2. Academic Validation
  3. Preclinical Characterization and Phase 1 Trial Results of INBRX-109, a Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma

Preclinical Characterization and Phase 1 Trial Results of INBRX-109, a Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma

  • Clin Cancer Res. 2023 Jun 2;CCR-23-0974. doi: 10.1158/1078-0432.CCR-23-0974.
Vivek Subbiah 1,  Sant P Chawla 2,  Anthony P Conley 3,  Breelyn A Wilky 4,  Anthony Tolcher 5,  Nehal J Lakhani 6,  David Berz 7,  Vasily Andrianov 8,  William Crago 8,  Monica Holcomb 8,  Abrahim Hussain 8,  Carson Veldstra 8,  James Kalabus 9,  Brianne O'Neill 8,  Lane Senne 10,  Emily Rowell 8,  Analeah B Heidt 8,  Katelyn M Willis 11,  Brendan P Eckelman 12
Affiliations

Affiliations

  • 1 Sarah Cannon, Nashville, TN, United States.
  • 2 Sarcoma Oncology Center, Santa Monica, California, United States.
  • 3 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • 4 University of Colorado School of Medicine, Aurora, CO, United States.
  • 5 South Texas Accelerated Research Therapeutics, San Antonio, TX, United States.
  • 6 START Midwest, Grand Rapids, Michigan, United States.
  • 7 Valkyrie Clinical Trials, United States.
  • 8 Inhibrx, Inc, United States.
  • 9 Inhibrx, Inc, San Diego, United States.
  • 10 Inhibrx, Inc, La Jolla, United States.
  • 11 Inhibrx, Inc, La Jolla, CA, United States.
  • 12 Inhibrix, San Diego, CA, United States.
PMID: 37265425 DOI: 10.1158/1078-0432.CCR-23-0974
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 of 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.

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