背景：The GeparNuevo 臨床研究結果示：在早期三陰性乳腺癌標準新輔助化療基礎上加用durvalumab（抗 PD-L1 檢查點抑製劑（CPI））可提高患者病理完全緩解（pCR）率，尤其是在接受化療前使用 durvalumab 治療的患者（Loibl 等人，Ann Oncol 2019）。

Background: The GeparNuevo trial investigated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), to standard neoadjuvant chemotherapy (NACT) in patients with early TNBC. Durvalumab increased the pathological complete response (pCR) rate particularly in patients treated with durvalumab alone before start of chemotherapy (Loibl et al. Ann Oncol 2019).

方法：GeparNuevo 研究中，cT1b-cT4a-d 的三陰性乳腺癌患者隨機分至至 durvalumab（D）1.5 g i.v 組 或安慰劑組，每 4 周一次。前 2 周（窗口期）給予 durvalumab /安慰劑單藥治療（0.75 g iv），隨後每周 durvalumab /安慰劑加白蛋白-紫杉醇 125 mg / m2，連續持續 12 周後 durvalumab/安慰劑加表柔比星/環磷酰胺 （EC）q2 周，共 4 個周期。 根據浸潤淋巴細胞（sTILs）（低（≤10％），中級（11-59％），高（≥ 60％））進行隨機分組。 主要目標是 pCR（ypT0 ypN0）。 次要時間事件終點包括侵襲性無病生存期（iDFS），遠處轉移無病生存期（DDFS）和總體生存期（OS）。

Methods: GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks. D/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by D/placebo plus nab-paclitaxel 125 mg/m² weekly for 12 weeks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS).

結果：在 2016 年 6 月至 2017 年 9 月之間，總共招募了 174 位患者。使用 durvalumab 的 pCR 率為 53.4％，而安慰劑為 44.2％（OR 1.45，95％CI 0.80-2.63，未經調整的 Wald p = 0.224）。Durvalumab 效應僅在窗口隊列中可見（pCR 61.0％對 41.4％，OR 2.22，95％CI 1.06-4.64，p = 0.035；相互作用 p = 0.048）。 在對患者進行 42.2 個月的中期隨訪之後，有 174 例患者發生了 34 例事件。 pCR 與非 pCR 的 3 年 iDFS 分別為 92.0％和 71.9％（對數秩 p = 0.002）。 接受 durvalumab 治療的 3 年 iDFS 為 84.9％，而接受安慰劑治療的為 76.9％（HR 0.54，95％CI 0.27-1.09，分層對數秩 p = 0.0559）; 3 年期 DDFS 為 91.4％和 79.5％（HR 0.37，95％CI 0.15-0.87，p = 0.0148）;3 年 OS 為 95.1％和 83.1％（HR 0.26，95％CI 0.09-0.79，p = 0.0076）。 窗口期和無窗口期組間之 iDFS，DDFS 和 OS 中均未見明顯差異。

Results: A total of 174 patients were enrolled between June 2016 and September 2017. The pCR rate with durvalumab was 53.4% versus placebo 44.2% (OR 1.45, 95% CI 0.80–2.63, unadjusted Wald p = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR 2.22, 95% CI 1.06–4.64, p = 0.035; interaction p = 0.048). After a median follow-up of 42.2 months, 34 events occurred in 174 patients. 3-year iDFS in pCR vs non pCR was 92.0% vs 71.9% (log-rank p = 0.002). 3-year iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR 0.54, 95%CI 0.27-1.09, stratified log-rank p = 0.0559); 3-year DDFS 91.4% vs 79.5% (HR 0.37, 95%CI 0.15-0.87, p = 0.0148); 3-year OS 95.1% vs 83.1% (HR 0.26, 95%CI 0.09-0.79, p = 0.0076). No difference was seen in iDFS, DDFS and OS between the window and no window cohort.

結論：盡管 pCR 改善較小且術後無持續性用藥，但在 TNBC 的新輔助化療中加入 Durvalumab 仍可顯著改善長期預後。 是否需要使用 CPI 進行輔助治療仍是問題。

Conclusions: Durvalumab added to neoadjuvant chemotherapy in TNBC significantly improved long-term outcome despite a small pCR increase and no continuation after surgery. It needs to be questioned whether adjuvant therapy with CPI is needed at all.