Positive Responses and Tolerability Reported With Pepinemab Plus Pembrolizumab in Head and Neck Cancer

The phase 1b/2 KEYNOTE-B84 trial (NCT04815720), which enrolled patients with recurrent or metastatic head and neck cancer, provided evidence of antitumor activity and positive responses with pepinemab and pembrolizumab treatment, according to a presentation from the American Assoication for Cancer Research (AACR) 2022 Annual Meeting.

Results from the phase 1b portion 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,” lead study author Terrence L. Fisher, PhD, and vice president of Clinical Science at Vaccinex, Inc., said in a virtual presentation.

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

Pepinemab is a novel monoclonal antibody that blocks 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.