Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sarah Cannon Research Institute, Nashville, Tennessee.
Sarcoma Oncology Research Center, Santa Monica, California.
Clin Cancer Res. 2023 Aug 15;29(16):2988-3003. doi: 10.1158/1078-0432.CCR-23-0974.
Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933).
INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS.
In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%).
INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
无法切除/转移性软骨肉瘤患者预后较差；传统软骨肉瘤患者在接受一线化疗后，无进展生存期（progression-free survival，PFS）中位数＜4 个月。目前尚无标准的靶向治疗方法。本研究介绍了第三代死亡受体 5（DR5）激动剂 INBRX-109 的临床前特征，以及 INBRX-109 治疗无法切除/转移性软骨肉瘤的 I 期临床试验的临床发现（NCT03715933）。
INBRX-109 首先被临床前鉴定为 DR5 激动剂，在体外评估其结合特异性和肝毒性，在体内和体外评估其抗肿瘤活性。INBRX-109（每 3 周 3mg/kg）在一项包含所有亚型软骨肉瘤和 IDH1/IDH2 突变型传统软骨肉瘤的实体瘤 I 期研究中进行了评估。主要终点为安全性。疗效为探索性终点，评估指标包括客观缓解率、疾病控制率和 PFS。
在临床前研究中，INBRX-109 在体外和患者来源的异种移植模型中显示出抗肿瘤活性，且肝毒性较小。在 I 期研究中，INBRX-109 具有良好的耐受性，并在无法切除/转移性软骨肉瘤中显示出抗肿瘤活性。INBRX-109 使疾病控制率达到 87.1%（27/31；40.7%的患者有持久的临床获益，27/31），包括 2 例部分缓解，中位 PFS 为 7.6 个月。大多数与治疗相关的不良事件，包括肝脏相关事件，均为低级别（软骨肉瘤队列中≥3 级事件为 5.7%）。
INBRX-109 对无法切除/转移性软骨肉瘤患者具有令人鼓舞的抗肿瘤活性，且安全性良好。一项随机、安慰剂对照的 II 期试验（ChonDRAgon，NCT04950075）将进一步评估 INBRX-109 在传统软骨肉瘤中的疗效。
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