ozekibart (INBRX-109)

In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib...Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis.

P2, N=201, Recruiting, Inhibrx Biosciences, Inc | Trial completion date: Jul 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Sep 2025

P1, N=321, Recruiting, Inhibrx Biosciences, Inc | N=240 --> 321 | Trial completion date: Jul 2026 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Jun 2026

Among new approaches, DR5 agonists such as INBRX-109 have shown single-agent efficacy, with minimal toxicity, opening possibilities for use in combination therapies to improve outcomes...The integration of multi-targeted approaches could enhance efficacy, address tumour heterogeneity, and overcome resistance, presenting a hopeful direction for systemic therapy in this challenging cancer. The investigation of combination regimens with IDH inhibitors, immunotherapy and DR5 agonists hold promise for transforming the management of advanced chondrosarcoma.

The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death...There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies. In vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

P2, N=201, Recruiting, Inhibrx, Inc. | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P1, N=240, Recruiting, Inhibrx, Inc. | Trial completion date: Dec 2024 --> Jul 2026 | Trial primary completion date: Aug 2024 --> Dec 2025

INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase 2 trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.

Irinotecan (IRI) and temozolomide (TMZ) are frequently used in the relapsed setting, but prognosis remains poor. 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.

Herein, we report that SDH-def tumors are sensitive to TMZ, which induces ER stress and upregulates DR5, a pro-apoptotic receptor that can be targeted by INBRX-109 (Figure 1). In turn, TMZ+INBRX-109 additively/synergistically reduces SDH-def GIST cell viability in vitro. These data provide the preclinical evidence for a Phase I clinical trial (3+3 dose escalation design with two dosing cohorts, NCT03715933) to study the safety/tolerability of TMZ+INBRX-109 in patients with aggressive SDH-def cancers, including GIST (Figure 2).

Designed to achieve a best-in-class therapeutic index, INBRX-109 induces robust apoptosis of cancer cells in vitro and in vivo while sparing healthy tissues. INBRX-109 was well tolerated and had anti-tumor activity in unresectable/metastatic conventional chondrosarcoma in a phase I study and is currently being evaluated in a blinded, placebo-controlled pivotal phase II trial.

Additionally, INBRX-109 used in combination with SN-38, the active metabolite of irinotecan (IRI), demonstrated synergistic activity across multiple ES model cell lines...Initiation of an ES expansion cohort to explore INBRX-109 combined with IRI and temozolomide (IRI/TMZ) is under way. 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)... This is a trial in progress. No conclusions can be drawn at this time.