Pepinemab/Pembrolizumab may be active in recurrent/metastatic head and neck cancer
According to the results of the phase 1b study KEYNOTE-B84, pepinemab plus pembrolizumab obtained complete responses in 2 of the first 3 patients with head and neck cancers included.
Preliminary safety results from the Phase 1b/2 KEYNOTE-B84 trial (NCT04815720) show that the combination of pepinemab and pembrolizumab can promote encouraging responses with tolerable safety as a first-line treatment for patients with recurrent or metastatic head and neck cancer.1
The results of the phase 1b study (NCT04815720) demonstrated that 2 of the first 3 patients enrolled achieved a confirmed complete response according to RECIST v1.1 criteria at the recommended phase 2 dose (RP2D) of 20 mg/kg pepinemab and 200 mg pembrolizumab, given every 3 weeks. Notably, both responders had a combined positive PD-L1 score (CPS) of less than 20 and negative HPV disease.
“A major goal of current head and neck cancer research, and of this study, is to identify a combination therapy that can increase the relatively small percentage of patients who benefit from current immunotherapies and other therapies. Treatment with pepinemab in combination with pembrolizumab was well tolerated in KEYNOTE-B84,” said Terrence L. Fisher, PhD, and Vice President of Clinical Sciences at Vaccinex, Inc., in a virtual presentation at the meeting. 2022 AACR Annual Report.
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 new monoclonal antibody, can block the activity of SEMA4D, which facilitates the recruitment and activity of immunosuppressive myeloid cells. Inhibition of SEMA4D limits the expansion and activation of myeloid-derived suppressor cells. In addition, inhibition of SEMA4D promotes tumor infiltration and activation of dendritic cells and CD8+ T cells.
Previous data from the Phase 1b/2 proof-of-concept trial CLASSICAL-Lung (NCT03268057) demonstrated that the combination of pepinemab and avelumab (Bavencio) induced responses in patients with prostate cancer. advanced non-small cell lung. Specifically, objective response rates (ORR) of 25% (n=2/8), 20% (n=2/10), and 33% (n=1/3) were observed in patients with PD -L1 negative (
Additionally, increased penetration of cytotoxic T cells after treatment with the combination was observed in CLASSICAL-Lung.
In phase 1b of KEYNOTE-B84, 3 patients received 20 mg/kg pepinemab plus 200 mg pembrolizumab.
In phase 2, which is being actively recruited, patients will receive the RP2D of 20 mg/kg pepinemab plus 200 mg pembrolizumab. Patients will be stratified by a PD-L1 CPS of less than 20 (n=31) and 20 or greater (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 should also undergo PD-L1 immunohistochemistry testing within 6 months of screening or at screening.
“The KEYNOTE-B84 study is enrolling patients in the Phase 2 expansion phase, which plans to enroll up to 62 additional patients in approximately equal groups of patients with CPS
The primary endpoint is ORR, and exploratory endpoints include progression-free survival, duration of response, and pharmacokinetic and pharmacodynamic biomarkers of immune response.
In terms of safety from phase 1b, no dose-limiting toxicity has been reported. One patient experienced a grade 1 rash and one patient discontinued treatment with a serious unrelated adverse event attributed to pre-existing diabetes comorbidity.
Fisher TL, Evans EE, Mallow C, et al. Phase 1/2 study of pepinemab, a semaphorin 4D inhibitor, in combination with pembrolizumab as first-line treatment for recurrent or metastatic ENT cancer (KEYNOTE B84). Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Summary CT111.