Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck The Active8 Randomized Clinical Trial
Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck The Active8 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2018.1888
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发表时间：
2018-11-01
期刊：
影响因子：
28.4
通讯作者：
Cohen, Ezra E. W.
中科院分区：
文献类型：
--
作者：
Ferris, Robert L.;Saba, Nabil F.;Cohen, Ezra E. W.
免疫疗法治疗复发性和/或转移性（R/M）头颈部鳞状细胞癌（SCCHN）是有希望的。Toll样受体8（TLR 8）激动剂motolimod可刺激先天性和适应性immunity.Objective确定motolimod是否改善R/M SCCHN的预后，当与标准therapy.DESIGN，SETTING，AND PARTICIPANTS结合时，Active 8研究是一项多中心研究。一项随机、双盲、安慰剂对照临床试验，招募了2013年10月至2015年8月期间经组织学证实的口腔、口咽、下咽或喉R/M SCCHN成人患者（年龄≥ 18岁）。随访于2016年9月结束。本报告的分析在2016年6月至2017年12月期间进行。干预铂（卡铂或顺铂）、氟尿嘧啶、西妥昔单抗（EXTREME方案）和安慰剂或motolimod的联合治疗，每3周一次静脉给药。患者接受最多6个化疗周期，之后患者接受每周一次的西妥昔单抗与安慰剂或motolimod.Main结局和测量无进展生存期（PFS），由独立的中心审查使用免疫相关的RECIST（实体瘤反应评价标准）确定。关键的次要终点包括总生存期（OS）和safety.Results的195例患者中，85%是男性（n = 166），82%是白色（n = 159），中位年龄为58岁（范围23- 81岁）。motolimod vs安慰剂的中位PFS为6.1 vs 5.9个月（风险比[HR]，0.99;单侧90%CI，0.00-1.22; P = .47），中位OS为13.5 vs 11.3个月（HR，0.95;单侧90%CI，0.00-1.22; P = .40）。使用motolimod时，注射部位反应、发热、寒战、贫血和痤疮样皮疹的发生率增加。83例口咽癌中，HPV阳性52例（63%）。在预先设定的HPV阳性受试者亚组分析中，motolimod与安慰剂相比，PFS（7.8 vs 5.9个月; HR，0.58;单侧90% CI，0.00-0.90; P = 0.046）和OS（15.2 vs 12.6个月; HR，0.41;单侧90% CI，0.00-0.77; P = 0.03）显著延长。在一项探索性分析中，发生注射部位反应的患者的PFS和OS较长（中位PFS，7.1 vs 5.9个月; HR，0.69;单侧90% CI，0.00-0.93; P = 0.06;中位OS，18.7 vs 12.6; HR，0.56;单侧90% CI，0.00-0.81;结论和相关性将motolimod加入EXTREME方案中耐受性良好，但在意向治疗人群中没有改善PFS或OS。在HPV阳性患者和注射部位反应患者中观察到显著益处，表明TLR 8刺激可能使亚组和生物标志物选择的患者受益。
IMPORTANCE Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity.OBJECTIVE To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy.DESIGN, SETTING, AND PARTICIPANTS The Active8 study was a multicenter. randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age >= 18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017.INTERVENTIONS Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks.MAIN OUTCOMES AND MEASURES Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety.RESULTS Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81; P = .02).CONCLUSIONS AND RELEVANCE Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients.