Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Oncology Center, Hospital Sírio-Libanês, Brasília, Brazil.
JAMA Oncol. 2020 Oct 1;6(10):1598-1605. doi: 10.1001/jamaoncol.2020.3524.
Prior studies have shown that only a small proportion of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy. There are data suggesting that activity may be greater with combination strategies.
To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)-negative MBC.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy.
Patients were randomized 1:1 to eribulin, 1.4 mg/m2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy.
The primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations.
Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade ≥3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1-positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS.
In this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1-positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed.
ClinicalTrials.gov Identifier: NCT03051659.
重要性：先前的研究表明，只有一小部分激素受体（HR）阳性转移性乳腺癌（MBC）患者从程序性细胞死亡 1（PD-1）/程序性细胞死亡配体 1（PD-L1）抑制剂单药治疗中获益。有数据表明，联合策略可能会更有效。
目的：比较厄瑞布林联合帕博利珠单抗与厄瑞布林单药治疗 HR 阳性、ERBB2（以前称为 HER2）阴性 MBC 患者的疗效。
设计、地点和参与者：一项多中心、2 期随机临床试验，纳入了接受过 2 线及以上激素治疗和 0 至 2 线化疗的 HR 阳性、ERBB2 阴性 MBC 患者。
干预措施：患者以 1:1 的比例随机分为厄瑞布林 1.4mg/m2 静脉注射，第 1 和第 8 天；帕博利珠单抗 200mg/m2 静脉注射，每 21 天周期的第 1 天。在疾病进展时，厄瑞布林单药治疗组的患者可以交叉接受帕博利珠单抗单药治疗。
主要终点和次要终点：主要终点是无进展生存期（PFS）。次要终点是客观缓解率（ORR）和总生存期（OS）。探索性分析评估了 PFS 与 PD-L1 状态、肿瘤浸润淋巴细胞（TILs）、肿瘤突变负荷（TMB）和基因组改变之间的关系。
结果：88 例患者开始接受方案治疗；中位（范围）年龄为 57（30-76）岁，中位（范围）化疗线数为 1（0-2），中位（范围）激素治疗线数为 2（0-5）。中位随访时间为 10.5（95%CI，0.4-22.8）个月。两组间 PFS 和 ORR 无差异（PFS：4.1 与 4.2 个月；危险比，0.80；95%CI，0.50-1.26；P=0.33；ORR：27%与 34%，分别；P=0.49）。14 例患者开始接受帕博利珠单抗交叉治疗；1 例患者病情稳定。所有患者均发生全因不良事件（≥3 级，65%），联合组发生 2 例治疗相关死亡，均为脓毒症相关免疫性结肠炎，归因于两种药物。对 65 例患者的存档肿瘤样本进行了 22C3 检测：24 例（37%）为 PD-L1 阳性肿瘤。分析表明，PD-L1 状态、TILs、TMB 和基因组改变与 PFS 无关。
结论和相关性：在这项 HR 阳性、ERBB2 阴性 MBC 患者的随机临床试验中，与厄瑞布林单药治疗相比，厄瑞布林联合帕博利珠单抗并未改善 PFS、ORR 或 OS，无论是在意向治疗人群还是 PD-L1 阳性人群中。需要进一步努力探索在较少接受过治疗的患者中添加检查点抑制联合化疗的获益。
试验注册：ClinicalTrials.gov 标识符：NCT03051659。
