The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r greater than 0·7 was used as criteria for clinically relevant surrogacy. We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51–62). Median follow-up was 4·2 years (3·1–5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r 0·83), and progression-free survival (Kendall's τ 0·88 and r 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r 0·88), distant metastasis-free survival (r 0·96), and progression-free survival (r 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

中文翻译：

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p16 阳性口咽鳞状细胞癌临床试验的替代终点：个体患者数据荟萃分析

人乳头瘤病毒（HPV）相关癌症发病率的增加促使人们努力优化这些预后良好的患者的治疗。验证总体生存率的替代物可以加快新疗法的研究。我们试图在评估化疗或放疗对 p16 阳性口咽癌根治性治疗的试验中评估候选中间临床终点。我们对五项多中心随机试验（NRG/RTOG 9003、0129、0234、0522 和 1016）进行了回顾性评价，这些试验测试了 p16 阳性局部头颈部鳞状细胞癌患者（年龄≥18 岁）的放疗联合或不联合化疗。 -细胞癌。八个中间临床终点被认为是总体生存的潜在替代指标：无局部进展、无区域进展、无远处转移、无局部区域进展、无任何进展、局部区域无进展生存、无进展生存和无远处转移生存。我们采用了两阶段荟萃分析框架，要求中间临床终点与患者层面（条件1）的总生存率高度相关，并且中间临床终点的治疗效果与总体生存率的治疗效果高度相关。生存（条件 2）。对于两者，r 大于 0·7 被用作临床相关代孕的标准。我们分析了2020年5月9日至2023年11月22日期间的1373名口咽癌患者。其中1231名（90%）名患者为男性，142名（10%）名女性，1207名（88%）名白人，中位年龄57 岁（IQR 51-62）。中位随访时间为 4·2 年 (3·1–5·1)。对于第一个条件，将中间临床终点与个体和试验水平的总生存率相关联，三个复合终点为局部区域无进展生存期（Kendall's τ 0·91 和 r 0·72）、远处无转移生存期（Kendall's τ 0·91 和 r 0·72）。 τ 0·93 和 r 0·83) 和无进展生存期（Kendall 的 τ 0·88 和 r 0·70）与患者水平和试验组水平的总生存率高度相关。对于第二种情况，将中间临床终点和总生存期的治疗效果相关联，局部区域无进展生存期 (r 0·88)、远处无转移生存期 (r 0·96) 和无进展生存期的复合终点(r 0·92) 仍然是强有力的替代者。对其余中间临床终点的治疗效果与总生存期的相关性不太强。我们确定局部无进展生存期、无远处转移生存期和无进展生存期作为接受化疗或放疗治疗的 p16 阳性口咽癌总体生存期的替代指标，这可以作为临床试验终点。 NRG 肿瘤业务、NRG 肿瘤 SDMC、国家癌症研究所、礼来公司、安万特和密歇根大学。