背景：The  GeparNuevo  临床研究结果示：在早期三阴性乳腺癌标准新辅助化疗基础上加用durvalumab（抗 PD-L1 检查点抑制剂（CPI））可提高患者病理完全缓解（pCR）率，尤其是在接受化疗前使用 durvalumab 治疗的患者（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 的三阴性乳腺癌患者随机分至至 durvalumab（D）1.5 g i.v 组 或安慰剂组，每 4 周一次。前 2 周（窗口期）给予 durvalumab /安慰剂单药治疗（0.75 g iv），随后每周 durvalumab /安慰剂加白蛋白-紫杉醇 125 mg / m2，连续持续 12 周后 durvalumab/安慰剂加表柔比星/环磷酰胺 （EC）q2 周，共 4 个周期。 根据浸润淋巴细胞（sTILs）（低（≤10％），中级（11-59％），高（≥ 60％））进行随机分组。 主要目标是 pCR（ypT0 ypN0）。 次要时间事件终点包括侵袭性无病生存期（iDFS），远处转移无病生存期（DDFS）和总体生存期（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).

结果：在 2016 年 6 月至 2017 年 9 月之间，总共招募了 174 位患者。使用 durvalumab 的 pCR 率为  53.4％，而安慰剂为 44.2％（OR 1.45，95％CI 0.80-2.63，未经调整的 Wald p  = 0.224）。Durvalumab 效应仅在窗口队列中可见（pCR 61.0％对 41.4％，OR 2.22，95％CI 1.06-4.64，p = 0.035；相互作用 p = 0.048）。 在对患者进行 42.2 个月的中期随访之后，有 174 例患者发生了 34 例事件。 pCR 与非 pCR 的 3 年 iDFS 分别为 92.0％和 71.9％（对数秩 p = 0.002）。 接受 durvalumab 治疗的 3 年 iDFS 为 84.9％，而接受安慰剂治疗的为 76.9％（HR 0.54，95％CI 0.27-1.09，分层对数秩 p = 0.0559）; 3 年期 DDFS 为 91.4％和 79.5％（HR 0.37，95％CI 0.15-0.87，p = 0.0148）;3  年 OS 为 95.1％和 83.1％（HR 0.26，95％CI 0.09-0.79，p = 0.0076）。 窗口期和无窗口期组间之 iDFS，DDFS 和 OS 中均未见明显差异。

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.

结论：尽管 pCR 改善较小且术后无持续性用药，但在 TNBC 的新辅助化疗中加入 Durvalumab 仍可显着改善长期预后。 是否需要使用 CPI 进行辅助治疗仍是问题。

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.