使用西妥昔单抗抑制表皮生长因子受体 (EGFR) 是头颈鳞状细胞癌 (HNSCC) 的标准治疗方法。受体酪氨酸激酶 AXL、MET 和 VEGFR 的激活可介导对西妥昔单抗的耐药性。卡博替尼是一种针对 AXL/MET/VEGFR 的多激酶抑制剂 (MKI)，已在 HNSCC 临床前模型中表现出抗肿瘤活性。这项由研究者发起的 I 期试验评估了西妥昔单抗联合卡博替尼治疗复发/转移性 (R/M) HNSCC 患者的安全性和有效性。患者每天同时接受西妥昔单抗和卡博替尼治疗，周期为 28 天。使用 3  3 剂量递增设计，主要终点是确定卡博替尼的最大耐受剂量 (MTD)。次要终点包括总体缓解率 (ORR)、疾病控制率 (DCR)、无进展生存期 (PFS) 和总体生存期 (OS) 结果：在入组的 20 名患者中，大多数患者既往在接受免疫检查点抑制剂治疗后出现疾病进展（95 %)、铂类化疗 (95%) 和西妥昔单抗 (80%)。没有记录剂量限制性毒性，卡博替尼的 MTD 确定为 60 毫克。 65% 的患者发生了 ≥ 3 级不良事件（n = 13）。 ORR 为 20%，有 4 例部分缓解 (PR)。在未接受过西妥昔单抗的患者 (n = 4) 中观察到 2 例 PR，该亚组的 ORR 为 50%。在总体人群中，DCR 为 75%，中位 PFS 为 3.4 个月，中位 OS 为 8.1 个月。西妥昔单抗加卡博替尼在经重治疗的 R/M HNSCC 患者中表现出可控的毒性特征和初步疗效。西妥昔单抗与针对 AXL/MET/VEGFR 轴的 MKI 的组合值得进一步研究，包括在未使用过西妥昔单抗的患者中。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC.Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months.Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.Copyright © 2024 Elsevier Ltd. All rights reserved.