Rationale:~Vulvar squamous cell carcinoma (VSCC) is a rare cancer with a rising incidence. Standard treatment comprises wide local excision of the primary tumour and inguinal lymph nodes and sometimes (chemo) radiotherapy. Treatment is associated with impressive and long-lasting morbidity, sexual and psychological dysfunction and wound healing disorders. Recurrent disease develops in up to 40% of all treated patients. The unmet need, therefore, is a less radical and more effective treatment for VSCC.~Hypothesis:~Based on the local immune profile in a large fraction of patients with primary VSCC the investigators hypothesize that neoadjuvant programmed cell death protein 1 (PD-1) checkpoint inhibition may reinvigorate tumor-specific T cells resulting in a reduced tumor load, potentially leading to less radical surgery and reduces the recurrence rate.~The primary objectives of this trial are to study clinical efficacy and immune activation of neoadjuvant PD-1 blockade in VSCC.~Study design: This is a prospective, multicenter phase II non-controlled clinical trial in 40 VSCC patients.~Study population: Clinically diagnosed FIGO I-III primary VSCC patients to be treated with surgery with curative intent.~Intervention (if applicable):~Anti-PD1 antibody pembrolizumab, 200 mg IV Q3W for a total of 2 administrations per patient over a period of 6 weeks prior to surgery.~Main study parameters/endpoints:~The primary endpoints are:~Clinical efficacy of neoadjuvant PD-1 blockade in VSCC, measured by objective change in tumour size (according to RECIST1.1)~The activation, proliferation and migration of the CD4+CD39+PD-1+ intratumoral T-cell population.~The secondary endpoints are:~Pathological complete responses (pCR) at time of surgery~Feasibility (defined as delay in planned surgery and surgical outcomes), safety according to NCI-CTC version 5.0,~The activation, proliferation and migration of the CD8+CD103+CD39+PD-1+ intratumoral T-cell population upon PD-1 blockade.~Exploratory endpoints:~To study the on-treatment effect of neoadjuvant PD-1 blockade on a) Local RNA-based immune signalling; b) The activation, proliferation and migration of CD39-negative T cells; c)The type 1 cytokine polarization of T cells as indicated by the percentage of Tbet+ T cells; d) The myeloid cell component, as determined by multiplex staining for CD68, CD14, CD11c, CD33, HLA-DR and CD163, present in VSCC tumors.~To study the relation between the T-cell inflamed gene expression profile (GEP) score and PD-1 blockade driven immunological changes in the tumor microenvironment (TME).~To study the relation between the T-cell infiltration pattern and PD-1 blockade driven immunological changes in TME.~To study the relation between immune cell changes in the TME and corresponding immune cells in the blood.~To study immune cell composition in TME post neoadjuvant checkpoint blockade by AURORA flow cytometry on fresh resection material.~To study PD-L1 expression and molecular subtype (HPV+, p53mut, other) in tumor material.~To assess quality of life (EORTC QLQ C-30 and QLQ-VU34).~To study the utility of plasma-derived circulating tumor DNA (ctDNA) as a potential future predictor for minimal residual disease and/or relapse.
Rationale:~Vulvar squamous cell carcinoma (VSCC) is a rare cancer with a rising incidence. Standard treatment comprises wide local excision of the primary tumour and inguinal lymph nodes and sometimes (chemo) radiotherapy. Treatment is associated with impressive and long-lasting morbidity, sexual and psychological dysfunction and wound healing disorders. Recurrent disease develops in up to 40% of all treated patients. The unmet need, therefore, is a less radical and more effective treatment for VSCC.~Hypothesis:~Based on the local immune profile in a large fraction of patients with primary VSCC the investigators hypothesize that neoadjuvant PD-1 checkpoint inhibition may reinvigorate tumor-specific T cells resulting in a reduced tumor load, potentially leading to less radical surgery and reduces the recurrence rate.~The primary objectives of this trial are to study clinical efficacy and immune activation of neoadjuvant PD-1 blockade in VSCC.~Study design: This is a prospective, multicenter phase II non-controlled clinical trial in 40 VSCC patients.~Study population: Clinically diagnosed FIGO I-III primary VSCC patients to be treated with surgery with curative intent.~Intervention (if applicable):~Anti-PD1 antibody pembrolizumab, 200 mg IV Q3W for a total of 2 administrations per patient over a period of 6 weeks prior to surgery.~Main study parameters/endpoints:~The primary endpoints are:~Clinical efficacy of neoadjuvant PD-1 blockade in VSCC, measured by objective change in tumour size (according to RECIST1.1)~The activation, proliferation and migration of the CD4+CD39+PD-1+ intratumoral T-cell population.