BACKGROUND MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC. METHODS In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional. RESULTS The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed. CONCLUSIONS Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.

中文翻译：

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一项 tivantinib 加西妥昔单抗与西妥昔单抗治疗复发/转移性头颈部鳞状细胞癌患者的随机 2 期网络试验。

背景 MET 信号转导是一种很好的描述抗 EGFR 治疗耐药的机制，并且 MET 过表达在头颈部鳞状细胞癌 (HNSCC) 中很常见。在目前的试验中，作者在复发/转移性 HNSCC 患者中比较了口服 MET 抑制剂 tivantinib (ARQ197) 与西妥昔单抗 (TC 组) 与接受西妥昔单抗单药治疗 (C) 的对照组。方法 共有 78 名可评估的西妥昔单抗初治、铂类难治性 HNSCC 患者入组，其中 TC 组 40 名，C 组 38 名（按人乳头瘤病毒 [HPV] 状态分层）。患者接受每日两次口服 tivantinib 360 mg 和每 2 周一次静脉注射西妥昔单抗 500 mg/m2。主要结果是反应率（根据实体瘤反应评估标准，版本 1.1），次要结局包括无进展生存期和总生存期。患者在 C 臂上进展后，可选择 tivantinib 单药治疗。结果 TC 组的反应率为 7.5%（N = 3；1 个完全反应），C 组为 7.9%（N = 3；无显着差异 [NS]）。两组的中位无进展生存期为 4 个月 (NS)，中位总生存期为 8 个月 (NS)。两种治疗均具有良好的耐受性，TC 组的血液学毒性有增加的趋势（12.5% 有 3 级白细胞减少症）。31 名 HPV 阳性/p16 阳性患者的反应率为 0%，而 HPV 阴性患者的反应率为 12.7%（TC 组为 12.5%，C 组为 13%）。15 名患者接受了 tivantinib 单药治疗，未观察到反应。结论 与单独使用西妥昔单抗相比，联合 tivantinib 加西妥昔单抗并未显着提高缓解率或生存率，但在未选择的 HNSCC 人群中确实增加了毒性。西妥昔单抗反应似乎仅限于 HPV 阴性 HNSCC 患者。针对 HNSCC 的 MET 畸变试验和更高效力的选择性 MET 抑制剂的使用仍然令人感兴趣。