Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma.

Autor:	Subbiah V; 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., Chawla SP; Sarcoma Oncology Research Center, Santa Monica, California., Conley AP; Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wilky BA; Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado., Tolcher A; NEXT Oncology, San Antonio, Texas., Lakhani NJ; START Midwest, Michigan., Berz D; Valkyrie Clinical Trials, Los Angeles, California., Andrianov V; Inhibrx, Inc, La Jolla, California., Crago W; Inhibrx, Inc, La Jolla, California., Holcomb M; Inhibrx, Inc, La Jolla, California., Hussain A; Inhibrx, Inc, La Jolla, California., Veldstra C; Inhibrx, Inc, La Jolla, California., Kalabus J; Inhibrx, Inc, La Jolla, California., O'Neill B; Inhibrx, Inc, La Jolla, California., Senne L; Inhibrx, Inc, La Jolla, California., Rowell E; Inhibrx, Inc, La Jolla, California., Heidt AB; Inhibrx, Inc, La Jolla, California., Willis KM; Inhibrx, Inc, La Jolla, California., Eckelman BP; Inhibrx, Inc, La Jolla, California.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Aug 15; Vol. 29 (16), pp. 2988-3003.
DOI:	10.1158/1078-0432.CCR-23-0974
Abstrakt:	Purpose: 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). Patients and Methods: 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. Results: 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%). Conclusions: 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. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu