，在纳武单抗组中有0个域出现有临床意义的恶化，在IC组中18个域中有8个（44%）出现恶化。nivolumab组的患者在EQ-5D视觉模拟量表上从基线到第15周的调整后平均变化有临床意义的改善（根据7分或更大的差异），而IC组的患者有临床意义的恶化（+ 7.3 vs - 7.8）。在第9周和第15周，nivolumab在EORTC QLQ-C30组的角色功能、社交功能、疲劳、呼吸困难和食欲下降以及在EORTC QLQ-H&N35组的疼痛和感觉问题上具有统计学意义和临床意义。在三份问卷中评估的35个领域中，纳武单抗与IC相比，13个（37%）的中位恶化时间明显更长。在CheckMate 141的探索性分析中，从基线到第9周和第15周，nivolumab稳定了症状和功能，而IC导致临床有意义的恶化。与单药IC治疗铂难治性R/M SCCHN患者相比，Nivolumab延迟了患者报告的生活质量结果恶化的时间。考虑到这一人群中显著的未满足需求，以及维持或改善R/M SCCHN患者生活质量的重要性，这些数据支持nivolumab作为这种情况下新的标准治疗选择。百时美施贵宝。
Patients with platinum-refractory recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator’s choice (IC) in Checkmate 141; here we report the impact of nivolumab on patient-reported outcomes (PROs). CheckMate 141 (NCT02105636) was a randomised, open-label, phase 3 trial in patients with R/M SCCHN who progressed within 6 months after platinum-based chemotherapy. Patients were randomised 2:1 to nivolumab 3 mg/kg every 2 weeks (n=240) or IC (n=121) of methotrexate (40–60 mg/m2 of body surface area), docetaxel (30–40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2). On 26 January 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over IC therapy (primary endpoint; described previously). The protocol was amended to allow patients in the IC arm to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC head and neck cancer–specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life–5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment arms in PROs were analysed by analyses of covariance (ANCOVA) among patients with baseline and ≥1 other assessment (n=129). Among all randomised patients (N=361), median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from −2·1 to +5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. In contrast, 8 (53%) of the 15 domains in the IC arm demonstrated clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, −24·5 to +2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in 0 domains in the nivolumab arm and 8 (44%) of 18 domains in the IC arm. Patients in the nivolumab arm experienced a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the IC arm (+7·3 vs −7·8). Differences between arms were statistically significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab vs IC for 13 (37%) of 35 domains assessed across the three questionnaires. In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas IC led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of IC in patients with platinum-refractory R/M SCCHN. Given the significant unmet need in this population and the importance of maintaining or improving quality of life for patients with R/M SCCHN, these data support nivolumab as a new standard-of-care option in this setting. Bristol-Myers Squibb.