|
英飞凡（度伐利尤单抗）属于免疫检查点程序性死亡蛋白配体PD-L1抑制剂，利普卓（奥拉帕利）属于多腺苷二磷酸核糖聚合酶PARP抑制剂。MEDIOLA研究已经证实，度伐利尤单抗＋奥拉帕利对HER2阴性晚期乳腺癌化疗失败患者有效。对于HER2阴性早期乳腺癌，度伐利尤单抗＋奥拉帕利能否提高术前标准新辅助化疗的效果？ 2021年6月17日，美国《细胞》旗下《癌细胞》（影响因子：26.602）在线发表耶鲁大学、旧金山加利福尼亚大学、莫菲特癌症中心、德克萨斯大学MD安德森癌症中心、圣迭戈加利福尼亚大学、伯明翰阿拉巴马大学、梅奥医学中心、科罗拉多大学、明尼苏达大学、芝加哥大学、芝加哥洛约拉大学、宾夕法尼亚大学、俄勒冈医科大学、哥伦比亚大学、乔治城大学、维克森林大学、乔治梅森大学、量子飞跃、毕瑞咨询、双子集团的I-SPY2研究报告，探讨了度伐利尤单抗＋奥拉帕利＋紫杉醇新辅助化疗对高风险HER2阴性早期乳腺癌术前患者的有效性和安全性。 I-SPY 2 TRIAL (NCT01042379): Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2 (Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer) 该多中心随机对照二期临床研究于2018年5月3日～2019年6月2日入组高风险HER2阴性II或III期乳腺癌术前患者372例，其中73例（三阴性21例、激素受体阳性52例）被随机分入度伐利尤单抗＋奥拉帕利＋紫杉醇组，其余299例（三阴性142例、激素受体阳性157例）被随机分入紫杉醇标准新辅助化疗对照组。 结果，度伐利尤单抗＋奥拉帕利＋紫杉醇组与紫杉醇标准新辅助化疗对照组相比，病理完全缓解率：
免疫反应相关基因表达水平与病理完全缓解率成正比，肥大细胞基因表达水平与未病理完全缓解相关。 因此，该小样本初步研究结果表明，对于HER2阴性早期乳腺癌术前患者，度伐利尤单抗＋奥拉帕利＋紫杉醇与紫杉醇标准新辅助化疗相比，病理完全缓解率较高，尤其对于高风险激素受体阳性HER2阴性乳腺癌高度敏感亚组患者。对于激素受体阳性HER2阴性乳腺癌，仅70基因复发风险评分较高患者才能获益。免疫反应相关基因高表达患者对度伐利尤单抗＋奥拉帕利较敏感，肥大细胞基因高表达患者对度伐利尤单抗＋奥拉帕利较不敏感。 相关链接 Cancer Cell. 2021 Jun 17. Online ahead of print. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Lajos Pusztai, Christina Yau, Denise M. Wolf, Hyo S. Han, Lili Du, Anne M. Wallace, Erica String-Reasor, Judy C. Boughey, A. Jo Chien, Anthony D. Elias, Heather Beckwith, Rita Nanda, Kathy S. Albain, Amy S. Clark, Kathleen Kemmer, Kevin Kalinsky, Claudine Isaacs, Alexandra Thomas, Rebecca Shatsky, Theresa L. Helsten, Andres Forero-Torres, Minetta C. Liu, Lamorna Brown-Swigart, Emmanuel F. Petricoin, Julia D. Wulfkuhle, Smita M. Asare, Amy Wilson, Ruby Singhrao, Laura Sit, Gillian L. Hirst, Scott Berry, Ashish Sanil, Adam L. Asare, Jeffrey B. Matthews, Jane Perlmutter, Michelle Melisko, Hope S. Rugo, Richard B. Schwab, W. Fraser Symmans, Doug Yee, Laura J. van't Veer, Nola M. Hylton, Angela M. DeMichele, Donald A. Berry, Laura J. Esserman. Yale School of Medicine, New Haven, CT, USA; University of California, San Francisco, CA, USA; Moffitt Cancer Center, Tampa, FL, USA; University of Texas MD Anderson Cancer Center, Houston, TX, USA; University of California San Diego, La Jolla, CA, USA; University of Alabama at Birmingham, Birmingham, AL, USA; Mayo Clinic, Rochester, MN, USA; University of Colorado, Aurora, CO, USA; University of Minnesota, Minneapolis, MN, USA; University of Chicago, Chicago, IL, USA; Loyola University Chicago Stritch School of Medicine, Chicago, IL, USA; University of Pennsylvania, Philadelphia, PA, USA; Oregon Health & Sciences University, Portland, OR, USA; Columbia University, New York, NY, USA; Georgetown University, Washington, DC, USA; Wake Forest University, Winston-Salem, NC, USA; George Mason University, Manassas, VA, USA; Quantum Leap Healthcare Collaborative, San Francisco, CA, USA; Berry Consultants, LLC, Austin, TX, USA; Gemini Group, Ann Arbor, MI, USA. HIGHLIGHTS
The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients. KEYWORDS: breast cancer; immunotherapy; DNA repair inhibitor; clinical trial DOI: 10.1016/j.ccell.2021.05.009
|
|
|
