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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
  1. Jong Chul Park1,2,
  2. David Berz3,
  3. Manish Sharma4,
  4. Erminia Massarelli5,
  5. Ralph J Hauke6,
  6. Frank Yung-Chin Tsai7,
  7. David Hong8,
  8. Neal Akhave8,
  9. Justin A Call9,
  10. Jennifer Carlisle10,
  11. Rachel E Sanborn11,
  12. Naomi B Haas12,
  13. John Hamm13,
  14. D Ross Camidge14,
  15. Alexander I Spira15,
  16. Vasily Andrianov16,
  17. Brianne O’Neill16,
  18. Heather Kinkead16 and
  19. Anthony W Tolcher17
  1. 1Massachusetts General Hospital, Boston, MA, USA
  2. 2Harvard Medical School, Boston, MA, USA
  3. 3Valkyrie Clinical Trials, Los Angeles, CA, USA
  4. 4START Midwest, Grand Rapids, MI, USA
  5. 5City of Hope, Duarte, CA, USA
  6. 6Nebraska Cancer Specialists, Omaha, NE, USA
  7. 7HonorHealth, Scottsdale, AZ, USA
  8. 8The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  9. 9START Mountain Region, West Valley City, UT, USA
  10. 10Winship Cancer Institute of Emory University, Atlanta, GA, USA
  11. 11Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA
  12. 12Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
  13. 13Norton Healthcare, Louisville, KY, USA
  14. 14University of Colorado Cancer Center, Aurora, CO, USA
  15. 15Virginia Cancer Specialists, Fairfax, VA, USA
  16. 16Inhibrx, Inc, La Jolla, CA, USA
  17. 17NEXT Oncology, San Antonio, TX, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


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 identifier, NCT03809624


  1. 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.

Ethics Approval The study protocol was reviewed and approved by the institutional review board at each participating institution; all patients provided written informed consent.

Abstract 742 Figure 1

Phase 1/2 study of the tetravalent PD-L1 and 4–1BB bispecific antibody INBRX-105 as a single agent and in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors

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