RESUMEN
PURPOSE: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events). METHODS: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected. RESULTS: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69). CONCLUSION: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Crizotinib/efectos adversos , Crizotinib/sangre , Crizotinib/farmacocinética , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Compuestos Organofosforados/efectos adversos , Compuestos Organofosforados/sangre , Compuestos Organofosforados/farmacocinética , Supervivencia sin Progresión , Pirimidinas/efectos adversos , Pirimidinas/sangre , Pirimidinas/farmacocinética , Calidad de Vida , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVES: Given a lack of universally-accepted standard-of-care treatment for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), study objectives were to assess treatment utilization and survival outcomes for R/M HNSCC in the real-world setting. MATERIALS AND METHODS: A multi-site retrospective chart review was conducted in Europe (Germany, United Kingdom, Italy, Spain), Asia Pacific (Australia, South Korea, Taiwan), and Latin/North America (Brazil and Canada) to identify patients who initiated first-line systemic therapy for R/M HNSCC between January 2011 and December 2013. Patients were followed through December 2015 to collect clinical characteristics, treatment and survival data. RESULTS: Among 733 R/M HNSCC patients across 71 sites, median age was 60 years (inter-quartile range 54-67), 84% male, and 70% Eastern Cooperative Oncology Group performance status 0-1; 32% had oral cavity and 30% oropharyngeal cancers. The most common first-line regimen across all countries consisted of platinum-based combinations (73%), including platinum + 5-fluorouracil (5-FU) (26%), cetuximab + platinum ± 5-FU (22%), or taxane + platinum ± 5-FU (16%). However, use of different platinum-based combinations varied substantially; administration of cetuximab + platinum ± 5-FU was frequent in Italy (81%), Germany (46%) and Spain (38%), whereas use in other countries was limited. Median follow-up was 22.6 months (95% confidence interval [CI]: 21.5-24.6 months). Median real-world overall survival was only 8.0 months (95% CI: 7.0-8.0), with one-year survival reaching only 30.9% (95% CI: 27.5-34.3). CONCLUSION: Systemic therapies used in clinical practice for patients with R/M HNSCC vary substantially across countries. Prognosis remains poor in this patient population, highlighting the need for newer, more efficacious treatments.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Anciano , Australia , Brasil , Hidrocarburos Aromáticos con Puentes , Canadá , Cetuximab/administración & dosificación , Intervalos de Confianza , Europa (Continente) , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Estimación de Kaplan-Meier , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Compuestos de Platino/uso terapéutico , República de Corea , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/secundario , Taiwán , Taxoides , Resultado del TratamientoRESUMEN
PURPOSE: Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. PATIENTS AND METHODS: Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). RESULTS: At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. CONCLUSION: Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.