背景：Clin Cancer Res 杂志 2020 报道 HPV 阴性、可手术、III~IV 期 HNSCC 患者单周期新辅助 pembrolizumab（pembro）治疗的肿瘤病理缓解（pathologic tumor response）>10%(pTR-any)和>50%(pTR-2)的发生率分别是 44%和 22%。那么 2 个周期的新辅助 pembro 治疗能否使 50%的受试者达 pTR-2？美国教授 Ravindra Uppaluri 口头报道增加新辅助 pembro 治疗的周期数可提高 HPV 阴性的局部晚期 HNSCC 患者的病理缓解率，其可能会对临床结局产生有利影响。

Background: We reported that one cycle of neoadjuvant pembrolizumab induced pathologic tumor response in >10% (pTR-any) and in >50% (pTR-2) of the resection bed in 44% and 22% of patients (pts) with surgically resectable HPV-negative, Stage III/IV HNSCC (Clin Cancer Res 2020). We hypothesized that two cycles of neoadjuvant pembrolizumab would induce pTR-2 in 50% of pts. Increasing the pathologic response rate may favorably impact clinical outcomes.

方法：多机构2期试验，局部晚期HPV阴性HNSCC患者在术前42天和21天接受两个周期的pembrolizumab（200mg）。由两位独立的病理学家分析切除的肿瘤在切除床（原发肿瘤和/或淋巴结）中的pTR（肿瘤坏死和/或巨细胞/组织细胞对角质碎片的反应）。其他定义：pTR-1（>10-49%）和主要病理反应（>90%）。主要终点是pTR-2。需要26个pts的样本量来检测显著更高的pTR-2率（50%），使用单侧α水平0.05的80%功率。术后30天对Pts进行严重不良事件（AE）随访，最后一次服用pembrolizumab后90天对临床关注的不良事件进行随访。Pts接受了基线血液采集和肿瘤活检，以与pembrolizumab后获得的血液和手术标本相匹配。计划的相关因素包括治疗前后血液和肿瘤组织中PD-L1的表达、免疫功能和激活的分子特征。

Methods: Multi-institutional phase 2 trial where pts with locally advanced, HPV-negative HNSCC received two cycles of pembrolizumab (200 mg), given 42 and 21 days prior to surgery. Resected tumor was analyzed by two independent pathologists for pTR (tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris) in the resection bed (primary tumor and/or lymph nodes). Additional definitions: pTR-1 (>10-49%) and major pathologic response ( > 90%). The primary endpoint was pTR-2. A sample size of 26 pts was needed to detect a significantly higher pTR-2 rate of 50%, with 80% power using a one-sided alpha level of 0.05. Pts were followed for serious adverse events (AEs) for 30 days after surgery and for AEs of clinical interest for 90 days following the last dose of pembrolizumab. Pts underwent baseline blood collection and tumor biopsies to match with blood and surgical specimens obtained post-pembrolizumab. Planned correlatives included PD-L1 expression, immune function, and molecular signatures of activation in the pre- and post-treatment blood and tumor tissue.

结果：入组的 29 例患者中位年龄 62 岁(30-82 岁)，62% (18 例)有吸烟史，cT2(n=6)、cT3(n=5)、cT4(n=18)和N0~1(n=17)、N2(n=12)。入组患者均接受了 2 个周期的新辅助 pembro 治疗，耐受性良好，仅有 1(3%)例 3 级不良事件(皮疹)的发生，无 4 级不良事件。25 例可评估终点事件，余下 1 例术前退组，3 例 pTR 待定。pTR-2 发生率为 44%(11/25)，其中 4 例(16%)为 MTR，包括 1 例(4%)原发部位达 pCR。

Results: Characteristics of 29 enrolled and treated pts were median age 62 (30-82) yrs, smoking history 62% (18 pts); clinical stage T2 (n = 6), T3 (n = 5), T4 (n = 18) and N0/1 (n = 17), N2 (n = 12). All treated patients received two cycles of neoadjuvant pembrolizumab, which was tolerated well with only one (3%) grade 3 AE (rash) and no grade 4 AEs. The primary endpoint was evaluable in 25 pts, and not evaluable in 4 pts (one pt withdrew before surgery and in three pts, pTR review was pending). pTR-2 occurred in 44% (11 of 25 pts), and 4 (16%) of these pts had a major pathologic response including 1 (4%) pathologic CR at the primary site.

结论：相比单周期，2 周期的新辅助 pembro 治疗使得 pTR-2 增加两倍(44% vs 22%)。这些数据表明可通过增加新辅助 pembro 治疗的周期数来提高 HPV 阴性的局部晚期 HNSCC 患者的 pTR。

Conclusions: Two (vs one) cycles of neoadjuvant pembrolizumab resulted in a two-fold increase in the frequency of pTR-2 (44% vs 22%). These data imply that the frequency of pTR to neoadjuvant pembrolizumab can be improved by increasing the number of cycles and the treatment interval.