ImportanceImmune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus−positive oropharyngeal cancer (HPV+ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV+ OPC may increase efficacy while reducing toxicity.ObjectiveTo determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV+ OPC.Design, Setting, and ParticipantsThis phase 2 nonrandomized clinical trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV+ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023.InterventionsAddition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV+ OPC stages III to IV.Main Outcomes and MeasuresPrimary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated.ResultsThe 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS.Conclusions and RelevanceThis phase 2 nonrandomized clinical trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV+ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection.Trial RegistrationClinicalTrials.gov Identifier: NCT03107182

中文翻译：

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新辅助纳武单抗加化疗，随后针对 HPV+ 口咽癌进行反应适应性治疗


重要性免疫检查点抑制剂可提高复发性和/或转移性头颈癌的生存率，但其在治愈人乳头瘤病毒阳性口咽癌 (HPV+ OPC) 中的作用仍不清楚。新辅助纳武利尤单抗和化疗随后针对 HPV+ OPC 进行反应适应性治疗可能会提高疗效，同时降低毒性。 目的 确定在 HPV+ 患者中在化疗中加入新辅助纳武单抗，随后进行反应适应性局部治疗 (LRT) 的深度缓解率和耐受性OPC. 设计、设置和参与者这项在单一学术中心进行的 2 期非随机临床试验，从 2017 年至 2020 年入组了 77 名局部晚期 HPV+ OPC 患者。数据分析于 2021 年 2 月 10 日至 2023 年 1 月 9 日进行。纳武单抗联合白蛋白结合型紫杉醇和卡铂新辅助治疗（在第一个 OPTIMA 试验中研究），然后对 HPV+ OPC III 至 IV 期患者进行适应反应的 LRT。 主要结果和措施主要结果是新辅助纳武单抗联合化疗的深度缓解率，定义为根据实体瘤疗效评估标准 1.1，缩小 50% 或以上的肿瘤比例。次要结局是无进展生存期（PFS）和总生存期（OS）。还评估了吞咽功能、生活质量以及基于组织和血液的生物标志物，包括程序性死亡配体 1 (PD-L1) 表达和循环肿瘤 HPV-DNA (ctHPV-DNA)。 结果 73 名符合条件的患者（中位数） [范围] 年龄，61 [37-82] 岁；6 [8.2%] 女性；67 [91.8%] 男性）开始新辅助纳武单抗和化疗。 51 名患者观察到深度缓解（70.8%；95% CI，0.59-0.81）。 随后的风险和反应适应性治疗分配如下：A组，单独单一放疗或经口机器人手术（28名患者）； B组，中剂量放化疗45～50格雷（34例）； C组，常规剂量放化疗70～75格雷（10例）。两年 PFS 和 OS 分别为 90.0%（95% CI，0.80-0.95）和 91.4%（95% CI，0.82-0.96）。按反应适应组，A 组的 2 年 PFS 和 OS 分别为 96.4% 和 96.4%，B 组分别为 88.0% 和 91.0%。在接受适应反应的 LRT 的患者中观察到较低的肠内喂养率和体重变化以及吞咽改善。接受经口机器人手术的患者病理完全缓解率为67.0%。 PD-L1 表达非显着较高，可实现更深入的缓解和改善的 PFS，而 ctHPV-DNA 清除率与改善的 PFS 显着相关。结论和相关性这项 2 期非随机临床试验发现，新辅助纳武单抗和化疗随后进行适应反应的 LRT 是可行的，并且具有HPV+ OPC（包括患有高危疾病的患者）具有良好的耐受性、出色的 OS 和改善的功能结果。此外，添加nivolumab可能有利于高PD-L1表达者，敏感的动态生物标志物（例如ctHPV-DNA）对于患者选择很有用。试验注册临床试验。政府标识符：NCT03107182