Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2022 May;10(5). doi: 10.1136/jitc-2022-004822.
Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP.
The study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs)).
Among 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response.
Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile.
NCT02721732.
癌症原发灶不明（CUP）是一种侵袭性罕见恶性肿瘤，治疗选择有限。目前缺乏关于免疫检查点抑制剂在 CUP 中的临床活性的数据。因此，我们评估了 pembrolizumab（一种程序性死亡-1 抑制剂）在 CUP 患者中的疗效。
该研究设计为独立罕见肿瘤队列的 2 期篮子试验，包括 CUP。既往全身治疗进展、表现状态 0/1 和根据实体瘤反应评估标准（RECIST V.1.1）可测量疾病的 CUP 成年患者符合条件。患者接受 pembrolizumab（200mg）静脉注射，每 21 天一次。2016 年 8 月至 2020 年 6 月期间共招募了 29 名患者并进行了治疗。主要终点为 27 周时的无进展率（NPR-27），按免疫相关 RECIST 评估。主要预设次要终点为确认客观缓解率（ORR）、安全性、缓解持续时间（DoR）、无进展生存期（PFS）和总生存期（OS）。对预处理活检进行了反应生物标志物（程序性死亡配体-1（PD-L1）表达和肿瘤浸润淋巴细胞（TILs））的检查。
在 29 名入组和可评估的合格患者中，有 25 名（占 25%）患者存在低分化癌。患者在入组前接受了中位数为两线的治疗。中位随访时间为 27.3 个月。在 7 名患者（28.0%（95%CI：12.1%至 49.4%））中观察到 NPR-27。ORR 为 20.0%（95%CI：6.8%至 40.7%），5 名患者获得免疫相关部分缓解，DoR 中位数为 14.7 个月（95%CI：9.8 至 19.6）。中位 PFS 和 OS 分别为 4.1（95%CI：3.1 至 5.1）和 11.3（95%CI：5.5 至 17.1）个月。任何级别的治疗相关不良事件发生率为 19 例（76%），≥3 级的治疗相关不良事件发生率为 4 例（16%）。1 例（4%）患者发生 3 级免疫相关急性肾损伤，需要停药。PD-L1 和 TILs 均与 NPR-27 无关。阳性 PD-L1 染色（44.4%比 6.3%；p=0.040）和密集 TIL 浸润（44.4%比 6.3%；p=0.040）均与反应相关。
pembrolizumab 在 CUP 患者中显示出令人鼓舞的疗效，安全性良好。
NCT02721732。
