(P 315) A RANDOMIZED, PLACEBO-CONTROLLED, PHASE 2 TRIAL OF INBRX-109 IN UNRESECTABLE OR METASTATIC CONVENTIONAL CHONDROSARCOMA

Objective: Outcomes in patients with unresectable or metastatic conventional chondrosarcoma (CS) remain poor since CS is generally resistant to chemotherapy, radiation, and molecular targeted agents. The expected progression-free survival (PFS) is < 4 months. INBRX-109 is a third-generation, tetravalent, agonistic antibody that targets human death receptor 5 (DR5), 1 of 2 pro-apoptotic receptors for the trimeric tumor necrosis factor–related apoptosis–inducing ligand (TRAIL). TRAIL selectively induces apoptosis in cancer cells while sparing normal tissues. The valency of INBRX-109 was empirically selected to include 4 DR5 binding domains to overcome the hyperclustering and subsequent hepatotoxicity of earlier-generation agonists. INBRX-109 potently stimulates DR5 through efficient receptor clustering, resulting in cell death, and eliminates recognition by preexisting antidrug antibodies. As of October 1, 2021, 20 patients with conventional CS were treated with INBRX-109 as part of an ongoing phase 1 dose-escalation study (NCT03715933). Of the 18 evaluable patients, 2 (11%) achieved a partial response and 14 (78%) had stable disease; the disease control rate (partial response + stable disease) was 89% (16/18). Notably, 11 of 18 patients (61%) had a reduction in the sum of target lesions, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; 6 patients (33%) had a decrease of ≥10%. Median PFS was 7.4 months. Among all 116 patients treated with INBRX-109, any grade of hepatotoxicity was observed in 13 patients (11%); higher grade (ie, grade ≥3) liver-related adverse events occurred in 5.2% of patients. The pharmacokinetics of INBRX-109 was approximately dose proportional across doses and supports dosing every 3 or 4 weeks without premedication. These findings support further evaluation of INBRX-109 in unresectable or metastatic CS.

Methods: ChonDRAgon (NCT04950075) is a multicenter, randomized, blinded, placebo-controlled phase 2 study of INBRX-109 in patients with grade 2 or 3 unresectable or metastatic conventional CS who are aged ≥18 years and have an Eastern Cooperative Oncology Group performance status of ≤1 (Figure). Inclusion criteria allow any prior lines of therapy, except for DR5 agonists. Patients with chronic liver disease, including nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD), are excluded; however, patients with NAFLD aged < 64 years are eligible if adequate hepatic function is confirmed. Approximately 201 patients will be randomized 2:1 to INBRX-109 (3 mg/kg intravenously, every 3 weeks) or placebo and stratified by histological grade (2 vs 3), isocitrate dehydrogenase (IDH) 1 R132/IDH2 R172 mutation status (wild type vs mutation), and lines of therapy (none vs prior). Treatment will continue until disease progression or unacceptable toxicity occurs. If disease progression occurs on placebo, participants can cross over to open-label INBRX-109. The primary endpoint is PFS per RECIST 1.1, as assessed by central real-time independent radiology review (IRR) in the intention-to-treat population. Secondary endpoints are overall survival, PFS by investigator assessment, quality of life, overall response rate, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity. Efficacy in patients who cross over to INBRX-109 will also be assessed but will not require central real-time IRR. Adverse events will be graded by Common Terminology Criteria for Adverse Events version 5.0.

Results: The randomized phase 2 ChonDRAgon study will evaluate INBRX-109 in unresectable or metastatic conventional CS. The study will be conducted across 51 sites in the US and Europe. Enrollment is ongoing; 28 sites are now active, and 14 patients have been randomized.

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

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