PMID- 30278378 OWN - NLM STAT- MEDLINE DCOM- 20191002 LR - 20191002 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 104 DP - 2018 Nov TI - A phase 1b study of afatinib in combination with standard-dose cetuximab in patients with advanced solid tumours. PG - 1-8 LID - S0959-8049(18)30970-5 [pii] LID - 10.1016/j.ejca.2018.07.011 [doi] AB - This phase 1b, open-label trial assessed the combination of afatinib, an ErbB family blocker, with cetuximab, an epidermal growth factor receptor (EGFR) monoclonal antibody, in heavily pretreated patients with unselected/EGFR wild-type, advanced solid tumours. In Part A, the maximum tolerated dose (MTD) of afatinib + cetuximab was evaluated using a 3 + 3 dose-escalation design; the starting dose was afatinib 30 mg/day plus cetuximab 250 mg/m(2)/week (after cetuximab 400 mg/m(2) loading dose), escalating to afatinib 40 mg/day. Part B further evaluated safety and tolerability at the MTD and preliminary anti-tumour activity in three patient cohorts with squamous non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and other solid tumours. Nine patients were treated in Part A; the MTD and recommended dose was determined as afatinib 40 mg/day plus cetuximab 250 mg/m(2)/week. In Part B, 49 patients were treated at the recommended dose (12 with squamous NSCLC, 15 with HNSCC and 22 with other tumours). The most common treatment-related adverse events (AEs) across all 58 patients were diarrhoea (63.8%) and acneiform dermatitis (43.1%). Overall, the best confirmed response was stable disease (SD; 53.4%); mean duration of disease control was 4.5 months; median progression-free survival was 2.6 months. In Part B, 55.1% of patients had SD (squamous NSCLC, 75.0%; HNSCC, 66.7%; other tumours; 36.4%). In conclusion, the recommended phase 2 dose was determined as afatinib 40 mg/day plus cetuximab 250 mg/m(2)/week. AEs were predictable and manageable, and anti-tumour activity was observed in some patients, particularly in those with squamous NSCLC and HNSCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02020577. CI - Copyright (c) 2018. Published by Elsevier Ltd. FAU - Gazzah, Anas AU - Gazzah A AD - Drug Development Department, Gustave Roussy Cancer Campus, 114 Rue Edouard-Vaillant, 94805 Villejuif Cedex, France. Electronic address: anas.gazzah@gustaveroussy.fr. FAU - Boni, Valentina AU - Boni V AD - Medical Oncology Division, START Madrid Centro Integral Oncologico Clara Campal, Calle de Ona, 10, 28050, Madrid, Spain. Electronic address: valentina.boni@start.stoh.com. FAU - Soria, Jean-Charles AU - Soria JC AD - Drug Development Department, Gustave Roussy Cancer Campus, 114 Rue Edouard-Vaillant, 94805 Villejuif Cedex, France. Electronic address: soria@igr.fr. FAU - Calles, Antonio AU - Calles A AD - Medical Oncology Division, START Madrid Centro Integral Oncologico Clara Campal, Calle de Ona, 10, 28050, Madrid, Spain; Medical Oncology Department, Hospital General Universitario Gregorio Maranon, Instituto de Investigacion Sanitaria Gregorio Maranon (IiSGM), Calle Del Dr. Esquerdo, 46, 28007 Madrid, Spain. Electronic address: antonio.calles@live.com. FAU - Even, Caroline AU - Even C AD - Department of Head and Neck Cancer, Gustave Roussy Cancer Campus, 114 Rue Edouard-Vaillant, 94805 Villejuif Cedex, France. Electronic address: caroline.even@gustaveroussy.fr. FAU - Doger, Bernard AU - Doger B AD - Medical Oncology Phase I Unit, START Madrid Fundacion Jimenez Diaz, Av. Reyes Catolicos, 2, 28040 Madrid, Spain. Electronic address: bernard.doger@start.stoh.com. FAU - Mahjoubi, Linda AU - Mahjoubi L AD - Drug Development Department, Gustave Roussy Cancer Campus, 114 Rue Edouard-Vaillant, 94805 Villejuif Cedex, France. Electronic address: linda.mahjoubi@gmail.com. FAU - Bahleda, Rastislav AU - Bahleda R AD - Drug Development Department, Gustave Roussy Cancer Campus, 114 Rue Edouard-Vaillant, 94805 Villejuif Cedex, France. Electronic address: rastilav.bahleda@igr.fr. FAU - Ould-Kaci, Mahmoud AU - Ould-Kaci M AD - Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. Electronic address: mahmoud.ould_kaci@boehringer-ingelheim.com. FAU - Esler, Anne AU - Esler A AD - Statistics, Syneos Health, 3201 Beechleaf Court, Raleigh, NC 27604, USA. Electronic address: anne.esler.ext@boehringer-ingelheim.com. FAU - Nazabadioko, Serge AU - Nazabadioko S AD - Medical Department, Boehringer Ingelheim, 12 Rue Andre Huet, 51721 Reims, France. Electronic address: serge.nazabadioko@boehringer-ingelheim.com. FAU - Calvo, Emiliano AU - Calvo E AD - Medical Oncology Division, START Madrid Centro Integral Oncologico Clara Campal, Calle de Ona, 10, 28050, Madrid, Spain. Electronic address: ecalvo@hmhospitales.com. LA - eng SI - ClinicalTrials.gov/NCT02020577 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20181001 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Neoplasm Proteins) RN - 41UD74L59M (Afatinib) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - PQX0D8J21J (Cetuximab) SB - IM EIN - Eur J Cancer. 2019 Sep;119:198. PMID: 31375258 MH - Acneiform Eruptions/chemically induced MH - Afatinib/administration & dosage/adverse effects MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use MH - Carcinoma, Squamous Cell/drug therapy MH - Cetuximab/administration & dosage/adverse effects MH - Diarrhea/chemically induced MH - Dose-Response Relationship, Drug MH - Drug Eruptions/etiology MH - ErbB Receptors/analysis MH - Female MH - Head and Neck Neoplasms/drug therapy MH - Humans MH - Lung Neoplasms/drug therapy MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Proteins/analysis MH - Neoplasms/chemistry/*drug therapy MH - Progression-Free Survival MH - Treatment Outcome OTO - NOTNLM OT - Afatinib OT - Cetuximab OT - ErbB family blocker OT - Phase 1b OT - Solid tumours EDAT- 2018/10/03 06:00 MHDA- 2019/10/03 06:00 CRDT- 2018/10/03 06:00 PHST- 2018/05/30 00:00 [received] PHST- 2018/07/12 00:00 [accepted] PHST- 2018/10/03 06:00 [pubmed] PHST- 2019/10/03 06:00 [medline] PHST- 2018/10/03 06:00 [entrez] AID - S0959-8049(18)30970-5 [pii] AID - 10.1016/j.ejca.2018.07.011 [doi] PST - ppublish SO - Eur J Cancer. 2018 Nov;104:1-8. doi: 10.1016/j.ejca.2018.07.011. Epub 2018 Oct 1.