Pepinemab/Pembrolizumab May Be Active in Recurrent/Metastatic Head and Neck Cancer

Safety run-in findings from the phase 1b/2 KEYNOTE-B84 trial (NCT04815720) show that combining pepinemab and pembrolizumab can promote encouraging responses with tolerable safety as frontline therapy for patients with recurrent or metastatic head and neck cancer.¹

Results from the phase 1b portion of the study (NCT04815720) demonstrated that 2 of the first 3 patients enrolled achieved a confirmed complete response per RECIST v1.1 criteria at the recommended phase 2 dose (RP2D) of 20 mg/kg of pepinemab and 200 mg of pembrolizumab, administered every 3 weeks. Notably, both responders had a PD-L1 combined positive score (CPS) below 20 and HPV-negative disease.

“A major goal of current head and neck cancer research, and this study, is to identify a combination therapy that can increase the relatively small percentage of patients who benefit from current immuno- and other therapies. Treatment with pepinemab in combination with pembrolizumab was well-tolerated in KEYNOTE-B84,” Terrence L. Fisher, PhD, and vice president of Clinical Science at Vaccinex, Inc., said in a virtual presentation during the AACR Annual Meeting 2022.

The high density of immunosuppressive myeloid cells in the tumor microenvironment limits the activity of checkpoint inhibitors in head and neck cancer.

Pepinemab being a novel monoclonal antibody, can block the activity of SEMA4D, which facilitates recruitment and activity of immunosuppressive myeloid cells. SEMA4D inhibition limits expansion and activation of myeloid-derived suppressor cells. Moreover, SEMA4D inhibition encourages tumor infiltration and activation of dendritic cells and CD8+ T cells.

Prior data from the proof-of-concept phase 1b/2 CLASSICAL-Lung trial (NCT03268057) demonstrated that the combination of pepinemab and avelumab (Bavencio) induced responses in patients with advanced non–small cell lung cancer. Specifically, objective response rates (ORRs) of 25% (n = 2/8), 20% (n = 2/10), and 33% (n = 1/3) were seen across patients with PD-L1–negative (<1%), PD-L1–low (1-49%), and PD-L1–low/intermediate (50%-79%) disease, respectively.

Moreover, increased penetration of cytotoxic T cells following treatment with the combination were seen in CLASSICAL-Lung.

In the phase 1b portion of KEYNOTE-B84, 3 patients received 20 mg/kg of pepinemab plus 200 mg of pembrolizumab.

In the phase 2 portion, which is actively enrolling, patients will receive the RP2D of 20 mg/kg of pepinemab plus 200 mg of pembrolizumab. Patients will be stratified by a PD-L1 CPS of below 20 (n = 31) and 20 or above (n = 31).

To be eligible for enrollment, patients must be at least 18 years of age and have measurable, histologically or cytologically confirmed head and neck squamous cell carcinoma; eligible histologies include squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, and larynx.

Patients must also undergo PD-L1 immunohistochemistry testing within 6 months of screening or at screening.

“The KEYNOTE-B84 study is accruing patients in the phase 2 expansion phase, which plans to enroll up to an additional 62 patients in approximately equal groups of patients with CPS < 20 and CPS ≥ 20 across 18 United States trial sites,” Fisher concluded.

The primary end point is ORR, and exploratory end points include progression-free survival, duration of response, and pharmacokinetic and pharmacodynamic biomarkers of immune response.

In terms of safety from the phase 1b phase, no dose-limiting toxicities were reported. One patient experienced grade 1 rash, and 1 patient discontinued treatment with a non-treatment–related serious adverse effect attributed to a preexisting comorbidity of diabetes.

_Reference

_{Fisher TL, Evans EE, Mallow C, et al. 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). Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT111.}