(P 95) THE TETRAVALENT DEATH RECEPTOR 5 AGONIST OZEKIBART (INBRX-109) IN PATIENTS WITH CHONDROSARCOMA: UPDATED RESULTS FROM A PHASE 1 STUDY

Objective: A member of the tumor necrosis factor (TNF) receptor superfamily, death receptor 5 (DR5) binds TNF-related apoptosis-inducing ligand, resulting in receptor multimerization and induction of apoptosis. Greater clustering of activated DR5 can increase proapoptotic signaling. DR5 is predominantly expressed on tumor cells vs normal cells and is an attractive target for cancer drug development. INBRX-109 is a next-generation, recombinant, humanized, tetravalent DR5 agonist that is based on a single-domain antibody platform and precisely engineered for optimal agonism and safety. INBRX-109 is currently being evaluated in a phase 1 study (NCT03715933) in patients with diverse solid tumors, including chondrosarcoma (CS), a tumor type generally resistant to chemotherapy and radiation. In previous results from this study (Subbiah et al. Clin Cancer Res. 2023), INBRX-109 had an acceptable safety profile in unresectable or metastatic CS (conventional and nonconventional) and demonstrated clinical benefit, with an increase in median progression-free survival (PFS) and disease control rate compared with historical data. We present updated results for patients with CS in this trial (data cutoff: December 1, 2023).

Methods: This is a 3-part, open-label, phase 1 trial. Part 1 (dose escalation; completed) included 1 patient with CS (no known IDH mutation) who received 10 mg/kg IV every 3 weeks (q3w) INBRX-109 in cohort A4. The remaining patients with CS in this analysis were enrolled in part 2 (dose expansion), in cohorts B4 (any subtype or histological grade CS), B6 (IDH1 [R132]- or IDH2 [R172]-mutant conventional CS, grade 2 or 3), or B7 (nonconventional CS), and received 3 mg/kg IV q3w INBRX-109. Part 3 (combination with chemotherapy; dose expansion) is ongoing in multiple tumor types. Demographics and efficacy analyses are presented for evaluable patients with CS (n=54). Safety analyses are presented for all patients with CS (n=55) and all patients on trial (N=218). The primary endpoint is safety; secondary endpoints are pharmacokinetics and immunogenicity. Response by RECIST v1.1 and median PFS are exploratory endpoints.

Results: Of the 54 evaluable patients with CS, 70.4% were male, and median age was 57.5 years; 59.3% had conventional CS, and 24.1% had an IDH1/2 mutation (Table). Most patients (88.9%) had metastatic disease; 74.1% had received prior systemic therapy.

The safety profile of INBRX-109 in CS (n=55) was largely unchanged from the previous analysis. The most common (≥5%) treatment-related adverse events (TRAEs) were increased AST (10.9%), increased ALT (9.1%), fatigue (9.1%), and increased blood bilirubin (5.5%). Increased blood bilirubin was the only grade ≥3 TRAE reported in more than 1 patient (n=2; 3.6%). The incidence of TRAEs in patients with CS was generally similar to or lower than that in the total study population (N=218).

INBRX-109 continued to demonstrate clinical activity in patients with CS (Figure). More than half of patients (52.1%) had reduction or stabilization of target lesions, including those with IDH-mutated CS. The median PFS in patients with IDH wild type/unknown or IDH-mutated CS was 7.42 and 6.21 months, respectively.

Additional follow-up data will be presented at the meeting.

Conclusion: Consistent with the prior analysis, INBRX-109 was found to be well tolerated, and no new safety signals were observed. INBRX-109 continued to demonstrate encouraging clinical efficacy in patients with unresectable or metastatic CS, regardless of IDH mutation status, and median PFS remained greater compared to historical data ( < 4 months). These results are being confirmed in a randomized, blinded, placebo-controlled, phase 2 trial of INBRX-109 in unresectable or metastatic conventional CS (ChonDRAgon, NCT04950075), which is currently enrolling in the US, Europe, and Australia. INBRX-109 is also being evaluated in the phase 1 study in Ewing sarcoma and SDH-deficient GIST.