Background: Patients with rHNSCC who have failed standard of care have poor prognoses and limited therapeutic options. In this study, final results are reported of a phase 2a trial of photoimmunotherapy (PIT) with a targeted drug RM-1929, consisting of the EGFR-directed antibody cetuximab conjugated to a photoactivatable dye (IRDye 700DX). Binding of the antibody-dye conjugate to cancer cells followed by photoactivation with nonthermal red light induces selective and rapid necrosis of the cancer cells, with minimal damage to surrounding tissue. Methods: A phase 2a, multicenter, open-label, study of RM-1929 PIT in patients with locoregional, rHNSCC who could not be satisfactorily treated with surgery, radiation, or platinum chemotherapy was conducted to evaluate the safety and efficacy of the drug, RM-1929. For each treatment, nonthermal red light (690 nm) was applied to the tumors 24 hours post IV infusion of the drug. Surface illumination was administered for superficial tumors and interstitial illumination via intratumoral placement of fiber optic diffusers for deep tumors. Therapeutic response was assessed using CT RECIST 1.1 by an independent blinded radiologist. Results: Thirty rHNSCC patients were enrolled. There were no dose-limiting toxicities and one Grade 1 photosensitivity reaction. Most reported AEs were mild to moderate in severity with 96.7% (29/30) of patients with Grade 1 and 83.3% (25/30) with Grade 2, respectively. There were 13 (43.3%) patients who had at least one SAE. 86% (19/22) of SAEs were deemed unlikely related to treatment, including all 3 fatal SAEs. Three SAEs were reported to be possibly/probably related to treatment (site/oral pain, tumor hemorrhage, and airway obstruction). ORR was 50% (15/30) with 16.7% (5/30) CR and 86.7% (26/30) DCR. Median PFS and OS results will be forthcoming. Conclusions: These data indicate that RM-1929 PIT treatment was generally well tolerated with majority of AEs as mild to moderate in severity. Preliminary data showed favorable response rates in a heavily pre-treated population. A global phase 3 clinical trial is currently underway. Clinical trial information: NCT02422979