Valemetostat in combination with pembrolizumab in head and neck cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

This is a phase Ib/II multicenter study of front line Pembrolizumab and valemetostat in PD-L1 positive, HPV-negative recurrent/metastatic squamous cell carcinoma (SCC) of the head and neck (the PANTHERAS study). Patients with recurrent or metastatic (R/M) pembrolizumab-naive human papillomavirus (HPV)-negative HNSCC have a low 6-month progression-free survival (PFS) (28%) with pembrolizumab monotherapy, thus novel interventions are needed to increase the efficacy of pembrolizumab. Valemetostat (DS-3201) is an enhancer of zeste homolog 1 and 2 (EZH1/2) dual inhibitor that is actively being investigated in phase I and II trials for hematologic malignancies and is approved for adult T-cell leukemia/lymphoma (ATL) indication in Japan. In the phase Ib part of this study, the safety and the maximum tolerable dose of valemetostat in combination with the standard of care dose of pembrolizumab will be determined. In the phase II part, the efficacy of this combination will be determined. Correlative studies will include immunohistochemistry staining of EZH1/2 and H3K27me3, whole-exome sequencing to assess if specific genetic alterations are associated with response to the combination treatment, multiplex IF and TCR sequencing to evaluate the changes in the tumor microenvironment and the TCR repertoire, as well as genome-wide mapping of EZH1/2 and H3K27me3, as well as other histone marks.