Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2)

Dirk Rades, Tobias Bartscht, Peter Hunold, Heinz Schmidberger, Laila König, Jürgen Debus, Claus Belka, Nils Homann, Patrick Spillner, Cordula Petersen, Thomas Kuhnt, Rainer Fietkau, Karsten Ridwelski, Kerstin Karcher-Kilian, Anne Kranich, Sofia Männikkö, Steven E Schild, Annett Maderer, Markus Moehler, Dirk Rades, Tobias Bartscht, Peter Hunold, Heinz Schmidberger, Laila König, Jürgen Debus, Claus Belka, Nils Homann, Patrick Spillner, Cordula Petersen, Thomas Kuhnt, Rainer Fietkau, Karsten Ridwelski, Kerstin Karcher-Kilian, Anne Kranich, Sofia Männikkö, Steven E Schild, Annett Maderer, Markus Moehler

Abstract

Purpose: To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer.

Methods: This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2‑year overall survival (OS). Arm A was considered insufficiently active if 2‑year OS was ≤40% (null hypothesis = H0), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable.

Results: Two-year OS was 71% in arm A (95% CI: 55-87%) vs. 53% in arm B (95% CI: 36-71%); H0 was rejected. Median OS was 49.1 vs. 24.1 months (p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30-1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25-1.04) for progression, 0.43 (0.13-1.40) for locoregional failure, and 0.43 (0.17-1.05) for distant metastasis. Overall response was 81% vs. 69% (p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044).

Conclusion: Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.

Keywords: Definitive treatment; EGFR antibody; Efficacy; Esophageal cancer; Feasibility.

Conflict of interest statement

D. Rades received speakers’ honoraria and travel grants from Merck Serono, Roche Pharma, Bristol Myers Squibb, Astra Zeneca, and Amgen until 2015. S.E. Schild edits and writes for UpToDate and has done consulting work for Noxopharm in the past. T. Bartscht, P. Hunold, H. Schmidberger, L. König, J. Debus, C. Belka, N. Homann, P. Spillner, C. Petersen, T. Kuhnt, R. Fietkau, K. Ridwelski, K. Karcher-Kilian, A. Kranich, S. Männikkö, A. Maderer, and M. Moehler declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the treatments administered in this trial. 5‑FU 5-fluorouracil
Fig. 2
Fig. 2
Consolidated Standards of Reporting Trials (CONSORT) diagram
Fig. 3
Fig. 3
Comparison of the two treatment groups (Kaplan–Meier analysis and log-rank test) with respect to overall survival (a), progression-free survival (b), locoregional control (c), and metastases-free survival (d)

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