Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the “THERAPY”phase 1-2 trial

Abstract

// Eric Assenat 1,2 , David Azria 2,3,4,5,6 , Caroline Mollevi 2 , Rosine Guimbaud 7 , Nicole Tubiana-Mathieu 8 , Denis Smith 9 , Jean-Pierre Delord 10 , Emmanuelle Samalin 2 , Fabienne Portales 2 , Christel Larbouret 3,4,5,6 , Bruno Robert 3,4,5,6 , Frédéric Bibeau 2 , Jean-Pierre Bleuse 2 , Evelyne Crapez 2 , Marc Ychou 1,2,3,4,5,6,* and André Pèlegrin 3,4,5,6,* 1 Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France 2 Institut Régional du Cancer de Montpellier (ICM)-Val d’Aurelle, Montpellier, France 3 IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France 4 INSERM, U896, Montpellier, France 5 Université Montpellier 1, Montpellier, France 6 Institut Régional du Cancer de Montpellier, ICM, Montpellier, France 7 Centre Hospitalier Universitaire (CHU) de Toulouse, TSA, Toulouse cedex, France 8 Centre Hospitalier Universitaire (CHU) de Limoges, Limoges cedex, France 9 Centre Hospitalier Universitaire (CHU) de Bordeaux, Talence cedex, France 10 Institut Claudius Régaud, Toulouse, France * These authors have contributed equally to the work Correspondence to: Eric Assenat, email: // Keywords : pancreatic cancer, cetuximab, trastuzumab, phase 1/2, antibody combination Received : December 12, 2014 Accepted : January 22, 2015 Published : February 28, 2015 Abstract To improve treatment efficacy, we decided to simultaneously target HER1 and HER2 with trastuzumab and cetuximab. Following promising preclinical results, we conducted a phase 1-2 trial in advanced pancreatic cancer patients after first-line gemcitabine-based chemotherapy failure. In this single-arm, non-randomized, multicenter trial, patients received weekly cetuximab (400mg/m², then 250mg/m²). They were sequentially included in two trastuzumab dose levels: 3.0 or 4.0mg/kg, then 1.5 or 2.0mg/kg/weekly. Endpoints were the objective response rate, safety, progression-free (PFS) and overall survival (OS). During phase 1 (n=10 patients), toxicities were evenly distributed except for skin toxicities that frequently caused compliance issues. The higher dose level was defined as the trastuzumab recommended dose. During phase 2 (n=39 patients), toxicities were mainly cutaneous reactions and asthenia. No objective response was observed. Nine patients were stabilized but arrested treatment due to toxicity. Median PFS was 1.8 months (95%CI: 1.7-2.0 months) and median OS was 4.6 months (95%CI: 2.7–6.6 months). Both were positively correlated with skin toxicity severity (P=0.027 and P=0.001, respectively). Conventional phase 1 dose-escalation schedules are unsuitable for targeted therapies because most cutaneous toxicities are not considered dose-limiting toxicities. The compliance issues caused by skin toxicities were particularly detrimental because of the toxicity-response correlation.