Phase 1 study of the tetravalent death receptor 5 agonist ozekibart (INBRX-109) combined with chemotherapy in locally advanced or metastatic, unresectable colorectal adenocarcinoma (CRC).

Abstract

3533 Background: Patients with metastatic CRC are typically treated with fluorouracil-based chemotherapy in combination with leucovorin and irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). However, patients who progress after 2 lines of therapy have limited treatment options, with poor outcomes (response rates of ≤6%). Ozekibart (INBRX-109) is a next-generation, tetravalent death receptor 5 agonist that has demonstrated robust efficacy as a single agent in chondrosarcoma. Additionally, ozekibart in combination with FOLFIRI showed early signs of antitumor activity in a small cohort of patients with CRC in the ongoing INBRX-109 phase 1 study (NCT03715933) (Berz D, et al. J Clin Oncol. 2025. Abstract 129). Based on these findings, the CRC cohort in this study was expanded to include additional patients who had received 2 or 3 prior lines of systemic therapy. We present initial findings from this cohort. Methods: Ozekibart + FOLFIRI was examined in patients with locally advanced or metastatic, unresectable CRC in the expansion cohort C4d of the open-label, INBRX-109 phase 1 study. Eligible patients were aged 18 to < 85 years, had received 2 or 3 prior lines of systemic therapy, and had no chronic or acute liver disease. Previous irinotecan-containing regimens were allowed but not as an immediate prior line of therapy. Patients received ozekibart 3 mg/kg every 4 weeks + FOLFIRI every 2 weeks. Safety and clinical response were primary endpoints. Results: As of the data cutoff (October 15, 2025), 44 patients had received ozekibart + FOLFIRI in this cohort. Median age was 54.5 years (range, 29-77 years), and > 70% were in the fourth-line treatment setting; 81.8% had previously received an irinotecan-based regimen. Overall, 28 patients (63.6%) remain on treatment; 11 patients had disease progression, 1 patient discontinued due to adverse events (AEs), and 4 patients discontinued for other reasons. Among evaluable patients for response at data cutoff (n = 26), ozekibart + FOLFIRI led to an ORR of 23% (all partial responses) and a disease control rate of 92%. Consistent with the safety profile of FOLFIRI, the most common AEs (in > 25% of patients) were anemia (any grade, 36.4%; grade ≥3, 9.1%), diarrhea (34.1%; 9.1%), nausea (31.8%; 0%), fatigue (27.3%; 2.3%), and alopecia (27.3%; 0%). Increased alanine aminotransferase was the only grade ≥3 hepatotoxicity event and occurred in 1 patient. Conclusions: Ozekibart + FOLFIRI demonstrated encouraging preliminary efficacy in a heavily pretreated patient population with metastatic, unresectable CRC. The safety profile of ozekibart + FOLFIRI was manageable, with most AEs being low grade. Our findings support further evaluation of ozekibart + FOLFIRI in advanced CRC. Updated data will be provided at the time of presentation. Clinical trial information: NCT03715933 .