Aims: ASP-1929 PIT is a novel drug-device technology in which cetuximab is conjugated to IRDye 700DX and locally illuminated by red light (690 nm). Preclinical data indicate that PIT induces rapid tumor cell disruption and antitumor immune responses enhanced by PD-1 checkpoint blockade. ASP-1929-181 (NCT04305795) was an open-label study to evaluate safety and efficacy of ASP-1929 PIT plus PEM in patients (pts) with R/M HNSCC.1 Methods: Eligibility criteria included pts with measurable disease by modified RECIST 1.1, ≥ 1 lesion accessible to illumination, CPS ≥ 1, and no locoregional therapy options. Treatment included ASP-1929 PIT (infusion day 8, target tumors illuminated 24 ± 4 hours later) plus anti-PD-1 (days 1 & 22) during a 6-week cycle up to 24 months. Primary objectives were safety/tolerability and objective response rate (ORR). Secondary objectives were duration of response (DoR), overall survival (OS) and progression-free survival (PFS). Results: Between 11/2020-4/2022, 19 pts were enrolled. Among 18 PIT-treated pts, median age was 63 (44-90), 73.7% male, 57.9% ECOG 0-1. All pts experienced at least 1 TEAE. The most common Grade≥3 TEAEs were muscle weakness (10.5%), dysphagia (10.5%), and weight loss (10.5%). Two pts discontinued ASP-1929 PIT treatment due to AEs. There were no fatal events. Confirmed ORR was 27.8% (95% CI 9.7–53.5); 80% of responders had complete responses (CRs), and median DoR was not reached. Median OS was 25.6 months (95% CI 14.6–NE); 24-month OS rate estimate 50.0% (95% CI 25.9–70.1); and median PFS was 2.9 months (95% CI 1.4–14.6). Conclusion: The encouraging efficacy results, particularly OS and CR rate, along with an acceptable tolerability profile supports the ongoing randomized, controlled global phase III study ASP-1929 381 (NCT06699212) evaluating this combination versus standard of care, PEM +/- chemotherapy in pts with recurrent HNSCC lacking locoregional treatment options. 1. Cognetti DM et al. Head Neck. 2026;48(1):160-74