Pusztai L, Denkert C, O'Shaughnessy J, Cortes J, Dent R, McArthur H, Kümmel S, Bergh J, Park Y H, Hui R, Harbeck N, Takahashi M, Untch M, Fasching P A, Cardoso F, Zhu Y, Pan W, Tryfonidis K, Schmid P
Yale School of Medicine, Yale Cancer Center, New Haven, USA.
Institute of Pathology, Philipps-University Marburg and University Hospital Marburg, Marburg, Germany.
Ann Oncol. 2024 May;35(5):429-436. doi: 10.1016/j.annonc.2024.02.002. Epub 2024 Feb 17.
KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group.
A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model.
Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group.
Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.
KEYNOTE-522研究表明，对于高危早期三阴性乳腺癌（TNBC）患者，新辅助帕博利珠单抗联合化疗在病理完全缓解（pCR）方面有统计学显著改善，新辅助帕博利珠单抗联合化疗后序贯辅助帕博利珠单抗在无事件生存期（EFS）方面有改善。既往研究显示了残余癌负荷（RCB）指数在量化新辅助化疗后残余疾病程度方面的预后价值。在这项预先计划的探索性分析中，我们按治疗组评估了RCB分布及RCB类别内的EFS。
总共1174例T1c/N1-2期或T2-4/N0-2期TNBC患者按2:1随机分组，每3周接受200mg帕博利珠单抗或安慰剂，同时接受4个周期的紫杉醇+卡铂，随后接受4个周期的多柔比星或表柔比星+环磷酰胺。术后，患者接受帕博利珠单抗或安慰剂治疗9个周期，或直至复发或出现不可接受的毒性。主要终点是pCR和EFS。RCB是一个预先指定的探索性终点。使用Cox回归模型评估EFS与RCB之间的关联。
与安慰剂相比，帕博利珠单抗使患者在整个范围内进入较低的RCB类别。帕博利珠单抗组中RCB-0（pCR）的患者更多，而帕博利珠单抗组中RCB-1、RCB-2和RCB-3的患者更少。EFS的相应风险比（95%置信区间）分别为0.70（0.38-1.31）、0.92（0.39-2.20）、0.52（0.32-0.82）和1.24（0.69-2.23）。最常见的首次EFS事件是远处复发，在所有RCB类别中，帕博利珠单抗组的远处复发事件较少。在RCB-0/1的患者中，所有事件的一半以上[21/38（55.3%）]是中枢神经系统复发，其中帕博利珠单抗组为13/22（59.1%），安慰剂组为8/16（50.0%）。
化疗中加入帕博利珠单抗使RCB-0、RCB-1和RCB-2类别中的EFS事件减少，在RCB-2类别中获益最大。这些发现表明，帕博利珠单抗不仅提高了pCR率，还改善了大多数未达到pCR患者的EFS。
