Division of Oncology, Washington University, St. Louis, Missouri.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
Clin Cancer Res. 2021 Jul 1;27(13):3641-3648. doi: 10.1158/1078-0432.CCR-21-0159. Epub 2021 Apr 21.
Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response.
Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level.
Forty patients were treated for a median duration of four cycles (range, 1-35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2-20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1-17.1) and median PFS (2.8 months; 95% CI, 2.7-4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs.
In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.
小肠腺癌（SBA）较为罕见，对于一线 FOLFOX/CAPOX 方案治疗后的转移性疾病，尚无标准的治疗方法。与其他胃肠道癌症相比，SBA 的微卫星不稳定性（MSI-H）和 T 淋巴细胞浸润率更高。我们假设 PD-1 抑制剂 pembrolizumab 可诱导抗肿瘤反应。
先前接受过治疗的晚期 SBA 患者接受 pembrolizumab 200mg，静脉输注，每 3 周一次，直至疾病进展（PD）、毒性或最多 35 个剂量。主要终点是确认总体缓解率（ORR），次要终点为无进展生存期（PFS）、总生存期（OS）和毒性评估。根据肿瘤位置、微卫星稳定性（MSS）或不稳定性（MSI-H）和 PD-L1 水平对结果进行分层。
40 名患者接受了中位数为 4 个周期（范围 1-35）的治疗。由于 PD（75%）、死亡（10%）、完成 35 个周期（8%）、拒绝（3%）和不良事件（AEs，5%），所有患者均停止了研究治疗。3 例确认的部分缓解[PR；8%；95%置信区间（CI），2-20]未达到 ORR 30%的预定成功标准。中位 OS（7.1 个月；95%CI，5.1-17.1）和中位 PFS（2.8 个月；95%CI，2.7-4.2）在原发肿瘤部位相似。在低 MSS/MSI 肿瘤患者中观察到 1 例确认的 PR（3%），与高肿瘤突变负荷（TMB）相关。50%的 MSI-H 肿瘤患者获得 PR 且无进展生存。25 名患者（63%）出现≥3 级 AEs，11 名患者（28%）出现 4/5 级 AEs。
在迄今为止最大的 SBA 研究中，pembrolizumab 并未诱导预期的缓解率；然而，我们确实在关键生物标志物选择的队列中发现了反应。
