FEASIBILITY AND SAFETY OF ORGAN PRESERVING THERAPY FOR EARLY STAGE OR INDUCED EARLY-STAGE ESOPHAGEAL CANCER USING ENDOSCOPIC SUBMUCOSAL DISSECTION (ESD) AND ADJUVANT IMMUNORADIOTHERPY WITH DURVALUMAB (OPERA-RADIO): A PHASE 1 CLINICAL TRIAL

Abstract

Purpose:

OPERA-RADIO (NCT05667298) is a phase I prospective study investigating organ preservation therapy for patients with early stage esophageal cancer (EC) who decline or are ineligible for esophagectomy. We report the feasibility and safety up front organ preserving therapy with ESD followed by adjuvant concurrent immunoradiotherapy (IORT) or adjuvant immunotherapy (IO) alone (in patients with prior neoadjuvant intent chemoradiotherapy).

Materials and Methods:

Patients with de novo early-stage (high risk pT1b/pT2N0M0) EC received upfront ESD followed by adjuvant IORT consisting of 41.4-45 Gy/23-25# with concurrent and consolidation durvalumab every 4 weeks x 13 cycles. The protocol was amended to also include patients with locally advanced EC who received neoadjuvant concurrent chemoradiotherapy (CROSS Regimen) with complete clinical response amenable to ESD (induced early stage disease) and declined esophagectomy. These patients received adjuvant durvalumab only (13 cycles). Patient, disease, and treatment characteristics were tabulated for descriptive purposes. Acute and late toxicities are reported using CTCAE V5.0.

Results:

From Feb 2023 until Apr 2024, 11 patients were enrolled with a mean follow-up of 2.0 years (range 1.2 to 2.5) with a mean age of 68 (range 54-78), of whom 4 (36%) were female. Ten (91%) patients had adenocarcinoma, and 1 (9%) had squamous cell carcinoma. Most tumours (91%) were located in the lower third of the esophagus/GEJ, while 1 (9%) was located in the middle third of the esophagus. Ten patients (91%) received durvalumab, of whom 4 received it as part of concurrent IORT and consolidation following ESD, while 6 patients received neoadjuvant CROSS followed by ESD and adjuvant durvalumab. The mean number of cycles of durvalumab received was 10. Reasons for early discontinuation of durvalumab (all of which occurred in patients with induced early stage post-CROSS) included: disease progression (n=1), and grade 2 arthralgias which resolved with cessation of durvalumab (n=2). Amongst patients receiving concurrent IORT, no grade 3 or higher toxicity occurred during follow-up. One patient treated with adjuvant durvalumab had grade 2 weight loss following endoscopic resection which resolved prior to receipt of adjuvant durvalumab. No unexpected safety signal with durvalumab was identified.

Conclusions:

This phase I study demonstrates that an organ preservation approach with ESD followed by radioimmunotherapy for esophageal cancer patients who are ineligible or declining esophagectomy is safe and feasible to deliver. There are ongoing plans to develop this approach into a randomized Phase 2/3 study.