Federica Tosi1, Andrea Sartore-Bianchi1, Sara Lonardi2, Alessio Amatu3, Francesco Leone4, Silvia Ghezzi3, Cosimo Martino5, Katia Bencardino3, Erica Bonazzina3, Francesca Bergamo2, Elisabetta Fenocchio6, Erika Martinelli7, Teresa Troiani7, Giulia Siravegna8, Gianluca Mauri1, Valter Torri9, Giovanna Marrapese3, Emanuele Valtorta3, Andrea Cassingena3, Giovanni Cappello5, Emanuela Bonoldi3, Angelo Vanzulli3, Daniele Regge5, Fortunato Ciardiello7, Vittorina Zagonel2, Alberto Bardelli8, Livio Trusolino8, Silvia Marsoni10, Salvatore Siena11. 1. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy. 2. Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy. 3. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. 4. Department of Oncology, ASL BI, Ospedale degli Infermi, Biella, Italy; Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy. 5. Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy. 6. Multidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy. 7. Università della Campania "L. Vanvitelli", Naples, Italy. 8. Istituto di Candiolo, Fondazione del Piemonte per l'Oncologia-IRCCS, Candiolo, Italy; Dipartimento di Oncologia, Università degli Studi di Torino, Turin, Italy. 9. Dipartimento di Oncologia, Istituto Mario Negri - IRCCS, Milan, Italy. 10. Precision Oncology, IFOM-FIRC Institute of Molecular Oncology, Milan, Italy. 11. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy. Electronic address: salvatore.siena@unimi.it.
Abstract
BACKGROUND: ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences. PATIENTS AND METHODS: Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging. RESULTS: A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval [CI] 3.7-6.1). Median overall survival was 10.0 months (95% CI 7.9-15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients. CONCLUSIONS: Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies. Clinicaltrials. Gov identifier: NCT 03225937.
BACKGROUND:ERBB2 amplification occurs in 5% of RAS wild-type metastatic colorectal cancer (mCRC) and it has been shown to be a target for treatment with 2 HER2-directed combinations of trastuzumab and lapatinib or trastuzumab and pertuzumab. We present long-term clinical results of trastuzumab and lapatinib (HERACLES-A trial) at 6.7 years (82 months) follow-up and focus on central nervous system (CNS) recurrences. PATIENTS AND METHODS: Patients had histologically confirmed KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive mCRC. HER2 positivity was assessed by immunohistochemistry and in situ hybridization HERACLES diagnostic criteria. Patients were treated with intravenous trastuzumab 4 mg/kg loading dose, then 2 mg/kg once per week, and oral lapatinib 1000 mg per day until disease progression or toxicity. Patients who presented with symptoms or signs of CNS disease received brain computed tomography scan or magnetic resonance imaging. RESULTS: A total of 35 patients received trastuzumab and lapatinib and 32 were evaluable for response. One patient (3%) achieved complete response (CR), 8 (25%) partial response, and 13 (41%) stable disease. Therefore, response rate was 28%. Median progression-free survival was 4.7 months (95% confidence interval [CI] 3.7-6.1). Median overall survival was 10.0 months (95% CI 7.9-15.8). One patient achieved sustained CR still maintained at 7 years of follow-up. Progression in the central nervous system (CNS) occurred in 6 (19%) of 32 patients. CONCLUSIONS: Long-term (6.7 years) follow-up analysis of HERACLES-A supports using of trastuzumab and lapatinib as treatment reference for KRAS wild-type, chemorefractory HER2-positive mCRC. In this subset of patients, prolongation of survival is accompanied by CNS recurrences that will require diagnostic and therapeutic attention in future studies. Clinicaltrials. Gov identifier: NCT 03225937.