背景：Clin Cancer Res 雜誌 2020 報道 HPV 陰性、可手術、III~IV 期 HNSCC 患者單周期新輔助 pembrolizumab（pembro）治療的腫瘤病理緩解（pathologic tumor response）>10%(pTR-any)和>50%(pTR-2)的發生率分別是 44%和 22%。那麼 2 個周期的新輔助 pembro 治療能否使 50%的受試者達 pTR-2？美國教授 Ravindra Uppaluri 口頭報道增加新輔助 pembro 治療的周期數可提高 HPV 陰性的局部晚期 HNSCC 患者的病理緩解率，其可能會對臨床結局產生有利影響。

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：多機構2期試驗，局部晚期HPV陰性HNSCC患者在術前42天和21天接受兩個周期的pembrolizumab（200mg）。由兩位獨立的病理學家分析切除的腫瘤在切除床（原發腫瘤和/或淋巴結）中的pTR（腫瘤壞死和/或巨細胞/組織細胞對角質碎片的反應）。其他定義：pTR-1（>10-49%）和主要病理反應（>90%）。主要終點是pTR-2。需要26個pts的樣本量來檢測顯著更高的pTR-2率（50%），使用單側α水平0.05的80%功率。術後30天對Pts進行嚴重不良事件（AE）隨訪，最後一次服用pembrolizumab後90天對臨床關注的不良事件進行隨訪。Pts接受了基線血液采集和腫瘤活檢，以與pembrolizumab後獲得的血液和手術標本相匹配。計劃的相關因素包括治療前後血液和腫瘤組織中PD-L1的表達、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.

結果：入組的 29 例患者中位年齡 62 歲(30-82 歲)，62% (18 例)有吸煙史，cT2(n=6)、cT3(n=5)、cT4(n=18)和N0~1(n=17)、N2(n=12)。入組患者均接受了 2 個周期的新輔助 pembro 治療，耐受性良好，僅有 1(3%)例 3 級不良事件(皮疹)的發生，無 4 級不良事件。25 例可評估終點事件，餘下 1 例術前退組，3 例 pTR 待定。pTR-2 發生率為 44%(11/25)，其中 4 例(16%)為 MTR，包括 1 例(4%)原發部位達 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.

結論：相比單周期，2 周期的新輔助 pembro 治療使得 pTR-2 增加兩倍(44% vs 22%)。這些數據表明可通過增加新輔助 pembro 治療的周期數來提高 HPV 陰性的局部晚期 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.