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
  • 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.

Products