Abstract CT111: Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE B84)
Authors: Fisher Terrence L. , Evans Elizabeth E. , Mallow Crystal , Foster Amber , Boise Megan , Smith Ernest , Leonard John E. , Chaney Marya F. , Beck J. Thaddeus , Hager Steven , Saba Nabil F. , Steuer Conor , Adkins Douglas , Burtness Barbara , Zauderer Maurice 
Published: June 2022

Abstract
Purpose: 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 (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC. Pembrolizumab (pembro) is approved as monotherapy or in combo with chemo 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 combo with pembro will yield increased clinical benefit compared to the reported activity for pembro monotherapy in R/M HNSCC.
Methods: KEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combo with pembro as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, ECOG PS of 0 or 1, and PD-L1 CPS ≥ 0 are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study includes a safety run-in (n=3) and dose-expansion phase (maximum n=62). Pepinemab, previously found to be well-tolerated in combo with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combo with 200 mg pembro, 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 &lt;20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints are 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.
Results: The safety run-in phase (n=3) was successfully completed. The combo was well tolerated with no DLTs observed. One of the three patients had a confirmed complete response, a second patient progressed with several SAEs attributed to comorbidities (diabetes) deemed unrelated to treatment, and the third patient has not yet completed tumor evaluation. The safety monitoring committee has recommended that the dose-expansion phase be initiated at 20 mg/kg pepinemab and 200 mg pembro Q3W.
Conclusions: The ongoing KEYNOTE B84 study completed the initial safety run-in phase. Phase 2 will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembro in R/M HNSCC.
Citation Format: Terrence L. Fisher, Elizabeth E. Evans, Crystal Mallow, Amber Foster, Megan Boise, Ernest Smith, John E. Leonard, Marya F. Chaney, J. Thaddeus Beck, Steven Hager, Nabil F. Saba, Conor Steuer, Douglas Adkins, Barbara Burtness, Maurice Zauderer. Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE B84) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT111.