748 Phase 1/2 study of the hexavalent OX40 agonist INBRX-106 alone and in combination with pembrolizumab in select solid tumors

<h3>Background</h3> OX40 is a member of the TNF receptor superfamily and a key costimulatory molecule. OX40 signaling can increase T-cell survival, augment clonal expansion of antigen-specific effector and memory T-cell populations, and inhibit regulatory T-cell–induced immunosuppression, making it an attractive therapeutic target. The endogenous trimeric OX40 ligand binds to 3 OX40 molecules to trigger downstream signaling; however, higher-order clustering of OX40 mediates more potent immune stimulation. INBRX-106 is an empirically designed, hexavalent, agonistic, single-domain antibody specific to OX40; the optimized valency of INBRX-106 can enhance OX40 clustering and elicit greater activation of pathways that promote antitumor immunity than bivalent and tetravalent agonists.¹ A murine INBRX-106 surrogate showed antitumor activity in mouse tumor models resistant or responsive to checkpoint inhibitors (CPIs). Combination with a PD-1 antagonist increased tumor growth inhibition. We describe a phase 1/2 study evaluating INBRX-106±pembrolizumab in select solid tumors. <h3>Methods</h3> This open-label, 4-part, phase 1/2 study (NCT04198766) of INBRX-106±pembrolizumab in patients with locally advanced unresectable or metastatic solid tumors (N≈333) is enrolling in the US (figure 1). Dose escalation (part 1, INBRX-106; part 3, combination) has been completed; the recommended phase 2 dose (RP2D) is being assessed in dose-expansion cohorts (part 2, INBRX-106; part 4, combination). Eligible patients are naive to OX40 agonists with disease that progressed despite all standard therapies or who have no alternative treatment options (except CPI-naive cohorts). Parts 2 and 4 include patients with non-small cell lung cancer (NSCLC), melanoma, head and neck squamous cell carcinoma, gastric or gastroesophageal junction adenocarcinoma, renal cell carcinoma, transitional (urothelial) cell carcinoma, or microsatellite instability (MSI)–/tumor mutation burden (TMB)–high solid tumors. In part 2, any PD-L1 combined positive score (CPS) is permitted in the 3 basket cohorts; patients in a fourth cohort (PD-L1+ NSCLC) require a tumor proportion score (TPS) ≥50% or TMB ≥10 mutations/Mb. Part 4 includes 2 PD-L1+ (CPS ≥1) basket cohorts (1 CPI relapsed/refractory; 1 CPI naive) and 2 CPI-relapsed/refractory PD-L1+ NSCLC cohorts (1 TPS ≥1%; 1 TPS ≥50% or TMB ≥10 mutations/Mb); 3 dosing regimens will be evaluated in the CPI-relapsed/refractory NSCLC cohort requiring TPS ≥50%. Additionally, a basket cohort of mismatch repair–deficient or MSI-high solid tumors and a cohort of uveal melanoma (both CPI relapsed/refractory) will be included. Primary objectives are safety and determination of the maximum tolerated dose and/or RP2D of INBRX-106±pembrolizumab. Secondary objectives include pharmacokinetics, immunogenicity, and preliminary antitumor activity per RECIST. <h3>Trial Registration</h3> ClinicalTrials.gov identifier, NCT04198766 <h3>Reference</h3> Rowell E, Kinkead H, Torretti E, <i>et al.</i> INBRX-106: A novel hexavalent anti-OX40 agonist for the treatment of solid tumors. <i>J Immunother Cancer</i>. 2021;<b>9</b>. Abstract 856. <h3>Ethics Approval</h3> The study protocol was reviewed and approved by the institutional review board at each participating institution; all patients provided written informed consent.