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.
['Assenat|Eric|E|', 'Azria|David|D|', 'Mollevi|Caroline|C|', 'Guimbaud|Rosine|R|', 'Tubiana-Mathieu|Nicole|N|', 'Smith|Denis|D|', 'Delord|Jean-Pierre|JP|', 'Samalin|Emmanuelle|E|', 'Portales|Fabienne|F|', 'Larbouret|Christel|C|', 'Robert|Bruno|B|', 'Bibeau|Frédéric|F|', 'Bleuse|Jean-Pierre|JP|', 'Crapez|Evelyne|E|', 'Ychou|Marc|M|', 'Pèlegrin|André|A|']
D000328:Adult D000368:Aged D000971:Antineoplastic Combined Chemotherapy Protocols D000068818:Cetuximab D003841:Deoxycytidine D018572:Disease-Free Survival D066246:ErbB Receptors D005260:Female D006801:Humans D053208:Kaplan-Meier Estimate D008297:Male D020714:Maximum Tolerated Dose D008875:Middle Aged D010190:Pancreatic Neoplasms D018719:Receptor, ErbB-2 D016879:Salvage Therapy D000068878:Trastuzumab
cetuximab trastuzumab pancreatic cancer antibody combination phase 1/2