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.
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.
Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France.|Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Eric
E
Assenat
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U896, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Institut Régional du Cancer de Montpellier, ICM, Montpellier, France.
David
D
Azria
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Caroline
C
Mollevi
Centre Hospitalier Universitaire (CHU) de Toulouse, TSA, Toulouse Cedex, France.
Rosine
R
Guimbaud
Centre Hospitalier Universitaire (CHU) de Limoges, Limoges Cedex, France.
Nicole
N
Tubiana-Mathieu
Centre Hospitalier Universitaire (CHU) de Bordeaux, Talence Cedex, France.
Denis
D
Smith
Institut Claudius Régaud, Toulouse, France.
Jean-Pierre
JP
Delord
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Emmanuelle
E
Samalin
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Fabienne
F
Portales
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U896, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Institut Régional du Cancer de Montpellier, ICM, Montpellier, France.
Christel
C
Larbouret
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U896, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Institut Régional du Cancer de Montpellier, ICM, Montpellier, France.
Bruno
B
Robert
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Frédéric
F
Bibeau
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Jean-Pierre
JP
Bleuse
Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.
Evelyne
E
Crapez
Centre Hospitalier Régional Universitaire (CHU) de Montpellier, Montpellier, France.|Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France.|IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U896, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Institut Régional du Cancer de Montpellier, ICM, Montpellier, France.
Marc
M
Ychou
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U896, Montpellier, France.|Université Montpellier 1, Montpellier, France.|Institut Régional du Cancer de Montpellier, ICM, Montpellier, France.
André
A
Pèlegrin
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage / Q000009:adverse effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D016879:Salvage Therapy / Q000379:methods; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects; D000093542:Gemcitabine
D000068818:Cetuximab; D003841:Deoxycytidine; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine; C512478:EGFR protein, human
antibody combination; cetuximab; pancreatic cancer; phase 1/2; trastuzumab