RESUMEN
BACKGROUND: To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS: Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS: Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS: Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION: NCT01679405 August, 2012.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Adulto , Afatinib/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/metabolismo , Neoplasias del Sistema Biliar/mortalidad , Biomarcadores , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Transducción de Señal , Investigación Biomédica Traslacional , Resultado del Tratamiento , GemcitabinaRESUMEN
INTRODUCTION: Lung cancer tumors present EGFR mutations associated with an increased response rate to tyrosine kinase inhibitors (TKIs). Afatinib acts as an irreversible pan-ErbB-TKI. Areas covered: This review summarizes the results of clinical trials in NSCLC regarding its safety and efficacy. Expert opinion: Afatinib in 40 mg doses is highly effective in patients with NSCLC and EGFR mutations, improving progression-free survival and disease-related symptoms compared to chemotherapy. Additionally, afatinib has a better response rate and shows a small benefit in progression free survival compared to first-generation TKIs, and patients with exon 19 deletion could represent a subgroup with better prognosis and overall survival. Diarrhea, mucositis and rash are frequent adverse events induced by afatinib, these can impair quality of life and sometimes afatinib discontinuation is necessary. Management of adverse events, including early antidiarrheal treatment and prophylactic or early antibiotic management can reduce the gastrointestinal and cutaneous adverse events, respectively. Different risk factors, including malnourishment, sarcopenia, and low body surface might be associated with a higher toxicity risk, and these groups of patients could begin treatment with a low dose of afatinib followed by a close evaluation on tolerability and toxicity in order to slowly increase the dosage of afatinib.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Afatinib , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Receptores ErbB , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Calidad de Vida , Quinazolinas/efectos adversos , Factores de RiesgoRESUMEN
AIMS: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. MATERIALS & METHODS: Patients received afatinib 10-20 mg daily plus nintedanib 150-200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. RESULTS: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. CONCLUSION: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Adulto , Afatinib , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Indoles/administración & dosificación , Indoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/administración & dosificación , Quinazolinas/farmacocinética , Resultado del TratamientoRESUMEN
To overcome T790M-mediated acquired resistance of lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), second generation TKIs such as BIBW2992 (afatinib) and third generation TKIs including WZ4002 have been developed. However, clinical data on their efficacy in treating T790M mutant tumors are lacking. Histone deacetylase (HDAC) inhibitors have been reported to arrest cell growth and to lead to differentiation and apoptosis of various cancer cells, both in vitro and in vivo. In the present study, we assessed whether the combination of suberoylanilide hydroxamic acid (SAHA, vorinostat), a potent HDAC inhibitor, and BIBW2992 or WZ4002 could overcome EGFR TKI resistance associated with T790M mutation in lung cancer cells. While treatment with BIBW2992 or WZ4002 alone slightly reduced the viability of PC-9G and H1975 cells, which possess T790M mutation, combining them with SAHA resulted in significantly decreased cell viability through the activation of the apoptotic pathway. This combination also enhanced autophagy occurrence and inhibition of autophagy significantly reduced the apoptosis induced by the combination treatment, showing that autophagy is required for the enhanced apoptosis. Caspase-independent autophagic cell death was also induced by the combination treatment with SAHA and either BIBW2992 or WZ4002. Finally, the combined treatment with SAHA and either BIBW2992 or WZ4002 showed an enhanced anti-tumor effect on xenografts of H1975 cells in vivo. In conclusion, the combination of new generation EGFR TKIs and SAHA may be a new strategy to overcome the acquired resistance to EGFR TKIs in T790M mutant lung cancer.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Receptores ErbB/genética , Ácidos Hidroxámicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Acrilamidas/farmacología , Afatinib , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis , Autofagia , Caspasas/metabolismo , Línea Celular Tumoral , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Ratones , Mutación , Trasplante de Neoplasias , Pirimidinas/farmacología , Quinazolinas/farmacología , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Afatinib (BIBW 2992) is an irreversible multi-target HER receptor tyrosine kinase inhibitor developed in patients with advanced solid tumours. Several phase I studies were conducted in patients with non-small cell lung cancer (NSCLC), as a single agent or in combination. In further phase II or III studies, patients were selected based on the duration of response to first generation EGFR-TKI in previous line (supposed to have greater chance to have an activating EGFR mutation) or based directly on the EGFR activating mutation status. Here, we report and comment the main results of these studies in lung cancer patients. This drug has been approved by the Food and Drug Administration in June 2013 for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR mutation. In Europe, it has been approved in September 2013 in the same indication.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Afatinib , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Ensayos Clínicos como Asunto , Análisis Mutacional de ADN , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Aprobación de Drogas , Francia , Humanos , Neoplasias Pulmonares/genética , Quinazolinas/efectos adversosRESUMEN
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are valuable treatments for EGFR-mutated non-small cell lung cancer (NSCLC). Anti-EGFR antibodies are widely used in the treatment of head and neck squamous cell carcinomas (HNSCC) and in KRAS wild-type colorectal cancer. The first-generation, reversible EGFR inhibitors erlotinib and gefitinib in the first-line setting provide superior progression-free survival and quality of life compared to conventional chemotherapy in NSCLC harboring activating EGFR mutations. However, these therapies eventually fail and new options are needed. Afatinib is a novel irreversible inhibitor of the ErbB family members EGFR, tyrosine kinase-type cell surface receptors HER2 and HER4. It shows preclinical efficacy in NSCLC with common EGFR-activating mutations and the T790M mutation typically associated with EGFR TKI resistance. Preclinical activity is seen in other tumor types as well, including HNSCC. Clinically, afatinib has been evaluated in the broad-reaching LUX Lung trial program, with significant activity seen in the first and later-line settings. It is also under investigation in multiple other tumor types. This review will stress on afatinib's preclinical pharmacology, pharmacokinetics and clinical activity with a focus on NSCLC.