一项 II 期随机试验，比较 cobimetinib 联合化疗与 cobimetinib 联合化疗加 atezolizumab 一线治疗局部晚期或转移性三阴性乳腺癌（COLET）的疗效：主要分析。

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.

机构信息

Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

出版信息

Ann Oncol. 2021 May;32(5):652-660. doi: 10.1016/j.annonc.2021.01.065. Epub 2021 Feb 1.

DOI:10.1016/j.annonc.2021.01.065

PMID:33539944

Abstract

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, an 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/m, D1, 8, and 15). Additional patients were randomized (1:1) to 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/m, 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 and 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 adverse events across all cohorts.

CONCLUSIONS

Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend toward 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.

摘要

背景

转移性三阴性乳腺癌（mTNBC）对标准化疗的耐药性与丝裂原活化蛋白激酶（MAPK）通路的上调有关。考比替尼是一种 MAPK/细胞外信号调节激酶（MEK）抑制剂，可能增加紫杉烷类药物和程序性死亡配体 1 抑制剂的敏感性。COLET 是一项三队列的 II 期研究，评估了一线考比替尼联合化疗，加或不加阿替利珠单抗，用于局部晚期或 mTNBC 患者。

患者和方法

患者年龄≥18 岁，患有局部晚期或 mTNBC。在安全性预试验后，队列 I 的患者以 1:1 的比例随机分配至考比替尼（60mg，每 28 天周期的第 3-23 天）或安慰剂，加紫杉醇（80mg/m，第 1、8 和 15 天）。其他患者以 1:1 的比例随机分配至队列 II 或 III，接受考比替尼联合阿替利珠单抗（840mg，第 1 天和第 15 天），并接受紫杉醇（队列 II）或nab-紫杉醇[队列 III（100mg/m，第 1、8 和 15 天）]。主要终点是研究者评估的无进展生存期（PFS）（队列 I）和确认的客观缓解率（ORR）（队列 II/III）。还评估了安全性和耐受性。

结果

在扩展阶段，队列 I 中考比替尼/紫杉醇的中位 PFS 为 5.5 个月，安慰剂/紫杉醇为 3.8 个月[风险比 0.73；95%置信区间（CI）0.43-1.24；P=0.25]。在队列 I 中，考比替尼/紫杉醇的客观缓解率为 38.3%（95%CI 24.40-52.20），安慰剂/紫杉醇为 20.9%（95%CI 8.77-33.09）；队列 II 和 III 的客观缓解率分别为 34.4%（95%CI 18.57-53.19）和 29.0%（95%CI 14.22-48.04）。所有队列中最常见的 3 级以上不良事件为腹泻。