(P 041) UPDATED EFFICACY AND SAFETY OF THE TETRAVALENT DEATH RECEPTOR 5 AGONIST INBRX-109 IN PATIENTS WITH CHONDROSARCOMA: DATA FROM THE PHASE 1 EXPANSION COHORTS

Objective: Death receptor 5 (DR5) is a proapoptotic receptor that forms multimers on the cell surface and is activated after binding tumor necrosis factor–related apoptosis–inducing ligand (TRAIL). Preferentially expressed on tumor cells, DR5 is an attractive drug target. INBRX-109 is a third-generation, recombinant, humanized, agonistic antibody against DR5. To avoid hyperclustering and the hepatotoxicity observed with previous DR5 agonists, INBRX-109 was precisely engineered, with a valency of 4 DR5-binding domains empirically selected and immunogenic epitopes removed to prevent antidrug antibody (ADA)–mediated crosslinking. INBRX-109 has demonstrated efficacy in vitro and in patient (pt)-derived xenograft models of various cancers. The safety and tolerability of INBRX-109 were demonstrated in pts with diverse solid tumors during part 1 of a phase 1 study (NCT03715933). Here we provide updated results for pts with unresectable or metastatic chondrosarcoma (CS) in this trial.

Methods: The INBRX-109 phase 1 trial is an ongoing 3-part study. Part 1 (3+3 single-agent dose escalation) was completed in 2019; 1 pt from cohort A4 (10 mg/kg IV q3w; CS, no known IDH mutation) is included here. INBRX-109 was well tolerated; a maximum tolerated dose was not reached. In part 2 (single-agent dose expansion), INBRX-109 3 mg/kg IV q3w is being evaluated in several cancer types, including CS (cohort B4; any subtype or histological grade) and IDH1 (R132)- or IDH2 (R172)-mutant conventional CS (B6; grade 2 or 3). The primary endpoint is safety; secondary endpoints are pharmacokinetics and ADAs. Exploratory endpoints are efficacy—including response by RECIST v1.1 and median progression-free survival (PFS)—and potential predictive biomarkers. Part 3 (combination dose expansion) is currently enrolling multiple tumor types, including Ewing sarcoma and SDH-deficient GIST.

Results: A total of 33 pts with CS (A4, n=1; B4, n=22; B6, n=10) were included in the analysis (data cut: 26 May 2022). The A4 pt was aged 65 y; median age was 60 y (range, 25-86 y) in cohort B4 and 54 y (range, 21-67 y) in cohort B6. Most pts were male (A4 pt; B4, 77.3%; B6, 80.0%) and had prior systemic therapy (A4 pt; B4, 68.2%; B6, 90.0%); 78.8% of pts had stage IV cancer at baseline; 9/33 pts remain on study treatment.

The disease control rate (best overall response of complete response, partial response [PR], or stable disease [SD]) in pts evaluable for efficacy (A4, n=1; B4, n=22; B6, n=8) was 87.1% (27/31). Two pts achieved PR (6.5%), and 25 pts had SD (80.6%); 11 pts had durable disease control (>6 mo). Median PFS was 7.6 mo (range, 0.03-17.8; median follow-up, 11.6 mo) (Fig 1); 5 pts were treated for >12 mo (including 2 pts with IDH mutation); the longest duration of SD was 17.8 mo (Fig 2). Of 22 evaluable pts, the median Von Hoff ratio (Von Hoff JCO 2010), using a modified analysis of time to progression on INBRX-109 vs prior treatment duration, was 1.1; 7 pts had a ratio ≥1.5 (Fig 3).

Treatment-related adverse events (AEs; CTCAE v5) were predominantly grade 1/2 across all cohorts (N=149). Most pts (93.3%) had no or low-grade liver-related AEs that were treatment related; grade ≥3 were reported in 10 pts (6.7%), including 2 deaths, 1 in a pt with mesothelioma (acute hepatic failure) and 1 in a pt with IDH2 CS (B6; hepatic failure).

Additional follow-up will be presented at the meeting.

Conclusion: INBRX-109 demonstrated anticancer activity in unresectable or metastatic CS, regardless of IDH mutation status, with a longer median PFS compared with limited historical data (7.6 vs < 4 mo). Such tumor reductions are rarely observed in this indication, which lacks an effective systemic therapy. The observed safety profile was favorable and consistent with prior results. These updated findings support further evaluation of INBRX-109 in unresectable or metastatic CS. A randomized, blinded, placebo-controlled, phase 2 trial of INBRX-109 in this indication (ChonDRAgon, NCT04950075) is currently enrolling in the US and Europe.

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