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Chondrosarcoma CS Foundation, Inc.

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    Preclinical Characterization and Phase 1 Trial Results of INBRX-109

    ABSTRACT
    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 1 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 1 study of solid tumors that 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 1 study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of120
    87.1% (27/31; durable clinical benefit, 40.7% [11/27]), including 2 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 2 trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.

    For More information: https://twitter.com/viveksubbiah/status/1664650580172722176?s=46

    Authors: Vivek Subbiah, 1 Sant P. Chawla, 2 Anthony P. Conley, 3 Breelyn A. Wilky, 4 Anthony Tolcher, 5 Nehal J. Lakhani, 6 David Berz, Vasily Andrianov, 8 William Crago, 8 Monica Holcomb, 8 Abrahim Hussain, 8 Carson Veldstra, 8 James Kalabus, 8 Brianne O’Neill, Lane Senne, 8 Emily Rowell,8 Analeah B. Heidt, 8 Katelyn M. Willis, 8 Brendan P. Eckelman