Phase 2 trial of enoblituzumab plus retifanlimab or tebotelimab in first-line treatment of patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

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TPS6102 Background: Head and neck cancer accounts for ̃900,000 cases and over 400,000 annual deaths worldwide as of 2021. Pts with R/M SCCHN have a poor prognosis with median overall survival <1 year. Programmed death (PD)-protein 1 (PD-1) and PD-ligand 1 (PD-L1) blockade has shown antitumor activity in advanced SCCHN. Enoblituzumab (MGA271) is an investigational monoclonal antibody (mAb) that binds B7-homolog 3 (B7-H3) with enhanced binding to the activating Fc gamma receptor CD16A, particularly the low-affinity allele CD16A-158. B7-H3 is overexpressed in many cancers, including SCCHN, but not in most normal tissues. Retifanlimab (MGA012, INCMGA00012) is an investigational anti-PD-1 mAb, blocking binding of PD-L1 or PD-ligand 2 (PD-L2) to PD-1. Tebotelimab (MGD013) is an investigational, Fc-bearing bispecific, tetravalent DART® molecule designed to bind PD-1 and lymphocyte activation gene 3, inhibiting their interaction with PD-L1 or PD-L2 and major histocompatibility complex class II. In vitro data suggest that both retifanlimab and tebotelimab have potential to sustain enoblituzumab-mediated immune activation and antitumor activity (Obara G, et al. Ann Oncol. 2021;32[suppl 5]:S814). Combination of enoblituzumab with retifanlimab or tebotelimab sustained the ability of natural killer cells and CD8+ T cells to produce interferon gamma upon restimulation. Both retifanlimab and tebotelimab enhanced enoblituzumab-dependent cytotoxicity targeting B7-H3–expressing tumor cells. In a phase 1/2 study, the combination of enoblituzumab with pembrolizumab was well tolerated (Aggarwal C, et al. J Immunother Cancer. 2022 [under review]). The overall response rate in anti-PD-1/PD-L1–naïve pts with SCCHN (post platinum) was 33% (6/18), including 1 confirmed complete and 5 confirmed partial responses, warranting further development of this combination in R/M SCCHN. Methods: This is an open-label, nonrandomized study in first-line treatment of pts with R/M SCCHN. Approximately 50 pts with PD-L1 combined positive score (CPS) ≥1 will receive enoblituzumab 15 mg/kg plus retifanlimab 375 mg and 30 pts with CPS <1 will receive enoblituzumab 15 mg/kg plus tebotelimab 600 mg. Dosing is once every 3 weeks with tumor assessment at the end of Cycle 2 and every 3 cycles thereafter. Pts with no prior systemic therapy for R/M SCCHN are eligible. Pts who completed systemic therapy >6 months before the study, if given as part of multimodal treatment for locally advanced disease, are eligible. In the tebotelimab cohort, safety data will be reviewed for dose-limiting toxicities through Cycle 2 Day 7 on the first 12 pts (2 mini cohorts of 6 pts each). All pts will be followed for survival after the last dose of study drug. The first pt was enrolled in March 2021, and 28 pts are on treatment as of January 19, 2022. Clinical trial information: NCT04634825.

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