(P 439) THE TETRAVALENT DEATH RECEPTOR 5 AGONIST INBRX-109 COMBINED WITH CHEMOTHERAPY IN EWING SARCOMA: PRELIMINARY DATA FROM A PHASE 1 STUDY

Objective: Ewing sarcoma (EWS) and desmoplastic small round cell tumor (DSRCT) are rare, aggressive tumors that occur in children and adults and are frequently metastatic at diagnosis. Relapse is common, and few effective treatments are available. Irinotecan (IRI) and temozolomide (TMZ) are frequently used in the relapsed setting, but prognosis remains poor.

INBRX-109 is a tetravalent, agonistic antibody targeting death receptor 5 (DR5), a proapoptotic TRAIL receptor. INBRX-109 is based on a single-domain antibody platform and is precisely engineered to achieve optimal balance of agonism and safety. INBRX-109 includes 4 DR5-binding domains to potently agonize DR5 through efficient receptor clustering and minimizes recognition by preexisting antidrug antibodies (ADAs), lessening the potential for hyperclustering and hepatotoxicity.

In preclinical analyses, INBRX-109+IRI significantly increased antitumor activity in an EWS xenograft model compared with either agent alone and led to complete tumor regression in all treated mice. INBRX-109+IRI/TMZ is being explored in patients (pts) with EWS and DSRCT as part of an ongoing phase 1 study (NCT03715933). We present preliminary findings from this cohort.

Methods: This 3-part study is evaluating INBRX-109 in advanced/metastatic solid tumors. Part 1 (single-agent dose escalation) was completed. INBRX-109 was well tolerated, with no significant toxicities observed; a maximum tolerated dose was not reached, and a 3-mg/kg dose was chosen for further investigation. Part 2 (single-agent expansion) and part 3 (combination therapy expansion) are ongoing. In part 3, INBRX-109+IRI/TMZ was examined in pts with advanced/metastatic, unresectable EWS or DSRCT who had received 1-4 prior lines of treatment with ≥1 first-line chemotherapy regimen (cohort C3). INBRX-109 (1 or 3 mg/kg intravenously [IV]; day 1) was administered with IRI (50 mg/m²/day IV; days 1-5) and TMZ (100 mg/m²/day orally; days 1-5) every 21 days. Starting dose of INBRX-109 was 1 mg/kg in the first safety lead-in (cohort C3A) and 3 mg/kg in the second (cohort C3B). Intrapatient escalation from 1 to 3 mg/kg in cohort C3A occurred after safety review committee approval. IRI/TMZ could be stopped after ≥6 cycles at investigator discretion due to potential risk of accumulating toxicities; INBRX-109 was continued. The primary endpoint was safety; pharmacokinetics (PK), immunogenicity, and efficacy were secondary endpoints.

Results: As of data cutoff (May 1, 2023), 10 pts (EWS, n=7; DSRCT, n=3) had received INBRX-109 in cohort C3: C3A (1 mg/kg), n=7 (1→3 mg/kg, n=4); C3B (3 mg/kg), n=3. Five pts were still receiving treatment (C3A [3 mg/kg], n=2; C3B, n=3). Median age was 35 y (range, 21-71 y), and pts had received a median of 2 prior lines of therapy (prior IRI and/or TMZ, n=3).

Consistent with the known safety profile of IRI/TMZ, the most common adverse events (AEs) were diarrhea (any grade, n=5; grade ≥3, n=2), fatigue (n=5; n=0), and decreased platelet count (n=5; n=2). One pt had increased alanine aminotransferase (grade 1); no other liver-related AEs were reported.

INBRX-109+IRI/TMZ demonstrated preliminary efficacy, with an overall response rate (ORR) of 60% (all confirmed partial responses [PRs]) and a disease control rate of 80%. Overall, 71% of pts with EWS (5 of 7) and 33% of pts with DSRCT (1 of 3) achieved PRs. Notably, a response was observed in 1 pt who had disease progression while receiving prior IRI or TMZ. Most pts with tumor shrinkage at first scan post treatment had further decreases in tumor size with continued treatment. Preliminary immunogenicity data suggest no impact of ADAs on PK.

Conclusion: INBRX-109+IRI/TMZ led to high response rates in pts with EWS (71%) and DSRCT (33%), with an ORR of 60% in cohort C3; no grade ≥2 hepatotoxicity or significant AEs leading to discontinuation were observed. Our findings support further evaluation of INBRX-109+IRI/TMZ in these tumors. Cohort C3C is now enrolling (n≈10) at the RP2D of 3 mg/kg. Updated data will be presented.