背景：研究評估在新輔助卡鉑-紫杉醇化療（CP）中加入 Pembrolizumab（P）是否可以提高最佳減瘤率， 患者間隔減瘤手術（IDS）後的完全切除率（CRR）最初不可切除的國際婦產科聯合會（FIGO） IIIC / IV期卵巢，輸卵管或腹膜 HGSC。
Background: To investigate whether adding Pembrolizumab (P) to neoadjuvant carboplatin-paclitaxel chemotherapy (CP) may increase the optimal debulking rate, assessed by Complete Resection Rate (CRR) after Interval Debulking Surgery (IDS) in patients (pts) with initially unresectable International Federation of Gynecology and Obstetrics (FIGO) stage IIIC/IV ovarian, tubal or peritoneal HGSC.
方法：多中心，開放，非比較性隨機 II 期臨床試驗。將患者隨機（2：1）接受 4 個周期的 CP±P 然後行 IDS。IDS 後，所有患者均接受了術後化療（2 至 4 周期）和選擇性貝伐單抗治療共 15 個月，±P 作為維持治療，總治療持續時間 2 年。隨機分組基於治療中心，FIGO 分期，Bev 計劃在 IDS 之後，病灶體積（<5cm>5cm）。主要終點被被設定為 IDS 時的 CRR。CP + P 組計劃 60 例（A’Hern 的單階段設計 P0 = 50％，P1 = 70％）。安全性（特別是添加 P），手術發病率，ORR， PFS 和 OS 是次要終點。
Methods: Multicenter, open-label, non-comparative randomized phase II trial. Pts were randomized (2:1) to receive 4 cycles of CP ± P before IDS. After IDS, all patients received post-operative chemotherapy (2 to 4 cycles) and optional bevacizumab for 15 months in total ± P as maintenance therapy for up to 2 years. Randomization was stratified on center, FIGO stage, Bev planned after IDS and disease volume (<5cm/>5cm). Primary endpoint was the centrally reviewed CRR at IDS. 60 pts were planned in the CP+P arm (A'Hern's single-stage design P0=50%, P1=70%). Safety (particularly due to P addition), surgical morbidity, ORR, PFS and OS were secondary endpoints.
結果：從 02/18 到 04/19，共有 91 例患者被隨機分組，腹膜癌指數中位數為 24（範圍 7-39）。80 例（88％）的患者接受 Bev 聯合 CP 治療，隨後接受 Bev±P 進行維持治療。在 CP + P 組（n = 61），有 58 例（95％）的患者接受了 IDS，78％的患者完成了完全切除。CRR 在這一組中比例為 74％，在統計學上優於預先設定的假設。在 CP 組，CRR 為 70％（接受 IDS 的 29/30 分）。4 周期化療後完全切除在 CP + P 和 CP 組分別有 41 例（71％）和 17 例（58％）（敏感性分析）。CP + P 組， IDS 前的 ORR 病例數更多（分別為76％和 61％）。3 級不良事件（AE）在 CP + P 組為 75％，CP 組為 67％：主要是血液和淋巴，胃腸道和血管疾病。CP + P 和 CP 組中分別有 20％和 13％的患者發生術後 AE（主要是感染性，血管和胃腸道）。兩組之間的致命事件數量沒有差異。18 個月的 PFS 在 CP + P 和 CP 組分別為 61％（95CI％[47-73]）和 57％（95CI％[37-72]）。
Results: 91 pts were randomized from 02/18 to 04/19 with a median Peritoneal Cancer Index at 24 (range 7-39). 80 pts (88%) received Bev in combination with CP followed by bev ± P in maintenance. In the CP+P group (n=61), 58 (95%) pts had IDS and 78% achieved complete resection. The CRR in this group was 74%, statistically superior to the pre-defined hypothesis. In the CP group, CRR was 70% (29/30 pts underwent IDS). Complete resection after strictly 4 cycles of CP±P was obtained for 41 pts (71%) and 17 (58%) pts in CP+P and CP group, respectively (sensitivity analysis). For CP+P group, numerically higher ORRs were observed before IDS compared to CP group (76% vs 61%). Grade ≥3 adverse events (AE) occurred in 75% of the CP+P group and 67% in the CP group: mainly blood and lymphatic, gastrointestinal and vascular disorders. Postoperative AE (mainly infectious, vascular and gastrointestinal) occurred in 20% and 13% of the pts in CP+P and CP arm, respectively. No difference in the number of fatal events between the two arms: 2 in the experimental arm vs 1 in the control arm. Progression free survival rate at 18 months was 61% (95CI% [47-73]) and 57% (95CI% [37-72]) in CP+P and CP arm, respectively.
結論：對於不能最佳切除的患者，新輔助化療中加入 P 可以提高 CRR。生存數據和包括 PDL1 狀態在內的轉化研究正在進行中，以更好地將 P 定義為這種情況下的治療選擇。
Conclusions: P may be safely added to preoperative treatment in pts deemed non-optimally resectable. The primary objective was met with an improved CRR on CP+P arm. The CRR in the control group was higher than expected. Survival data and translational research including PDL1 status are ongoing to better define P as treatment option in this setting.
