Division of Hematology and Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Clin Cancer Res. 2022 Mar 1;28(5):903-914. doi: 10.1158/1078-0432.CCR-21-2547.
Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.
Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.
Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.
Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.
程序性死亡受体-1（PD-1）受体抑制剂已在头颈部鳞状细胞癌（HNSCC）中显示出疗效，但大多数患者会出现治疗失败或继发耐药。在临床前鼠类癌模型中，抑制布鲁顿酪氨酸激酶（BTK）可诱导髓样细胞重编程，从而增强 CD8+T 细胞反应，进而增强抗肿瘤活性。这项 2 期、多中心、开放标签、随机研究评估了在复发性或转移性 HNSCC 患者中使用派姆单抗（抗 PD-1 单克隆抗体）联合阿卡替尼（BTK 抑制剂）的疗效。
患者每 3 周接受 200mg 静脉注射派姆单抗，单独使用或联合每日口服 100mg 阿卡替尼。安全性和总缓解率（ORR）是主要共同终点。次要终点是无进展生存期（PFS）和总生存期。
76 例患者接受了评估（派姆单抗组 39 例，派姆单抗+阿卡替尼组 37 例）。与单药治疗相比，联合治疗组更常见 3-4 级治疗相关不良事件（AE；65% vs. 39%）和严重 AE（68% vs. 31%）。单药治疗的 ORR 为 18%，联合治疗的 ORR 为 14%。联合治疗组的中位 PFS 为 2.7 个月（95%CI，1.4-6.8），单药治疗组为 1.7 个月（95%CI，1.4-4.0）。由于联合治疗无临床获益，该研究提前终止。为了评估在接受治疗前和治疗后活检的患者中肿瘤免疫微环境如何受到治疗的影响，进行了空间蛋白质组学分析，结果显示在第 43 天，派姆单抗（单药治疗组 n=5；联合治疗组 n=2）的肿瘤 CD45+白细胞浸润呈上升趋势，联合治疗组似乎更高；然而，由于样本量有限，无法得出明确的结论。
尽管缺乏临床疗效，但免疫亚群分析表明该联合用药具有附加作用；然而，相关毒性限制了在复发性或转移性 HNSCC 患者中联合使用派姆单抗和阿卡替尼的可行性。
