Astellas Pharma presented new results from cohort 9 of the EV-202 trial at the European Society for Medical Oncology (ESMO) Congress 2025, held in Berlin, Germany, from 17 to 21 October. Conducted in collaboration with Merck and Seagen, the single-arm, open-label, multicohort, multicentre Phase II study investigated Padcev (enfortumab vedotin) as an add-on therapy to Keytruda (pembrolizumab) in patients with PD-L1-positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) who had not received previous systemic therapy. After Padcev demonstrated promising antitumour activity as a monotherapy in heavily pretreated HNSCC, the trial explored its potential in the first-line setting.
Padcev is an antibody-drug conjugate (ADC), consisting of a fully human monoclonal antibody AGS-22 directed against nectin-4 and the cytotoxic payload monomethyl auristatin E (MMAE). Following internalisation, MMAE inhibits tubulin polymerisation, inducing cell cycle arrest and apoptosis in nectin-4 expressing tumour cells. Nectin-4 is expressed in up to 86% of HNSCC cases.
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Padcev plus pembrolizumab demonstrated encouraging antitumour activity, meeting the predefined efficacy threshold. Among 41 enrolled patients, objective responses were observed in 16 (39.0%; 95% confidence interval [CI]: 24.2, 55.5) including four complete responses (9.8%). An additional 15 patients achieved stable disease, resulting in a disease control rate of 75.6% (95% CI: 59.7, 87.6). The median duration of response (DOR) had not yet been reached, although the six-month DOR was 81.7% (95% CI: 42.0, 95.4). While median overall survival remains immature, median progression-free survival was 5.1 months (95% CI: 3.5, not estimable).
The safety profile was acceptable and consistent with previous studies. A total of 41.5% of participants experienced grade 3 or above treatment-related adverse events (AEs), leading to discontinuation in 14.5% of patients and dose reduction in 22.0% of patients. The most frequent AEs were fatigue (9.8%), along with acute respiratory failure, dehydration, dysphagia, maculopapular rash, syncope and tumour bleeding (each 7.3%). A further evaluation of the regimen in a Phase III study may soon be underway.
HNSCC ranks as the sixth most common malignancy worldwide and recurs in around half of all cases. GlobalData estimates that there were 303,429 incident cases of HNSCC in 2024 across the eight major pharmaceutical markets (8MM: China, France, Germany, Italy, Japan, Spain, the UK and the US). However, the first-line treatment space remains relatively uncrowded, with only incremental advances in recent years. Beyond platinum-based chemotherapy, the EGFR inhibitor Eli Lilly’s Erbitux (cetuximab) was approved in 2011, followed by PD-1 inhibitors including Merck’s Keytruda (2019), Junshi Biosciences’ Loqtorz (toripalimab, 2023) and Sino Cell Technologies’ finotonlimab (An Youping, China, 2025). Nevertheless, the durability of response and prognosis remains poor in R/M HNSCC.
If the Padcev plus pembrolizumab combination gains approval, it could become the first therapy with a novel mechanism of action in this space since 2019 and the first ADC approved for this indication. Padcev was first approved in 2019 for metastatic urothelial tract cancer, which is its sole approved indication to date. According to GlobalData’s analyst consensus forecast, Padcev will reach sales of $7.3 billion in 2030.
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By GlobalDataResearch and development is speeding up in the first-line R/M HNSCC space, with 50 Phase II and 18 Phase II/III or Phase III trials sponsored by companies currently underway globally. Several late-stage candidates targeting alternate oncogenic signalling pathways could enter the market ahead of enfortumab vedotin, including Johnson & Johnson’s (J&J’s) amivantamab (EGFR/MET), Merus’ petosemtamab (EGFR/LGR5), J&J’s JNJ-1900 (radioenhancer), Akeso’s ivonescimab (PD-1/VEGF-A) combined with ligufalimab (CD47), Inhibrx Biosciences’ ordastobart (OX40), Exelixis’ zanzalintinib (tyrosine kinase) and Bicara Therapeutics’ ficerafusp alfa (EGFR/ TGF-β). Thus, Padcev’s adoption will depend on its ability to stand out in an evolving treatment landscape.
