|
对于缺乏靶向治疗药物且无法手术的晚期三阴性乳腺癌，化疗仍为主要治疗方法。不过，晚期三阴性乳腺癌对化疗耐药的发生率较高。既往研究发现，晚期三阴性乳腺癌化疗耐药患者的丝裂原活化蛋白激酶（MAPK）信号传导通路显著上调，可促进癌细胞分裂繁殖。罗氏旗下基因泰克研发的MAPK细胞外信号调节激酶（MEK）抑制剂考比替尼可能提高癌细胞对紫杉类化疗药物和免疫细胞程序性死亡蛋白配体（PD-L1）抑制剂阿替利珠单抗的敏感性。 2021年2月1日，欧洲肿瘤内科学会《肿瘤学报》在线发表美国基因泰克、匹兹堡大学医疗中心、韩国蔚山大学首尔峨山医院、延世大学癌症中心、拉脱维亚大学医院、罗马尼亚克卢日纳波卡癌症研究所、比利时哈瑟尔特大学医院、加拿大罗氏、英国罗氏、弗农山癌症中心、澳大利亚墨尔本大学彼得麦卡伦癌症中心的COLET研究报告，探讨了考比替尼＋紫杉类化疗±阿替利珠单抗一线治疗晚期三阴性乳腺癌患者的有效性和安全性。 COLET (NCT02322814): A Multistage, Phase II Study Evaluating the Safety and Efficacy of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as First-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer 该多中心三队列随机对照二期临床研究于2015年3月12日～2016年10月31日从12个国家或地区45家医院入组年龄≥18岁的晚期三阴性乳腺癌患者153例。经过安全性准备期，队列一患者90例，按1∶1的比例随机分为两组，分别给予紫杉醇＋考比替尼（47例）或紫杉醇＋安慰剂（43例）。其他患者63例，按1∶1的比例随机分为两个队列，分别给予考比替尼＋阿替利珠单抗＋紫杉醇（队列二，32例）或考比替尼＋阿替利珠单抗＋白蛋白紫杉醇（队列三，31例）。主要终点为研究者评定的无进展生存（队列一）和集中复核的客观缓解率（队列二和队列三），并对安全性和耐受性进行评定。 结果，对于队列一患者，考比替尼＋紫杉醇与安慰剂＋紫杉醇相比：
队列二（考比替尼＋阿替利珠单抗＋紫杉醇）与队列三（考比替尼＋阿替利珠单抗＋白蛋白紫杉醇）相比：
对于队列二和队列三，PD-L1阳性与阴性患者相比：
全部患者发生率最高的≥3级不良事件为腹泻。 因此，该初步研究结果表明，对于晚期三阴性乳腺癌患者，考比替尼＋紫杉醇与安慰剂＋紫杉醇相比，无进展生存或客观缓解率的数值较高，但不显著，未见统计学意义。考比替尼＋阿替利珠单抗＋紫杉类并未提高客观缓解率。不过，PD-L1阳性患者对考比替尼＋阿替利珠单抗＋紫杉类的客观缓解率较高，故有必要针对PD-L1阳性患者开展进一步研究。 Ann Oncol. 2021 Feb 1. Online ahead of print. A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis. Brufsky A, Kim SB, Zvirbule Z, Eniu A, Mebis J, Sohn JH, Wongchenko M, Chohan S, Amin R, Yan Y, McNally V, Miles D, Loi S. University of Pittsburgh Medical Center, Pittsburgh, USA; Genentech, Inc., South San Francisco, USA; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; Latvian Oncology Centre of Riga East Clinical University Hospital, Riga, Latvia; Cancer Institute “Prof. Dr. Ion Chiricuta” (IOCN), Cluj-Napoca, Romania; Jessa Ziekenhuis, University of Hasselt, Belgium; F. Hoffmann-La Roche, Ltd., Mississauga, Canada; Roche Products Ltd, Welwyn Garden City, UK; Mount Vernon Cancer Centre, Northwood, UK; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia. HIGHLIGHTS
BACKGROUND: Resistance to standard chemotherapy in metastatic triple-negative breast cancer (mTNBC) is associated with upregulation of the mitogen-activated protein kinase (MAPK) pathway. Cobimetinib, a MAPK/extracellular signal-regulated kinase (MEK) inhibitor, may increase sensitivity to taxanes and programmed death-ligand 1 inhibitors. COLET is a three-cohort phase II study evaluating first-line cobimetinib plus chemotherapy, with or without atezolizumab, in patients with locally advanced or mTNBC. PATIENTS AND METHODS: Patients were ≥18 years with locally advanced or mTNBC. Following a safety run-in, patients in Cohort I were randomized 1:1 to cobimetinib (60 mg, D3-D23 of each 28-day cycle) or placebo, plus paclitaxel (80 mg/m2, D1, 8, and 15). Additional patients were randomized (1:1) into Cohort II or III to receive cobimetinib plus atezolizumab (840 mg, D1 and D15) and either paclitaxel (Cohort II) or nab-paclitaxel (Cohort III [100 mg/m2, D1, D8, and D15]). Primary endpoints were investigator-assessed progression-free survival (PFS) (Cohort I) and confirmed objective response rate (ORR) (Cohorts II/III). Safety/tolerability were also assessed. RESULTS: In the expansion stages, median PFS was 5.5 months for cobimetinib/paclitaxel versus 3.8 months for placebo/paclitaxel in Cohort I (hazard ratio 0.73; 95% confidence interval [CI] 0.43-1.24; P = 0.25). In Cohort I, ORR was 38.3% (95% CI 24.40-52.20) for cobimetinib/paclitaxel and 20.9% (95% CI 8.77-33.09) for placebo/paclitaxel; ORRs in Cohorts II and III were 34.4% (95% CI 18.57-53.19) and 29.0% (95% CI 14.22-48.04), respectively. Diarrhea was the most common grade ≥3 AE across all cohorts. CONCLUSIONS: Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend towards a numerical increase was observed. Cobimetinib plus atezolizumab and a taxane did not appear to increase ORR. This demonstrates the potential activity of a combinatorial MEK inhibitor, chemotherapy, and immunotherapy in this difficult-to-treat population. KEYWORDS: cobimetinib; triple-negative breast cancer; MEK inhibitor; atezolizumab; programmed death-ligand 1 inhibitor DOI: 10.1016/j.annonc.2021.01.065
|
|
|
