Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial
Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial
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DOI：
10.1001/jamaoncol.2019.6650
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发表时间：
2020-05-01
期刊：
影响因子：
28.4
通讯作者：
Esserman, Laura J.
中科院分区：
文献类型：
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作者：
Nanda, Rita;Liu, Minetta C.;Esserman, Laura J.
重要性接受(NEO)辅助化疗的早期乳腺癌患者中，大约25%的患者在5年内复发。治疗方面的改进是非常需要的。目的确定培溴利珠单抗联合新辅助化疗(NACT)治疗早期乳腺癌是否有可能在300例患者中取得成功，这是一项验证性随机3期新辅助临床试验。设计、设置和参与者I-SPY2研究是一项正在进行的针对高风险、II/III期乳腺癌的开放标签、多中心、适应性随机的2期平台试验，同时评估多项研究。标准NACT作为公共控制臂，调查人员(S)加入这一中坚力量。2015年11月至2016年11月期间，ERBB2(前HER2)阴性乳腺癌患者有资格随机接受培溴利珠单抗治疗。干预措施参与者随机接受接受或不接受培溴利珠单抗的紫杉烷和蒽环类药物NACT，然后进行确定的手术。主要结果和指标主要终点为病理完全应答(PCR)。次要终点是残留癌症负担(RCB)和3年无事件和无远处复发的生存率。当在假设的验证性第三阶段试验中显示85%的预测成功概率时，研究人员就毕业了。结果：在纳入最终分析的250名妇女中，181人被随机分配到标准NACT对照组(中位数[范围]，47[24.77]岁)。69名女性(年龄中位数，50[27-71]岁)被随机分成4个周期，分别接受培溴利珠单抗联合每周紫杉醇和AC；40个激素受体(HR)阳性和29个三阴性。Pembrolizumab在所研究的所有3个生物标志物签名中毕业。在2017年3月评估的最终估计PCR率，在ERBB2阴性、HR阳性/ERBB2阴性和三阴性队列中，pembrolizumab与对照组相比分别为44%比17%、30%比13%和60%比22%。Pembrolizumab改变了RCB的分布，使每个评估队列的疾病负担更低。不良事件包括免疫相关的内分泌疾病，特别是甲状腺异常(13.0%)和肾上腺功能不全(8.7%)。达到聚合酶链式反应似乎预示着长期结果，在培溴利珠单抗加化疗后进行聚合酶链式反应的患者有很高的无事件生存率(3年93%，中位随访2.8年)。结论和相关性当加入标准的新辅助化疗时，pembrolizumab使HR阳性/ERBB2阴性和三阴性乳腺癌的估计PCR率增加了一倍以上，这表明在早期、高风险、ERBB2阴性的乳腺癌女性中，检查点阻断很有可能在第三阶段试验中成功。Pembrolizumab是HR阳性/ERBB2阴性的10种药物中第一个毕业的。问题是，在标准的新辅助化疗中添加免疫检查点抑制剂Pembrolizumab是否提高了早期、高风险、ERBB2(以前称为HER2)阴性乳腺癌的疗效？这项适应性随机的2期I-SPY2试验的分析结果包括250名早期乳腺癌患者，在标准新辅助化疗的基础上加用培溴利珠单抗，激素受体阳性/ERBB2阴性和三阴性乳腺癌的完全病理应答率比单独化疗增加一倍以上。I-SPY2试验的这些结果表明，在ERBB2阴性乳腺癌的3期随机临床试验中，培溴利珠单抗加新辅助化疗的预测概率超过99%，明显好于单独化疗。这项对正在进行的开放标签适应性随机2期试验的数据分析检验了在早期、高风险、ERBB2阴性乳腺癌患者的标准新辅助化疗中加入培溴利珠单抗的有效性。
Importance Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. Objective To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. Design, Setting, and Participants The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Interventions Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. Main Outcomes and Measures The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Results Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up). Conclusions and Relevance When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.Question Does the addition of the immune checkpoint inhibitor pembrolizumab to standard neoadjuvant chemotherapy improve efficacy in early-stage, high-risk, ERBB2 (formerly HER2)-negative breast cancer? Findings In this analysis of the adaptively randomized phase 2 I-SPY2 trial, including 250 women with early-stage breast cancer, the addition of pembrolizumab to standard neoadjuvant chemotherapy more than doubled complete pathologic response rates compared with chemotherapy alone for both hormone receptor-positive/ERBB2-negative, and triple-negative breast cancer. Meaning These results from the I-SPY2 trial suggest that there is a greater than 99% predictive probability that pembrolizumab plus neoadjuvant chemotherapy will be significantly better than chemotherapy alone in a phase 3 randomized clinical trial in ERBB2-negative breast cancer.This analysis of data from an ongoing open-label adaptively randomized phase 2 platform trial examines the efficacy of adding pembrolizumab to standard neoadjuvant chemotherapy in patients with early-stage, high-risk, ERBB2-negative breast cancer.