Tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) + FOLFIRI in 2L+ colorectal adenocarcinoma (CRC): Preliminary results from a phase 1 study.
Authors: David Berz, Olatunji B. Alese, David S. Hong, Nehal J. Lakhani, Elena Elez, Manish R Sharma, Brianne O'Neill, Yang Li, Emily Piccione, James Kalabus, Josep Garcia, Lee P. Hartner, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2025)

129 Background: DR5, a proapoptotic receptor, is selectively expressed on tumor vs normal cells, making it an attractive target. DR5 binds to its ligand, TRAIL, resulting in DR5 multimerization and apoptosis; greater DR5 clustering enhances downstream effects. Ozekibart is a next-generation, recombinant, humanized, tetravalent DR5 agonist that is based on a single-domain antibody platform and precisely engineered to balance agonism and safety. Ozekibart previously demonstrated an acceptable safety profile and clinical benefit in chondrosarcoma (1), prompting a phase 2, randomized trial (ChonDRAgon; NCT04950075). An ongoing phase 1 study (NCT03715933) is evaluating ozekibart in various solid tumors, including 2L+ CRC, for which effective therapies are lacking. We present preliminary results of ozekibart + FOLFIRI in 2L+ CRC (data cutoff: Aug 9, 2024). Methods: Parts 1 (single-agent dose escalation) and 2 (single-agent dose expansion; recommended phase 2 dose [RP2D] ozekibart 3 mg/kg IV Q3W) of this 3-part, open-label trial are complete. Part 3 (combination dose expansion with chemo) is ongoing in pts with CRC, Ewing sarcoma, or SDH-deficient GIST. Pts with locally advanced or metastatic, unresectable CRC who received oxaliplatin-based chemo were eligible for part 3. Pts with chronic liver disease were ineligible. Pts in the part 3 CRC cohorts (N=13; enrollment complete) received ozekibart 1 mg/kg (n=5) or 3 mg/kg (n=8) IV Q28D (1 cycle) + FOLFIRI Q14D (FOLFIRI could be stopped after ≥6 cycles); in 4/5 pts, ozekibart dose was escalated to 3 mg/kg (RP2D). The primary endpoint is safety; clinical response is an exploratory endpoint. Results: In total, 13 pts with CRC (male, 62%) received ozekibart + FOLFIRI. Median age was 60. All pts had metastatic disease; median number of prior lines of therapy was 2 (range, 1-6). At data cutoff, 2 pts remained on treatment. Ozekibart-related adverse events (AEs) were reported in 85% of pts (grade ≥3, 31%) and led to ozekibart interruption in 3 pts and discontinuation in 1 pt. One combo-related AE (neutropenic sepsis) led to death. The most common ozekibart-related AEs were nausea (n=5) and diarrhea, fatigue, and increased alanine aminotransferase (each n=4). Four pts (31%) had responses (all partial). Disease control rate (response + stable disease) was 77% (10/13) and durable (&gt;180 days) in 46% (6/13) of pts. Most pts had tumor shrinkage. Median PFS was 7.85 mo. Conclusions: Ozekibart + FOLFIRI showed encouraging preliminary efficacy, including PRs and durable disease control, as 2L+ therapy in pts with CRC. Given these promising data, a new expansion cohort (C4d) is open to validate these findings in a more homogeneous population. Eligible pts will have had 2 or 3 prior lines of systemic therapy (irinotecan allowed but not in the immediately prior line) and must have archival or fresh biopsy tissue. 1. Subbiah. Clin Cancer Res. 2023. Clinical trial information: NCT03715933 .