Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute; Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts.
Department of Medicine, The University of Chicago, Chicago, Illinois.
Clin Cancer Res. 2021 Jul 1;27(13):3556-3566. doi: 10.1158/1078-0432.CCR-20-4513. Epub 2021 Apr 5.
Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors.
This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days.
In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response.
ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted.
富含亮氨酸重复序列 15（LRRC15）在多种实体瘤的肿瘤微环境中的基质成纤维细胞中表达，可能是一种有前途的治疗靶点，特别是在肉瘤患者中，LRRC15 也由恶性细胞表达。ABBV-085 是一种针对 LRRC15 的单甲基奥瑞他汀 E 抗体药物偶联物，在临床前实验中显示出抗肿瘤疗效。在此，我们报告了 ABVV-085 单药或联合治疗成人肉瘤和其他晚期实体瘤患者的研究结果。
这是一项首次人体 I 期研究（NCT02565758），评估了 ABVV-085 的安全性、药代动力学/药效学和初步抗肿瘤活性。该研究由两部分组成：剂量递增和剂量扩展。ABBV-085 以 0.3 至 6.0mg/kg 的剂量静脉输注，每 14 天一次。
共入组 85 例患者；45 例患者接受了推荐的 3.6mg/kg ABVV-085 单药治疗扩展剂量，包括 10 例骨肉瘤和 10 例未分化多形性肉瘤（UPS）。最常见的治疗相关不良事件是疲劳、恶心和食欲下降。接受 3.6mg/kg 治疗的骨肉瘤/UPS 患者的总缓解率为 20%，包括 4 例确认的部分缓解。接受 3.6mg/kg 治疗的其他晚期癌症患者均无单药缓解。1 例接受 ABVV-085 联合吉西他滨治疗的患者获得部分缓解。
ABBV-085 在 3.6mg/kg、每 14 天给药的剂量下表现出安全且可耐受，在骨肉瘤和 UPS 患者中观察到初步抗肿瘤活性。鉴于这些孤儿恶性肿瘤存在巨大的未满足需求，进一步研究针对这些肉瘤中的 LRRC15 可能是合理的。
