742 Phase 1/2 study of the bispecific 4–1BB and PD-L1 antibody INBRX-105 alone and in combination with pembrolizumab in select solid tumors

<h3>Background</h3> 4–1BB is a costimulatory receptor upregulated on tumor-infiltrating lymphocytes. 4–1BB signaling promotes T-cell proliferation and activation and decreases T-cell exhaustion. 4–1BB agonists have shown promising antitumor activity but have been limited by hepatotoxicity resulting from systemic 4–1BB activation. INBRX-105 is a 4–1BB×PD-L1 bispecific antibody designed to localize 4–1BB costimulatory signaling to PD-L1-rich environments. INBRX-105 consists of 2 agonistic 4–1BB single-domain antibodies (sdAbs) and 2 PD-L1 sdAbs, which allow anchoring to PD-L1. Cross-linking of PD-L1 to 4–1BB by INBRX-105 leads to conditional 4–1BB activation at sites of high PD-L1 expression, potentially limiting toxicities associated with prior 4–1BB agonists. In mouse tumor models, an INBRX-105 surrogate (INBRX-105-a) exhibited antitumor efficacy and increased T-cell frequency in the tumor microenvironment.¹ Robust proliferation of CD8⁺ T effector memory cells was observed intratumorally and in peripheral blood. INBRX-105-a plus a PD-1 antagonist resulted in greater inhibition of tumor growth. We describe a phase 1/2 study (NCT03809624) of INBRX-105 alone and in combination with pembrolizumab in patients with solid tumors. <h3>Methods</h3> This open-label, 4-part study of INBRX-105±pembrolizumab in locally advanced unresectable/metastatic solid tumors (N≈300) is enrolling in the US (figure 1). Dose escalation (part 1, INBRX-105 single agent; part 3, combination) was completed. INBRX-105 is being assessed in dose-expansion cohorts (part 2, INBRX-105 single agent; part 4, combination). Patients naive to 4–1BB agonists with disease that progressed despite standard therapy or who have no alternative treatment options (except checkpoint inhibitor [CPI]-naive cohorts) were included. Part 2a (recommended phase 2 dose [RP2D] expansion) consists of 4 cohorts: non-small cell lung cancer (NSCLC; PD-L1+), melanoma/solid tumors, head and neck squamous cell carcinoma (HNSCC), and other solid tumors (PD-L1+). Part 2b includes PD-L1-high HNSCC (including nasopharyngeal carcinoma). All part 2 cohorts, except melanoma (noncutaneous)/solid tumors, were CPI relapsed/refractory. PD-L1+ NSCLC (part 2a) and PD-L1-high HNSCC (part 2b) cohorts were opened based on encouraging early single-agent activity. Cohorts are enrolling and complete data readouts are forthcoming. Part 4 consists of CPI-relapsed/refractory cohorts (PD-L1+ NSCLC, cutaneous melanoma, PD-L1+ HNSCC, microsatellite instability-/tumor mutation burden-high or mismatch repair-deficient solid tumors) and CPI-naive cohorts (PDL1+ NSCLC and HNSCC). PD-L1 immunohistochemistry scores are required in parts 2 and 4, with threshold scores defined per protocol. Primary objectives are safety and determination of the maximum tolerated dose and/or RP2D of INBRX-105 as monotherapy and with pembrolizumab. Secondary objectives include pharmacokinetics, immunogenicity, and preliminary antitumor activity per RECIST. <h3>Trial Registration</h3> Clinicaltrials.gov identifier, NCT03809624 <h3>Reference</h3> Kinkead H, Macedo C, Sanabria A, <i>et al.</i> Key pharmacokinetic and pharmacodynamic parameters that correlate with the anti-tumor activity of a bispecific PD-L1 conditional 4–1BB agonist. <i>J Immunother Cancer</i>. 2021;<b>9</b>. Abstract 12. <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.