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676 Pepinemab, a semaphorin 4D inhibitor, in combination with pembrolizumab induced formation of organized lymphoid aggregates in phase 1b/2 study for first-line treatment of R/M HNSCC (KEYNOTE-B84)
  1. Terrence Fisher1,
  2. Elizabeth Evans1,
  3. Crystal Mallow1,
  4. Amber Foster1,
  5. John Leonard1,
  6. Marya Chaney2,
  7. Tarek Mekhail3,
  8. Nagashree Seetharamu4,
  9. Conor Steuer5,
  10. Nabil F Saba5,
  11. Douglas Adkins6,
  12. J Thaddeus Beck7,
  13. Alain Algazi8,
  14. Barbara Burtness9,
  15. Megan Baumgart10,
  16. Steven Hager11,
  17. Christopher Chay12,
  18. Alexander Spira13 and
  19. Maurice Zauderer1
  1. 1Vaccinex, Inc, Rochester, NY, USA
  2. 2Merck and Co., Inc, Rahway, NJ, USA
  3. 3Advent Health Cancer Institute, Orlando, FL, USA
  4. 4Northwell Health, Lake Success, NY, USA
  5. 5Winship Cancer Institute of Emory University, Atlanta, GA, USA
  6. 6Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, Saint Louis, MO, USA
  7. 7Highlands Oncology, Springdale, AR, USA
  8. 8UCSF Medical Center at Mission Bay, San Francisco, CA, USA
  9. 9Yale University School of Medicine, New Haven, CT, USA
  10. 10University of Rochester, Rochester, NY, USA
  11. 11California Cancer Associates for Research and Excellence, Inc, Fresno, CA, USA
  12. 12Messino Cancer Centers, Ashville, NC, USA
  13. 13Virginia Cancer Specialists, Fairfax, VA, 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 Immunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) reverses immunosuppression, including attenuation of MDSC recruitment and function1 and promotes organization of lymphoid aggregates within tumors,2 leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination with avelumab was well tolerated and provided clinical benefit in patients with ICI-resistant, PD-L1-low NSCLC.3 The primary hypothesis of this proof-of-concept study is that pepinemab in combination with pembrolizumab will improve the efficacy of immunotherapy in R/M HNSCC.

Methods KEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of R/M HNSCC. The study includes immunotherapy naïve patients who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20 with an interim analysis when 36 patients complete the first tumor response assessment. The primary efficacy endpoint is ORR, and secondary endpoints include PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies are collected for evaluation of immune contexture in TME. Data presented here include pre-specified interim analysis of safety, efficacy, and biomarker assessments.

Results The combination appears to be well tolerated with no DLTs observed or safety signals identified by the SMC. Notably, in the PD-L1 low population (CPS<20, N=19), we observed approximately a doubling in ORR, DCR, and PFS for the combination of pepinemab and pembrolizumab, as compared to reported single agent pembrolizumab.4 Among the CPS<20 population, ORR was 21.1% (2 CR and 2 PR), DCR was 73.7%, and median PFS was 5.79 months. In contrast, in the CPS≥20 subgroup, the ORR was 17.6% (n=17), similar to ICI monotherapy for this population. Spatial multiplex IHC analysis of pre- and post-treatment tumor biopsies demonstrated an increase in activated APC, reduced recruitment of MDSC, and highly organized immune aggregates (figure 1) that corresponded with disease control.

Conclusions The pre-specified interim analysis of the ongoing KN-B84 study showed that pepinemab in combination with pembrolizumab was well-tolerated, suggested early signs of improved anti-tumor response over single agent pembrolizumab in the difficult to treat PD-L1 low group, and provided evidence of treatment-induced biomarker changes in the TME of responder tumors, including formation of high-density lymphoid aggregates.


  1. Clavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Cancer Immunol Res. 2019 Feb;7(2):282–291. doi: 10.1158/2326–6066.CIR-18–0156.

  2. Olson B, Mallow C, Reilly C, et al. Neoadjuvant SEMA4D blockade with nivolumab alters suppressive myeloid cells while elevating B cell and CD26hi T cell infiltration in the tumors of patients with resectable stage III melanoma. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0613

  3. Shafique MR, Fisher TL, Evans EE, et al. A Phase Ib/2 Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2021, doi: 10.1158/1078–0432.CCR-20–4792

  4. Burtness B, Rischin D, Greil R, Soulières D, Tahara M, et al. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 2022 Jul 20;40(21):2321–2332. doi: 10.1200/JCO.21.02198.

Ethics Approval This study was approved by WIRB Copernicus Group’s Ethics Board; approval number 20210250.

Abstract 676 Figure 1

Treatment induced improved balance of activated APC and MDSC and presence of highly organized immune aggregates consisting of high density of B cells, DC and T cell zones, and stem- like CD8, and correlate with disease control. (A, B) Representative images of on-treatment biopsies. (C) B cell density/aggregate, each dot represents one aggregate. CR: complete response SD: stable disease, PD: progressive disease.

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