Keam Bhumsuk, Hong Min Hee, Shin Seong Hoon, Heo Seong Gu, Kim Ji Eun, Ahn Hee Kyung, Lee Yun-Gyoo, Park Keon-Uk, Yun Tak, Lee Keun-Wook, Kim Sung-Bae, Lee Sang-Cheol, Kim Min Kyoung, Cho Sang Hee, Oh So Yeon, Park Sang-Gon, Hwang Shinwon, Nam Byung-Ho, Kim Sangwoo, Kim Hye Ryun, Yun Hwan Jung
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
J Clin Oncol. 2024 Feb 10;42(5):507-517. doi: 10.1200/JCO.22.02786. Epub 2023 Sep 12.
A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC.
In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment.
Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths.
To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.
对头颈部鳞状细胞癌（HNSCC）采用精确的肿瘤学治疗方法很有必要。我们针对铂类难治性复发和/或转移性HNSCC患者开展了一项基于基因组图谱的伞式试验。
在这项多中心、开放标签、单臂II期试验中，我们进行了靶向二代测序（NGS）。根据患者匹配的基因组图谱将其分配到各治疗组：1组，阿培利司，一种PIK3CA抑制剂；2组，波齐替尼，一种表皮生长因子受体/HER2抑制剂；3组，尼达尼布，一种成纤维细胞生长因子受体抑制剂；4组，阿贝西利，一种CDK4/6抑制剂。如果没有匹配的靶点，患者被分配到5组，度伐利尤单抗±曲美木单抗，抗PD-L1/细胞毒性T淋巴细胞相关抗原4抑制剂。当1-4组出现疾病进展（PD）时，允许交叉至5组。主要终点是研究者评估的1组疾病控制率（DCR）和2-5组的总缓解率（ORR）。
2017年10月至2020年8月期间，共纳入203例患者，包括交叉患者。1组的ORR为21.2%，DCR为65.6%。2组的ORR为0%，3组为 42.9%，4组为0%，5组为15.6%。对于使用度伐利尤单抗出现PD的情况，加用曲美木单抗，度伐利尤单抗+曲美木单抗的ORR为2.2%。每组的中位无进展生存期分别为3.4、3.2、5.6、1.6和1.7个月。中位总生存期分别为12.4、6.1、11.1、9. 1和12.7个月。总体而言，毒性特征可控，且没有与治疗相关的死亡。
据我们所知，本研究是首个使用匹配的分子靶向药物针对铂类难治性HNSCC开展的生物标志物驱动的伞式试验。我们发现基于NGS的基因组表型分析在方法上是可行的且适用的。
