Cosiporfin sodium (DVDMS)-mediated photodynamic therapy (PDT) versus treatment of physician’s choice (TPC) in patients (pts) with advanced esophageal cancer (aEC): A phase III, randomized, open-label, multicenter trial.

4016 Background: Challenges persist in the treatment of aEC, particularly for pts with esophageal stenosis and dysphagia, conditions that deteriorate the nutrition status and hinder anti-tumor therapies, leading to dismal prognosis. Building on the promising anti-tumor activity and improvement in dysphagia in a phase II single-arm trial, the phase III DYNA-Esophagus03 trial assessed DVDMS, a novel photosensitizer, -mediated PDT in aEC, comparing to TPC. Methods: Pts with local recurrence or metastasis EC and Stoller dysphagia grade ≥2, stratified by previous treatment lines (1 st vs 2 nd -line), were randomized 2:1 to DVDMS-mediated PDT (PDT delivered 24 hours after 0.2 mg/kg DVDMS injection at a light dose of 102 J/cm² and wavelength of 630±5 nm) or TPC. The primary endpoint was esophageal stenosis overall response rate (es-ORR) assessed by endoscopy at 28 days. A sample size of 186 pts achieved a 90% power to detect an es-ORR increase from 10% to 35% at a 1-side 2.5% level, considering a 30% drop-off rate. Results: As of November 11, 2024, 186 pts were randomly assigned (124 DVDMS-PDT group/62 TPC group). The baseline characteristics were: mean age 67.6 ± 8.7 years, 32.3% distant metastasis, 52.2% grade 3 dysphagia, and 1.1% grade 4. The es-ORR was 51.6% with DVDMS-PDT vs 8.1% with TPC at day 28 (P < 0.0001). At a median follow-up of 8.9 months (mos), the median progression-free survival was 2.8 vs 2.2 mos (HR = 0.61, 95%CI 0.40-0.93; P = 0.0244), respectively. Time to progression was 5.9 vs 3.9 mos (HR = 0.45, 95% CI: 0.25-0.82, P = 0.0056). Median overall survival (OS) was 7.0 vs 6.4 mos (HR = 0.88, 95%CI 0.59-1.32; P = 0.5169), respectively. Considering the high cross-over rate (45.2%), the rank preserving structural failure time-adjusted median OS was 7.0 vs 4.7 mos (HR = 0.64, 95%CI 0.42-0.97; P = 0.0223). The improvement of dysphagia and quality of life are detailed in the Table. Phototoxicity was negative in 64.9% pts in DVDMS-PDT group on day 7, increasing to 91.4% by day 28. Grade ≥3 treatment-emergent adverse events occurred in 38.2% of the DVDMS-PDT group and 49.2% of the TPC group. Six deaths were due to treatment-related adverse events (4.9%) were reported in the DVDMS-PDT group and 5 (8.5%) in the TPC group. Conclusions: DVDMS-PDT significantly improved esophageal stenosis and dysphagia compared to the treatment of physician’s choice in pts with aEC, with prolonged PFS and TTP, potential better OS and a manageable safety profile. Clinical trial information: CTR20221271 . DVDMS-PDT (n=124) TPC (n=62) Reduction at least 1 grade in Stooler's score in 6 mons, % 47.8% 8.6% (P<0.0001) Change in EORTC QLQ-C30 total score -26.7 ± 2.5 -39.8 ± 4.3 Change in dysphagia score 16.0 ± 2.6 24.6 ± 4.3 Change in eating score 16.9 ± 2.4 30.6 ± 4.1 Values are least-squares mean ± standard error unless otherwise noted. Symptom scores were assessed using EORTC QLQ-OES18.