Clinical Research Papers:
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
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Eric Assenat1,2, David Azria2,3,4,5,6, Caroline Mollevi2, Rosine Guimbaud7, Nicole Tubiana-Mathieu8, Denis Smith9, Jean-Pierre Delord10, Emmanuelle Samalin2, Fabienne Portales2, Christel Larbouret3,4,5,6, Bruno Robert3,4,5,6, Frédéric Bibeau2, Jean-Pierre Bleuse2, Evelyne Crapez2, Marc Ychou1,2,3,4,5,6,* and André Pèlegrin3,4,5,6,*
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
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
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.
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