背景：HNSCC 术后高风险(切缘阳性、包膜外侵)或中风险的患者预计 1 年的 OS 分别为 65%和 69%。免疫检查点抑制剂提高了 R/M HNSCC 患者的 OS，既往数据表明放疗与 PD-1 有协同作用。本研究为可切除、局部晚期(cT3~4 和/或≥2 个转移淋巴结)的 HNSCC 患者术前和术后给予 PD-1 抑制剂 pembrolizumab (pembro)+辅助放疗±顺铂的临床研究。

Background: Patients with resected HNSCC, with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year DFS of 65% and 69%, respectively. Immune checkpoint blockade improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiotherapy (RT) synergizes with anti-PD-1. Therefore, we administered the PD-1 inhibitor pembrolizumab (pembro) pre- and post-surgery with adjuvant RT +/- cisplatin in patients with resectable, locoregionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093).

方法：入组的 92 例患者为术前 1~3 周接受 pembro (200mg 静脉注射一次)治疗的 HNSCC 患者，高风险和中风险患者可予以辅助放疗(60~66Gy)+pembro(q3w×6)±顺铂(40mg/m2×6)。主要终点为 1-y DFS。对新辅助 pembro 的病理反应(PR)通过术前和术后病理治疗效果(TE)来评估，TE 定义为肿瘤坏死和/或组织细胞炎症以及对角蛋白碎片的巨细胞反应。病理反应 PR 分为无病理缓解(NPR,<20%)、部分病理缓解(PPR,≥20%且<90%)和主要病理缓解(MPR, ≥90%)。

Methods: Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin (40mg/m2 X 6) for patients with high-risk and intermediate-risk features, respectively. The primary endpoint was 1-year DFS estimated by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Pathological response (PR) to neoadjuvant pembro was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE), defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. PR was classified as no (NPR, < 20%), partial (PPR, ≥20% and < 90%) and major (MPR, ≥90%). Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS).

结果：入组患者的中位年龄 58 岁(27~80 岁)，32%为女性，其中188体育平台论坛 癌占 88%，喉癌占 8%，HPV 阴性口咽癌占 3%；86%的患者为 cT3~4；53%的患者为高风险(45%切缘阳性; 78%包膜外侵); 64%的患者为 PD-L1 CPS≥1。中位随访 20 个月，高风险组 1-y DFS 为 67%(95%CI 0.52-0.85)，中风险组为 93%(95%CI 0.84-1)。80 例大病理反应 PR, TE 评分中 48 例为 NPR, 26 例为 PPR，6 例为 MPR，与 NPR 相比，病理反应为 PPR/MPR 的患者有显著 1-y DFS 的获益 (100% vs 68%,p=0.01;HR=0.23)。PD-L1 CPS≥1 与 1-y DFS 无关,但与 MPR/PPR 高度相关(p=0.0007).PPR/MPR 在 PD-L1 CPS<1,≥1 和≥20,分别为 20%,55%和 90%。62%的患者发       了 3 级不良事件，最常见不良事件为吞咽困难(15%)、中性粒细胞减少症(15%)、皮肤/伤口感染(10%)和粘膜炎(9%)。

Results: Ninety-two patients were enrolled. Seventy-six patients received adjuvant pembro and were evaluable for DFS. Patient characteristics included: median age 58 (range 27 – 80) years; 32% female; 88% oral cavity, 8% larynx, and 3% human papillomavirus negative oropharynx; 86% clinical T3/4 and 65% ≥2N; 49 (53%) high-risk (positive margins, 45%; ECE, 78%); 64% (44/69 available) had PD-L1 CPS ≥1. At a median follow-up of 20 months, 1-year DFS was 67% (95%CI 0.52-0.85) in the high-risk group and 93% (95%CI 0.84-1) in the intermediate-risk group. Among 80 patients evaluable for PR, TE scoring resulted in 48 NPR, 26 PPR and 6 MPR. Patients with PPR/MPR had significantly improved 1-year DFS when compared with those with NPR (100% versus 68%, p = 0.01; HR = 0.23). PD-L1 CPS ≥ 1 was not independently associated with 1-year DFS, but was highly associated with MPR/PPR (p = 0.0007). PPR/MPR in PD-L1 CPS < 1, ≥1 and ≥20, were estimated as 20, 55 and 90%, respectively. Grade ≥ 3 adverse events occurred in 62% patients with most common including dysphagia (15%), neutropenia (15%), skin/wound infections (10%), and mucositis (9%).

结论：可切除、局部晚期 HNSCC 患者新辅助 pembro 的病理反应率与 PD-L1 CPS≥1 和较高的 DFS 显著相关。

Conclusions: PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC.