The University of Chicago, Chicago, Illinois.
Mayo Clinic, Rochester, Minnesota.
JAMA Oncol. 2020 May 1;6(5):676-684. doi: 10.1001/jamaoncol.2019.6650.
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.
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.
Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery.
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.
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).
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.
ClinicalTrials.gov Identifier: NCT01042379.
大约 25%接受（新）辅助化疗的早期乳腺癌患者在 5 年内会出现复发。非常需要改善治疗方法。
确定在一项有 300 名患者的确认性、随机 3 期新辅助临床试验中，派姆单抗联合新辅助化疗（NACT）是否有可能在早期乳腺癌中取得成功。
设计、设置和参与者：I-SPY2 研究是一项正在进行的、开放性、多中心、适应性随机 2 期平台试验，用于评估高危、II/III 期乳腺癌的多种研究药物，同时平行评估多个研究臂。标准 NACT 作为共同对照臂；在这个基础上加入研究药物。ERBB2（以前称为 HER2）阴性乳腺癌患者有资格在 2015 年 11 月至 2016 年 11 月期间随机接受派姆单抗治疗。
参与者被随机分配接受紫杉烷和蒽环类药物为基础的 NACT，加或不加派姆单抗，然后进行确定性手术。
主要终点是病理完全缓解（pCR）。次要终点是残留肿瘤负担（RCB）和 3 年无事件和远处无复发生存率。当在假设的确认性 3 期试验中显示出 85%的成功预测概率时，研究臂会毕业。
在最终分析的 250 名女性中，181 名被随机分配到标准 NACT 对照组（中位[范围]年龄，47[24.77]岁）。69 名女性（中位[范围]年龄，50[27-71]岁）被随机分配到 4 个周期的派姆单抗联合每周紫杉醇，然后是 AC；40 名激素受体（HR）阳性和 29 名三阴性。派姆单抗在所有 3 个生物标志物特征中都取得了成功。2017 年 3 月评估的最终估计 pCR 率分别为 44%对 17%、30%对 13%和 60%对 22%，分别为派姆单抗组和对照组在 ERBB2 阴性、HR 阳性/ERBB2 阴性和三阴性队列中的 pCR 率。派姆单抗将 RCB 分布转移到更低的疾病负担，在每个评估的队列中都有体现。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%）。实现 pCR 似乎对长期预后有预测作用，在接受派姆单抗联合化疗后达到 pCR 的患者具有较高的无事件生存率（3 年时为 93%，中位随访时间为 2.8 年）。
当与标准新辅助化疗联合使用时，派姆单抗使 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 ERBB2 阴性、高危、早期乳腺癌女性中使用检查点阻断治疗在 3 期试验中很有可能成功。派姆单抗是第一个在 HR 阳性/ERBB2 阴性特征中毕业的 10 个药物之一。
ClinicalTrials.gov 标识符：NCT01042379。
