Phase 1/2 Study of Pepinemab in Combination with Pembrolizumab as First-Line Treatment of Advanced, Recurrent or Metastatic Head and Neck Cancer (KEYNOTE B84)

Abstract

<h3>Purpose/Objective(s)</h3> 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) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a humanized SEMA4D blocking antibody, in combination with avelumab provided clinical benefit in some patients with difficult to treat ICI-resistant and PD-L1-low NSCLC. Pembrolizumab is approved as monotherapy or in combination with chemotherapy for the first-line treatment of recurrent or metastatic (R/M) HNSCC. More effective treatments are, however, needed to increase the frequency and duration of responses. The primary hypothesis of this proof-of-concept study is that pepinemab in combination with pembrolizumab will yield increased clinical benefit compared to the reported activity for pembrolizumab monotherapy in R/M HNSCC. <h3>Materials/Methods</h3> KEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study to evaluate the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, and an ECOG PS of 0 or 1, are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study will include a safety run-in phase (n=3-6) and dose-expansion phase (maximum n=62). Pepinemab, previously found to be well-tolerated in combination with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combination with 200 mg pembrolizumab, both administered i.v. Q3W. The dose expansion phase will include an equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints include PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. <h3>Results</h3> Enrollment has been initiated at several of 18 participating sites. Preliminary data from the safety run-in phase will be evaluated at a safety monitoring review meeting planned for December 2021. In addition, multiplex immunohistochemistry panels have been established to immunophenotype cells in the TME, including CD8+ T cells, DCs, MDSCs, Tregs, monocytes, and macrophages. <h3>Conclusion</h3> There remains a clear unmet need for more effective treatment options to overcome immunosuppressive factors in the TME. The KEYNOTE B84 study will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembrolizumab in R/M HNSCC.