Bauman Julie E, Julian Ricklie, Saba Nabil F, Wise-Draper Trisha M, Adkins Douglas R, O'Brien Paul, Fidler Mary Jo, Gibson Michael K, Duvvuri Umamaheswar, Heath-Chiozzi Margo, Alvarado Diego, Gedrich Richard, Golden Philip, Cohen Roger B
Division of Hematology/Oncology, Department of Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
Division of Hematology/Oncology, Department of Medicine, GW Cancer Center, The George Washington University, Washington, DC 20052, USA.
Cancers (Basel). 2022 May 10;14(10):2355. doi: 10.3390/cancers14102355.
In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the -mutated versus 0/17 (0%; 95% CI: 0-19.5) in the -wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the hypothesis warrant consideration.
在I期开发中，抗ErbB3单克隆抗体CDX-3379在头颈部鳞状细胞癌（HNSCC）中单独或与西妥昔单抗联合使用时，显示出有前景的分子活性和抗肿瘤活性。初步生物标志物数据提出了在携带 突变的肿瘤中反应增强的假设。这项II期多中心试验采用Simon两阶段设计，研究CDX-3379和西妥昔单抗对30例复发/转移性、人乳头瘤病毒（HPV）阴性、西妥昔单抗耐药的HNSCC患者的疗效。主要终点是客观缓解率（ORR）。次要终点包括有体细胞 突变患者的ORR、无进展生存期（PFS）、总生存期（OS）和安全性。2018年3月至2020年9月共招募了30例患者。基因组未筛选患者的ORR为2/30（6.7%；95%置信区间[CI]，0.8 - 22.1）。中位PFS和OS分别为2.2个月（95% CI：1.3 - 3.6）和6.6个月（95% CI：2.7 - 7.5）。27例患者有组织样本，其中包括两名缓解者之一。 突变队列的ORR为1/10（完全缓解；10%；95% CI 0.30 - 44.5），而野生型队列的ORR为0/17（0%；95% CI：0 -
