Background: Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. Patients and Methods: PEVOsq is an open-label, non-randomized, multi-center, basket phase II trial, evaluating the efficacy of pembrolizumab in combination with vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma of the cervix, head and neck, anus, vulva/vagina, penis, and lung. Patients had to be PD1/PD-L1 antagonist-naïve. There was no selection based on PD-L1 expression nor on HPV status, and no restriction in terms of prior lines of treatments. Pembrolizumab dose was 200 mg Q3W IV, and vorinostat 400 mg QD PO. Sample size was determined for each cohort using an A’Hern design. Primary endpoint was objective response rate (ORR) according to RECISTv1.1. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Results: Among 112 included patients, 111 were evaluable for safety and 107 for efficacy. The lung cohort was closed prematurely because of lack of enrollment. Median age was 61 years old [range: 18-85] and the median number of prior lines of therapies was 1 [range: 0-4]. ORR, PFS, G3/4 treatment related adverse events (TRAE), and OS are reported. 28 patients (26%) had an objective response and median DOR was 9.7 months [95%CI: 3.1-15.2]. Results per PD-L1 status will be presented at the meeting. Pembrolizumab and vorinostat were stopped for toxicity in 9% and 39% of patients, respectively. 60% of patients had a dose-reduced of vorinostat for toxicity. Pembrolizumab safety was as expected. Main vorinostat toxicities included hematological toxicity, gastrointestinal disorders, and asthenia and creatinine increase. Conclusions: Pembrolizumab combined with vorinostat showed encouraging antitumor activity in squamous cell carcinoma with unselected PD1/PD-L1 status, especially in cervical and anal cancer, although vorinostat dose had to be reduced because of toxicity in a substantial proportion of patients. Clinical trial information: NCT04357873.