rHNSCC carries a poor prognosis and a low survival rate. Locoregional (LR) progression contributes substantially to both morbidity and mortality, underscoring the importance of LR disease control. Although anti-PD-1 inhibitors have expanded treatment options for rHNSCC, response rates with monotherapy remain low. ASP-1929 photoimmunotherapy (PIT) is a novel drug-device treatment conjugating a light-activatable dye (IR700) to cetuximab to selectively target EGFR-expressing cancer cells and cause rapid cell membrane destruction following focused laser illumination. Preclinical data show that ASP-1929 PIT-mediated tumor necrosis and immunogenic cell death induces antitumor immunity and enhances anticancer activity when combined with anti-PD-1 therapy. In a phase I/IIa study, ASP-1929 PIT plus PEM showed favorable activity in 19 patients with metastatic and/or rHNSCC not amenable to standard LR therapies, with a median overall survival (OS) of 25.6 months, objective response rate (ORR) of 27.8%, and a disease control rate of 61.1% with a median follow-up of 31.7 months.1 ASP-1929 381 is a global, phase III, randomized, open-label, controlled study evaluating ASP-1929 PIT plus PEM vs PEM-based SOC as first-line treatment for LR rHNSCC without distant metastases. Key inclusion criteria: rHNSCC patients eligible for PEM-based SOC, anti-PD-1/PD-L1-naïve, with ≥1 RECIST 1.1 measurable lesion accessible for PIT, ECOG 0-1. Key exclusion criteria: additional malignancy within 2 years, history of ≥ grade 3 cetuximab infusion reactions, prior allogeneic transplant, life expectancy <3 months. Around 412 patients will be randomized 2:2:1 to ASP-1929 PIT (320 mg/m2 or 640 mg/m2) plus PEM or physicians’-choice PEM-based SOC. The primary endpoint is OS. Key secondary endpoints include complete response rate and ORR. The study is enrolling in the US, Japan, Taiwan, Ukraine, with plans to expand to other territories (NCT06699212). 1. Cognetti DM et al. Head Neck 2026;48:160-74