(P 317) INBRX-109 IN EWING SARCOMA: PRECLINICAL RATIONALE FOR INITIATION OF A PHASE 1 CHEMOTHERAPY COMBINATION EXPANSION COHORT

Objective: INBRX-109 is a precisely engineered, single domain–based agonist antibody targeting death receptor 5 (DR5), 1 of 2 pro-apoptotic receptors for the trimeric tumor necrosis factor–related apoptosis–inducing ligand (TRAIL). The valency of INBRX-109 was empirically selected to include 4 DR5 binding domains to overcome the limitations of earlier-generation agonists, which lacked efficacy or failed due to hepatotoxicity, likely due to hyperclustering by antidrug antibodies (ADAs). INBRX-109 eliminates recognition by preexisting ADAs, lessening the potential for hyperclustering and hepatotoxicity. In preclinical analyses, INBRX-109 demonstrated potent anticancer activity against Ewing sarcoma (ES). In in vitro studies, INBRX-109 bound to several ES model cell lines with high affinity and induced potent cytotoxicity. It also showed antitumor activity in 15 patient-derived xenograft models of various tumor types, including ES. Additionally, INBRX-109 used in combination with SN-38, the active metabolite of irinotecan (IRI), demonstrated synergistic activity across multiple ES model cell lines. In in vivo studies, INBRX-109 and IRI coadministration significantly increased antitumor efficacy compared with single-agent treatment in an ES xenograft animal model; complete tumor regression was observed in all treated mice. INBRX-109 did not induce cell death in HepaRG cells (in the absence or presence of ADA) or in a liver toxicology model and was well tolerated in vivo, demonstrating no hepatotoxicity. These preclinical data suggest that DR5 agonism combined with IRI confers an added benefit, with INBRX-109–mediated DR5 crosslinking providing key pro-apoptotic signaling in in vitro and in vivo models of ES. Initiation of an ES expansion cohort to explore INBRX-109 combined with IRI and temozolomide (IRI/TMZ) is under way.

Methods: A 3-part, phase 1 study (NCT03715933) evaluating the safety and efficacy of INBRX-109 in patients with advanced/metastatic solid tumors was initiated in November 2018 (Figure). Part 1 (single-agent dose escalation) was completed in 2019. INBRX-109 was well tolerated, with no significant toxicities observed; a maximum tolerated dose was not reached, and a dose of 3 mg/kg was chosen for further investigation. Part 2 (single-agent expansion) and part 3 (combination therapy expansion) will evaluate safety as a primary endpoint and pharmacokinetics, immunogenicity, and efficacy as secondary endpoints. Potential predictive diagnostic biomarkers of INBRX-109 will also be explored. A chemotherapy combination cohort in ES opened in September 2021 and will enroll 20 patients with locally advanced or metastatic, unresectable ES who have received ≥1 prior lines of treatment with a preferred first-line chemotherapy regimen (eg, VDC/IE, VAI, VIDE, VDC) and who are candidates for IRI/TMZ given as second-, third-, or fourth-line therapy. INBRX-109 (1 or 3 mg/kg intravenously [IV], day 1) will be administered in combination with IRI (50 mg/m2/day IV, days 1-5) and TMZ (100 mg/m2/day orally, days 1-5) every 21 days. The starting dose of INBRX-109 will be 1 mg/kg in the first safety lead-in cohort and 3 mg/kg in the second. Escalation to 3 mg/kg will only occur once approved by the safety review committee. IRI/TMZ can be stopped after ≥6 cycles at investigator discretion due to the potential risk of accumulating toxicities; INBRX-109 treatment will continue. Other chemotherapy combination cohorts, including succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST), are also now enrolling (Figure).

Results: Preclinical anticancer activity warrants further investigation of INBRX-109 in combination with IRI-based chemotherapy in unresectable or metastatic ES. Part 3 (combination therapy expansion) is currently enrolling multiple tumor types, including ES and SDH-deficient GIST.

Conclusion: This is a trial in progress. No conclusions can be drawn at this time.

34023183_CTOS_2022_Ph1_Ewing_TiP_R3.pdf