高风险早期乳腺癌术前化疗Ｋ免疫治疗
大约四分之一的早期乳腺癌患者术前辅助化疗后5年内复发，故亟需新的治疗方案。程序性细胞死亡蛋白PD-1是主要表达于T淋巴细胞表面的免疫检查点，与癌细胞表面的程序性细胞死亡配体PD-L1结合以后，可以抑制T淋巴细胞杀死癌细胞。帕博利珠单抗（可瑞达，俗称K药）是用于癌症免疫治疗的人源化PD-1单克隆抗体，通过抑制T淋巴细胞的PD-1，能够阻断癌细胞的免疫逃避机制，从而允许T淋巴细胞杀死癌细胞。2014年和2018年，帕博利珠单抗先后被美国和中国内地批准上市，主要用于黑色素瘤、非小细胞肺癌等实体肿瘤。KEYNOTE-012、KEYNOTE-028、KEYNOTE-086、PANACEA研究相继证实帕博利珠单抗可以有效治疗晚期三阴性乳腺癌、晚期激素受体HR阳性乳腺癌、晚期HER2阳性乳腺癌。
2020年2月13日，《美国医学会杂志》肿瘤学分册在线发表芝加哥大学、梅奥医学中心、旧金山加利福尼亚大学、圣地亚哥加利福尼亚大学、耶鲁大学、伯明翰阿拉巴马大学、瑞典人癌症中心、莫菲特癌症中心、宾夕法尼亚大学、芝加哥洛约拉大学、科罗拉多大学、乔治城大学、俄勒冈医科大学、量子飞跃医疗、毕瑞咨询、德克萨斯大学MD安德森癌症中心、明尼苏达大学、双子集团的I-SPY2研究报告，探讨了术前化疗＋帕博利珠单抗对早期乳腺癌女性病理完全缓解的影响。
I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis): Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (NCT01042379)
该多中心非盲适配型随机对照二期临床研究是一个多组并行研究平台，将高风险II～III期乳腺癌标准术前化疗患者作为多个药物的共同对照组。该研究于2015年11月26日～2016年11月5日入组HR阳性HER2阴性或三阴性乳腺癌患者250例，随机分入两组：
标准术前化疗组181例（HR阳性96例、三阴性85例，年龄24～77岁、中位47岁）每周紫杉醇→多柔比星＋环磷酰胺
帕博利珠单抗组069例（HR阳性40例、三阴性29例，年龄27～71岁、中位50岁）帕博利珠单抗＋每周紫杉醇→多柔比星＋环磷酰胺
上述治疗结束后，进行最终手术。主要研究终点为病理完全缓解，次要研究终点为残癌负荷、三年无事件生存、无远处复发生存。
结果，截至2017年3月，帕博利珠单抗组与标准术前化疗组相比：
HER2阴性乳腺癌：病理完全缓解率高2.6倍（44%比17%）
HR阳性HER2阴性：病理完全缓解率高2.3倍（30%比13%）
三阴性乳腺癌：病理完全缓解率高2.7倍（60%比22%）
不良事件包括免疫相关内分泌疾病，尤其甲状腺功能异常（13.0%）和肾上腺功能不全（8.7%）。
帕博利珠单抗组中位随访2.8年时，获得与未获得病理完全缓解患者相比，3年无事件生存率较高（93.5%比77.1%）。
因此，该研究结果表明，帕博利珠单抗＋标准术前化疗与标准术前化疗相比，HER2阴性高风险早期乳腺癌的病理完全缓解率高一倍以上，无论HR阳性HER2阴性还是三阴性，故有必要进一步开展三期临床研究对三阴性乳腺癌（KEYNOTE 522）和高风险HR阳性HER2阳性乳腺癌（KEYNOTE 756）进行验证。
相关链接
JAMA Oncol. 2020 Feb 13. [Epub ahead of print]
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.
Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, Chien AJ, Forero-Torres A, Ellis E, Han H, Clark A, Albain K, Boughey JC, Jaskowiak NT, Elias A, Isaacs C, Kemmer K, Helsten T, Majure M, Stringer-Reasor E, Parker C, Lee MC, Haddad T, Cohen RN, Asare S, Wilson A, Hirst GL, Singhrao R, Steeg K, Asare A, Matthews JB, Berry S, Sanil A, Schwab R, Symmans WF, van 't Veer L, Yee D, DeMichele A, Hylton NM, Melisko M, Perlmutter J, Rugo HS, Berry DA, Esserman LJ.
The University of Chicago, Chicago, Illinois; Mayo Clinic, Rochester, Minnesota; University of California, San Francisco; University of California, San Diego; Yale University, New Haven, Connecticut; University of Alabama, Birmingham; Swedish Cancer Center; Moffitt Cancer Center, Tampa, Florida; University of Pennsylvania, Philadelphia; Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; University of Colorado, Aurora; Georgetown University, Washington, DC; Oregon Health & Science University, Portland; Quantum Leap Healthcare Collaborative, San Francisco, California; Berry Consultants, LLC; MD Anderson Cancer Center, Houston, Texas; University of Minnesota, Minneapolis; Gemini Group, Ann Arbor, Michigan.
Pembrolizumab Plus Neoadjuvant Chemotherapy and Pathologic Complete Response in Women With Early-Stage 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.
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.
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.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379
PMID: 32053137
DOI: 10.1001/jamaoncol.2019.6650