Enfortumab vedotin and pembrolizumab as first-line treatment in recurrent or metastatic head and neck squamous cell carcinoma: A cohort of the EV-202 trial.

TPS6116 Background: Novel treatment strategies are needed to treat recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) given the poor durability of response and prognosis with standard therapy. In KEYNOTE-048, among patients with R/M HNSCC and PD-L1 combined positive score (CPS) ≥1, first-line (1L) treatment with pembrolizumab demonstrated a median overall survival (OS) of 12.3 months. Nectin-4 is widely expressed in a variety of solid tumors, including bladder cancers and HNSCC. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate approved for use in previously treated (EV monotherapy) or 1L (EV + pembrolizumab) locally advanced or metastatic urothelial carcinoma (la/mUC). EV + pembrolizumab showed superior OS and progression-free survival (PFS) vs chemotherapy in 1L la/mUC. EV-202 is a multicenter, open-label, phase 2 study (NCT04225117) evaluating the efficacy and safety of EV in multiple tumor-specific cohorts. In the previously treated R/M head and neck cancer cohort, 11 of 46 patients (23.9%) had a confirmed objective response with EV monotherapy; median PFS was 3.9 months (Swiecicki P, et al. ASCO 2023. Poster #6017). We hypothesize that EV + pembrolizumab may demonstrate benefit as a 1L therapy in patients with R/M HNSCC and CPS ≥1. Methods: Patients in the R/M HNSCC cohort of EV-202 have histologically or cytologically confirmed HNSCC, an ECOG performance status 0 or 1, no prior systemic therapy administered in the R/M setting (with the exception of systemic therapy completed >6 months prior if given as part of treatment for locally advanced disease), and CPS ≥1. A total of 40 patients are expected to be enrolled. An interim analysis will be conducted when 20 patients are evaluable for tumor response; 5 responders will be needed to proceed. Of 40 total patients, 14 must demonstrate response to claim promising antitumor activity. Patients will receive EV 1.25 mg/kg intravenously on days 1 and 8 and 200 mg of pembrolizumab intravenously on day 1 of each 21-day cycle until discontinuation, for reasons including disease progression or toxicity. Disease assessments will be performed 9 weeks from the first dose and every 6 weeks thereafter until disease progression, start of subsequent anticancer therapy, death, consent withdrawal, loss to follow-up, or study end, whichever occurs first. The primary endpoint is investigator-assessed, confirmed ORR per RECIST v1.1. Secondary endpoints include investigator-assessed duration of response, disease control rate, PFS, OS, and safety/tolerability. Analyses will also be evaluated per iRECIST. Exploratory analyses will include pharmacokinetics, immunogenicity, quality of life, and assessment of biomarkers that may correlate with treatment outcome, including Nectin-4 expression. Recruitment for this cohort began in November 2023 and is ongoing. Clinical trial information: NCT04225117 .