Background 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.
Methods 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.
Trial Registration Clinicaltrials.gov identifier, NCT03809624
Kinkead H, Macedo C, Sanabria A, et al. Key pharmacokinetic and pharmacodynamic parameters that correlate with the anti-tumor activity of a bispecific PD-L1 conditional 4–1BB agonist. J Immunother Cancer. 2021;9. Abstract 12.
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