Overall survival (OS) of locally advanced esophageal cancer remains poor with a 5-year survival of 15-34%. The standard treatment is definitive radiotherapy delivered with oxaliplatin-based chemotherapy (RCT). Majority of patients (pts) die due to non-complete response, local recurrence and/or metastatic progression and the efficacy of definitive RCT need to be increased. The immune checkpoint inhibitors, anti-programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), demonstrated promising antitumor activity and manageable safety profile when used as monotherapy in metastatic esophageal squamous cell carcinoma. PD-L1 expression increased in esophageal cancer pts after neoadjuvant RCT but still associated with poor OS. The immune tumor microenvironment for tumor response has raised novel hypotheses regarding newer immunomodulatory approaches during radiotherapy, especially abscopal effect to improve local and distant outcome. Durvalumab (MEDI4736) is a selective high affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. We hypothesize that combining durvalumab with RCT can increase local response to treatment and prevent distant metastases.
This multicentric, open-label, comparative phase II trial plans to randomize (1:1) 120 pts (≥18 years old, WHO <2, unresectable disease) and evaluates the activity of durvalumab (1500 mg) delivered over 12 months in combination with definitive RCT (IMRT 50 Gy for 5 weeks + FOLFOX4 simplified 1 infusion every 2 weeks during 3 months) compared to definitive RCT alone. Given the lack of safety data from this association, a safety run-in of 6 pts is planned. The main objective is to increase 12-months progression-free survival (PFS) centrally reviewed from 50% to 68% (HR = 0.55). 74 events are necessary to detect this difference with a power of 90% using a one–sided logrank test at 10% level of significance. Main secondary endpoints are safety, PFS and quality of life. Ancillary studies mains to identify biomarkers predicting response to treatment. The first patient will be randomized in May 2019 and 12 sites will recruit pts.
Clinical trial identification
Legal entity responsible for the study
Unicancer GI tumors.
L. Quero: Research grant / Funding (institution): AstraZeneca. E.L. Cohen-Jonathan Moyal: Research grant / Funding (institution): AstraZeneca. A. Modesto: Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.