Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): A proof-of-concept, multicentre, open-label, phase 2 trial
| Autor: | Andrea Bertotti, Salvatore Siena, Andrea Cassingena, Francesco Leone, Ilaria Depetris, Silvio Veronese, Daniele Regge, Cosimo Martino, Fortunato Ciardiello, Emanuele Valtorta, Erika Martinelli, Paolo M. Comoglio, Valter Torri, Silvia Ghezzi, Katia Bencardino, Giovanna Marrapese, Andrea Sartore-Bianchi, Francesca Bergamo, Vittorina Zagonel, Giulia Siravegna, Patrizia Racca, Sara Lonardi, Livio Trusolino, Silvia Marsoni, Calogero Lauricella, Angelo Vanzulli, Teresa Troiani, Alessio Amatu, Laura Palmeri, Alberto Bardelli |
|---|---|
| Přispěvatelé: | Sartore Bianchi, A, Trusolino, L, Martino, C, Bencardino, K, Lonardi, S, Bergamo, F, Zagonel, V, Leone, F, Depetris, I, Martinelli, Erika, Troiani, Teresa, Ciardiello, Fortunato, Racca, P, Bertotti, A, Siravegna, G, Torri, V, Amatu, A, Ghezzi, S, Marrapese, G, Palmeri, L, Valtorta, E, Cassingena, A, Lauricella, C, Vanzulli, A, Regge, D, Veronese, S, Comoglio, Pm, Bardelli, A, Marsoni, S, Siena, S. |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Male Colorectal cancer Receptor ErbB-2 medicine.disease_cause Immunoenzyme Techniques 0302 clinical medicine Trastuzumab Antineoplastic Combined Chemotherapy Protocols Medicine Molecular Targeted Therapy Neoplasm Metastasis skin and connective tissue diseases education.field_of_study Cetuximab Middle Aged Prognosis Survival Rate 030220 oncology & carcinogenesis Female KRAS Colorectal Neoplasms medicine.drug Adult medicine.medical_specialty Population Lapatinib Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Internal medicine Biomarkers Tumor Panitumumab Humans metastaticCRC HER2 lapatinib trastuzumab education Codon Aged Neoplasm Staging Salvage Therapy business.industry Cancer medicine.disease Surgery 030104 developmental biology Drug Resistance Neoplasm Quinazolines Neoplasm Recurrence Local business Follow-Up Studies |
| Popis: | Summary Background We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2 -amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. Methods HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Findings Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51–127), eight (30%, 95% CI 14–50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI −3 to 11) achieving a complete response, and seven (26%, 95% CI 9–43) achieving partial responses; 12 (44%, 95% CI 25–63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. Interpretation The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Funding Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|