背景：HNSCC 術後高風險(切緣陽性、包膜外侵)或中風險的患者預計 1 年的 OS 分別為 65%和 69%。免疫檢查點抑製劑提高了 R/M HNSCC 患者的 OS，既往數據表明放療與 PD-1 有協同作用。本研究為可切除、局部晚期(cT3~4 和/或≥2 個轉移淋巴結)的 HNSCC 患者術前和術後給予 PD-1 抑製劑 pembrolizumab (pembro)+輔助放療±順鉑的臨床研究。

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：入組的 92 例患者為術前 1~3 周接受 pembro (200mg 靜脈注射一次)治療的 HNSCC 患者，高風險和中風險患者可予以輔助放療(60~66Gy)+pembro(q3w×6)±順鉑(40mg/m2×6)。主要終點為 1-y DFS。對新輔助 pembro 的病理反應(PR)通過術前和術後病理治療效果(TE)來評估，TE 定義為腫瘤壞死和/或組織細胞炎症以及對角蛋白碎片的巨細胞反應。病理反應 PR 分為無病理緩解(NPR,<20%)、部分病理緩解(PPR,≥20%且<90%)和主要病理緩解(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).

結果：入組患者的中位年齡 58 歲(27~80 歲)，32%為女性，其中口腔癌占 88%，喉癌占 8%，HPV 陰性口咽癌占 3%；86%的患者為 cT3~4；53%的患者為高風險(45%切緣陽性; 78%包膜外侵); 64%的患者為 PD-L1 CPS≥1。中位隨訪 20 個月，高風險組 1-y DFS 為 67%(95%CI 0.52-0.85)，中風險組為 93%(95%CI 0.84-1)。80 例大病理反應 PR, TE 評分中 48 例為 NPR, 26 例為 PPR，6 例為 MPR，與 NPR 相比，病理反應為 PPR/MPR 的患者有顯著 1-y DFS 的獲益 (100% vs 68%,p=0.01;HR=0.23)。PD-L1 CPS≥1 與 1-y DFS 無關,但與 MPR/PPR 高度相關(p=0.0007).PPR/MPR 在 PD-L1 CPS<1,≥1 和≥20,分別為 20%,55%和 90%。62%的患者發 了 3 級不良事件，最常見不良事件為吞咽困難(15%)、中性粒細胞減少症(15%)、皮膚/傷口感染(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%).

結論：可切除、局部晚期 HNSCC 患者新輔助 pembro 的病理反應率與 PD-L1 CPS≥1 和較高的 DFS 顯著相關。

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