Volrustomig monotherapy for recurrent/metastatic HNSCC: Substudy 2 of the eVOLVE-02 phase 2 study.

6025 Background: Inhibition of PD-1 is an important part of standard of care treatment options for patients (pts) with recurrent/metastatic (R/M) HNSCC, but prognosis remains poor and there is a need for novel regimens to improve outcomes. Dual PD-(L)1 and CTLA-4 inhibition has shown a trend towards improved survival vs the EXTREME regimen as first-line (1L) therapy in PD-L1-expressing R/M HNSCC. Volrustomig, a monovalent, bispecific, humanized IgG1 monoclonal antibody, inhibits PD-1 and CTLA-4, with increased CTLA-4 blockade on PD-1-positive activated T cells compared to PD-1-negative resting peripheral T cells. We report safety and efficacy from the planned interim analysis of substudy 2 of the phase 2 eVOLVE-02 (NCT06535607) study, investigating volrustomig monotherapy in pts with R/M HNSCC. Methods: Eligible pts had histologically or cytologically confirmed R/M HNSCC of the hypopharynx, oral cavity, larynx, or oropharynx (HP, OC, LX, OP), had ECOG performance status (PS) 0/1, and were either treatment-naïve in the 1L setting with confirmed PD-L1 positivity or had disease progression (PD) on/after a 1L platinum-containing regimen. Pts received IV volrustomig until PD (RECIST v1.1)/discontinuation criteria were met. Primary endpoints: safety and confirmed objective response rate (cORR). Secondary endpoints include progression-free survival (PFS) and overall survival. Data cutoff (DCO): August 15, 2025. Results: 23 pts with recurrent (n=12) or metastatic (n=11) HNSCC (7 HP, 8 OC, 4 LX, 4 OP) received volrustomig as 1L (n=12) or 2L (n=11) treatment. Median age was 61 years; 16 pts (69.6%) had PS 1; 19 (82.6%) had a PD-L1 combined positive score (CPS) ≥1. Median duration of exposure was 2.1 months (range 0.7–6.4). Treatment-emergent adverse events (TEAEs) were reported in 91.3% of pts (30.4% grade 3/4, 34.8% serious TEAEs); treatment-related AEs per investigator were reported in 82.6% (8.7% grade 3/4, 4.3% serious AEs). No pts discontinued treatment due to AEs. Grade 5 AEs were reported in 13.0% of pts (none considered related to treatment). At DCO, median follow-up was 5.4 months. In pts with CPS ≥1: 5 had partial responses (3 LX, 1 HP, 1 OC); cORR was 26.3%; disease control rate was 52.6%. Median time to response was 2.6 months (IQR 1.4–2.8); responses were ongoing in 60% of responders at DCO. Blood RNA seq showed increased CTLA-4-associated immune proliferation/activation (Ki67/ICOS gene expression) with volrustomig on cycle 1, day 8 vs at baseline. Conclusions: Volrustomig monotherapy showed an acceptable safety profile and encouraging activity in pts with R/M HNSCC, warranting further clinical development. Volrustomig is under investigation in combination with chemotherapy as 1L treatment for R/M HNSCC in the phase 2 eVOLVE-02 substudy 3, and as consolidation monotherapy in locally advanced HNSCC after concurrent chemoradiotherapy in the phase 3 eVOLVE-HNSCC (NCT06129864) study. Clinical trial information: NCT06535607 .