Aims There are no approved consolidation therapies for patients (pts) with unresected locally advanced (LA)-HNSCC after definitive cCRT. Anti-PD-1 immune checkpoint inhibitors have efficacy in recurrent/metastatic (R/M) HNSCC and resectable LA-HNSCC. Dual CTLA-4 and PD-(L)1 inhibition is approved in solid tumours including RCC, NSCLC, and melanoma, and has shown a trend towards improved survival vs the EXTREME regimen as 1L treatment in PD-L1-expressing R/M HNSCC. Volrustomig, a PD-1/CTLA-4 bispecific antibody, has shown encouraging efficacy and manageable safety in a Phase 1 study in solid tumours. eVOLVE-HNSCC (NCT06129864), a Phase 3, randomised, multicentre study, will assess consolidation volrustomig vs observation in pts with unresected LA-HNSCC and no progression after definitive cCRT. Methodology Pts must be aged ≥18 yrs and have histologically/cytologically confirmed, unresected LA-HNSCC with no metastatic disease (AJCC 8th edition [TNM staging] stage IVA/B or select stage III [i.e. T3N1] cancers of the hypopharynx, oral cavity, larynx or HPV-negative oropharynx, or stage III HPV-positive oropharynx cancer) and WHO/ECOG PS of 0/1. Tumour tissue samples collected ≤6 mo prior to cCRT are required for PD-L1 testing. Key exclusion criteria: resected LA-HNSCC; R/M disease; >1 primary tumour; unresolved toxicity grade >1 (local RT-related toxicities grade ≤2 allowed). After definitive cCRT (cisplatin/carboplatin + paclitaxel or carboplatin + 5-FU, plus RT), ~1145 pts with no progression after cCRT will be randomised 1:1 to: volrustomig IV Q3W for up to 12 mo/18 cycles or until RECIST 1.1-defined progression or unacceptable toxicity; or observation. Primary endpoint: PFS in pts with PD-L1-expressing tumours. Secondary endpoints include: PFS (all randomised pts); OS (pts with PD-L1-expressing tumours; all randomised pts); safety; PROs. Results Enrolment (plan ≈250 sites in 20–25 countries) began in Dec 2023. Conclusion Estimated primary completion date is April 2028.