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Anticuerpos Monoclonales Humanizados , Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Quimioterapia Adyuvante , Neoplasias Hepáticas/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores de Puntos de Control Inmunológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab/uso terapéuticoRESUMEN
BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Humanos , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Espera Vigilante , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugíaRESUMEN
We assess the longitudinal tumor growth inhibition (TGI) metrics and overall survival (OS) predictions applied to patients with advanced biliary tract cancer (BTC) enrolled in IMbrave151 a multicenter randomized phase II, double-blind, placebo-controlled trial evaluating the efficacy and safety of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine. Tumor growth rate (KG) was estimated for patients in IMbrave151. A pre-existing TGI-OS model for patients with hepatocellular carcinoma in IMbrave150 was modified to include available IMbrave151 study covariates and KG estimates and used to simulate IMbrave151 study outcomes. At the interim progression-free survival (PFS) analysis (98 patients, 27 weeks follow-up), clear separation in tumor dynamic profiles with a faster shrinkage rate and slower KG (0.0103 vs. 0.0117 week-1 ; tumor doubling time 67 vs. 59 weeks; KG geometric mean ratio of 0.84) favoring the bevacizumab containing arm was observed. At the first interim analysis for PFS, the simulated OS hazard ratio (HR) 95% prediction interval (PI) of 0.74 (95% PI: 0.58-0.94) offered an early prediction of treatment benefit later confirmed at the final analysis, observed HR of 0.76 based on 159 treated patients and 34 weeks of follow-up. This is the first prospective application of a TGI-OS modeling framework supporting gating of a phase III trial. The findings demonstrate the utility for longitudinal TGI and KG geometric mean ratio as relevant end points in oncology studies to support go/no-go decision making and facilitate interpretation of the IMbrave151 results to support future development efforts for novel therapeutics for patients with advanced BTC.
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Neoplasias del Sistema Biliar , Neoplasias Hepáticas , Humanos , Bevacizumab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/etiología , Neoplasias del Sistema Biliar/patología , Cisplatino/uso terapéutico , Modelos de Riesgos Proporcionales , Toma de DecisionesRESUMEN
INTRODUCTION: Biliary tract cancers (BTCs) have a dismal prognosis and limited treatment options. The role of immunotherapy in BTC is unclear. BTCs respond poorly to PD-(L)1 blockade, highlighting the need for combination regimens to augment antitumor immunity. Atezolizumab (anti-PD-L1) combined with other therapies is under investigation in advanced BTC. AREAS COVERED: This paper provides an overview of the recent progress and future applications of immunotherapy for BTCs and sheds light on the status and therapeutic potential of atezolizumab. We discuss published data for atezolizumab and an examine the rationale and design of ongoing clinical studies. We offer insights and opinions on the future applications and challenges of immunotherapy in BTC. EXPERT OPINION: Atezolizumab monotherapy has demonstrated limited antitumor activity in BTC, indicating the need for combination regimens to unlock effective anticancer immunity, and the development of predictive biomarkers to enrich the population. Data for atezolizumab combined with chemotherapy, anti-VEGF agents and other targeted drugs in solid tumors justifies their evaluation in BTC. Several novel atezolizumab-based combinations have been or are currently under investigation in Phase II studies. It is hoped that data from these studies, along with other immunotherapy trials, will provide more effective treatments for patients with BTC.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias del Sistema Biliar/tratamiento farmacológico , Inmunoterapia/métodos , Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias del Sistema Biliar/patología , Humanos , Terapia Molecular Dirigida , PronósticoRESUMEN
BACKGROUND: Biliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit. METHODS: IMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses. DISCUSSION: IMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC. TRIAL REGISTRATION: NCT identifier: NCT04677504; EUDRACT number: 2020-003759-14.
RESUMEN
Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.
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Inhibidores de la Angiogénesis/farmacología , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunomodulación/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Pronóstico , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma. METHODS: GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment. FINDINGS: In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0-16·2), 37 (36%; 95% CI 26-46) of 104 patients had a confirmed objective response. The most common grade 3-4 treatment-related adverse events were hypertension (13 [13%]) and proteinuria (seven [7%]). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5-8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2-8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6-7·4) versus 3·4 months (1·9-5·2; hazard ratio 0·55; 80% CI 0·40-0·74; p=0·011). The most common grade 3-4 treatment-related adverse events in group F were hypertension (in three [5%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two [3%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths. INTERPRETATION: Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial. FUNDING: F Hoffmann-La Roche/Genentech.
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Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Neovascularización Patológica , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/inmunología , Transducción de Señal , Factores de Tiempo , Adulto JovenRESUMEN
Hepatocellular carcinoma recurs in 70-80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival. Clinical Trial Registration: NCT04102098.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/mortalidad , Ablación por Catéter , Terapia Combinada , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/mortalidad , Masculino , Cuidados Posoperatorios , Proyectos de Investigación , RetratamientoRESUMEN
BACKGROUND: Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222). MATERIALS AND METHODS: Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations. RESULTS: Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. CONCLUSION: Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversosRESUMEN
IMPORTANCE: Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. OBJECTIVE: To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry. INTERVENTIONS: Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg). MAIN OUTCOMES AND MEASURES: Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab. CONCLUSIONS AND RELEVANCE: Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01662869.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Unión Esofagogástrica , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/metabolismo , Método Doble Ciego , Transición Epitelial-Mesenquimal , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Análisis de Intención de Tratar/métodos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismoRESUMEN
PURPOSE: To characterize cobimetinib pharmacokinetics and evaluate impact of clinically relevant covariates on cobimetinib pharmacokinetics. METHODS: Plasma samples (N = 4886) were collected from 487 patients with various solid tumors (mainly melanoma) in three clinical studies (MEK4592g, NO25395, GO28141). Cobimetinib was administered orally, once daily on either a 21-day-on/7-day-off, 14-day-on/14-day-off or 28-day-on schedule in a 28-day dosing cycle as single agent or in combination with vemurafenib. Cobimetinib doses ranged from 2.1 to 125 mg. NONMEM was used for pharmacokinetic analysis. RESULTS: A linear two-compartment model with first-order absorption, lag time and first-order elimination described cobimetinib pharmacokinetics. The typical estimates (inter-individual variability) of apparent clearance (CL/F), central volume of distribution (V2/F) and terminal half-life were 322 L/day (58 %), 511 L (49 %) and 2.2 days, respectively. Inter-occasion variability on relative bioavailability was estimated at 46 %. CL/F decreased with age. V2/F increased with body weight (BWT). However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib. CONCLUSION: A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.
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Antineoplásicos/farmacocinética , Azetidinas/farmacocinética , Neoplasias/tratamiento farmacológico , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azetidinas/sangre , Azetidinas/uso terapéutico , Peso Corporal , Citocromo P-450 CYP3A/metabolismo , Esquema de Medicación , Femenino , Glucuronosiltransferasa/metabolismo , Semivida , Humanos , Inactivación Metabólica/efectos de los fármacos , Indoles/administración & dosificación , Riñón/fisiopatología , Hígado/fisiopatología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias/sangre , Piperidinas/sangre , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Sulfonamidas/administración & dosificación , Vemurafenib , Adulto JovenRESUMEN
BACKGROUND: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azetidinas/administración & dosificación , Indoles/administración & dosificación , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Piperidinas/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azetidinas/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Indoles/efectos adversos , Estimación de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Mutación , Piperidinas/efectos adversos , Sulfonamidas/efectos adversos , Tasa de Supervivencia , VemurafenibRESUMEN
Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias Esofágicas/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Animales , Antineoplásicos/farmacología , Diseño de Fármacos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Factor de Crecimiento de Hepatocito/genética , Humanos , Terapia Molecular Dirigida/métodos , Proteínas Proto-Oncogénicas c-met/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway is associated with poor prognosis, more aggressive biological characteristics of the tumor, and shortened survival in patients with metastatic colorectal cancer (mCRC). Onartuzumab (MetMAb) is a recombinant humanized monovalent monoclonal antibody directed against MET. We present the treatment rationale and protocol for an ongoing randomized multicenter placebo-controlled phase II study designed to evaluate the efficacy and safety of MetMAb combined with bevacizumab and mFOLFOX-6 (5-fluoruracil, leucovorin, and oxaliplatin). PATIENTS AND METHODS: Eligible patients with previously untreated mCRC are randomized 1:1 to either mFOLFOX-6 combined with bevacizumab and placebo followed by 5-fluorouracil/leucovorin plus bevacizumab and placebo or mFOLFOX6, bevacizumab plus MetMAb followed by 5 FU/LV, bevacizumab, and MetMAb. The primary end point of this study is progression-free survival (PFS) in the intent-to-treat (ITT) population. Secondary end points include overall survival (OS), objective response rate, and safety. Subanalyses will be performed to evaluate the effect of MET receptor expression on study primary and secondary end points. Correlative studies will be performed on tissue- and blood-derived biomarkers related to both HGF/MET signaling and other associated pathway markers.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Proyectos de Investigación , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/secundario , Método Doble Ciego , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
AIM: The objective of this economic evaluation, which was based on patients from two randomized controlled clinical trials (NO16966 and NO16967), was to compare direct medical costs to the Australian health-care system of capecitabine plus oxaliplatin (XELOX) and bolus and/or infusional 5-fluorouracil (5-FU) plus folinic acid combined with oxaliplatin (modified [m] FOLFOX-6) in first-line and second-line treatment of advanced or metastatic colorectal cancer (mCRC). METHODS: Direct medical costs were estimated for five treatment settings from a public and private hospital. The costs included in evaluation were for drug acquisition, preparation (oxaliplatin, bolus and infusional 5-FU), administration and wastage. The cost of drug acquisition was calculated based on dosage data and the mean number of treatment cycles from the pivotal studies NO16966 and NO16967. There were no costs associated with preparing capecitabine and leucovorin. An oncology grouping and costing study was performed to determine the relevant administration costs associated with central venous access devices, their placement, maintenance and removal (for oxaliplatin administration) and the continuous infusion of 5-FU via a continuous ambulatory delivery device pump or infuser. RESULTS: This economic evaluation has shown that treating mCRC patients with XELOX in the first and second-line settings results in average cost savings of $9110 and $7113, respectively, compared with mFOLFOX-6. A multi-way sensitivity analysis demonstrated that the use of XELOX remained cost-saving from an Australian government health budget perspective. CONCLUSION: The use of XELOX, compared with mFOLFOX-6, for the treatment of mCRC is cost-saving in the Australian government health budget.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/economía , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Australia , Capecitabina , Neoplasias Colorrectales/patología , Análisis Costo-Beneficio , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/economía , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Fluorouracilo/economía , Humanos , Leucovorina/administración & dosificación , Leucovorina/economía , Masculino , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/economía , Oxaloacetatos , Ensayos Clínicos Controlados Aleatorios como Asunto/economíaRESUMEN
Delta-opioid receptor (DOPr) activation fails to produce cellular physiological responses in many brain regions, including the periaqueductal gray (PAG), despite neural expression of high densities of the receptor. Previous histochemical studies have demonstrated that a variety of stimuli, including chronic morphine treatment, induce the translocation of DOPr from intracellular pools to the surface membrane of CNS neurons. PAG neurons in slices taken from untreated mice exhibited mu-opioid receptor (MOPr) but not DOPr-mediated presynaptic inhibition of GABAergic synaptic currents. In contrast, after 5-6 d of chronic morphine treatment, DOPr stimulation inhibited synaptic GABA release onto most neurons. Shorter exposure to morphine in vitro (upto 4 h) or in vivo (18 h) did not induce functional DOPr responses. DOPr-mediated presynaptic inhibition could not be induced in slices from untreated animals by increasing synaptic activity in vitro using high extracellular potassium concentrations or activation of protein kinase A. Induction of functional DOPr signaling by chronic morphine required MOPr expression, because no DOPr receptor responses were observed in MOPr knock-out mice. DOPr agonists also had no effect on miniature IPSCs in beta-arrestin-2 knock-out mice after chronic morphine. These results suggest that induction of DOPr-mediated actions in PAG by chronic morphine requires prolonged MOPr stimulation and expression of beta-arrestin-2.
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Morfina/administración & dosificación , Narcóticos/administración & dosificación , Neuronas/efectos de los fármacos , Sustancia Gris Periacueductal/citología , Receptores Opioides delta/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Arrestinas/deficiencia , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/fisiología , Glicinérgicos/farmacología , Técnicas In Vitro , Isoquinolinas/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Potenciales de la Membrana/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas de Narcóticos/farmacología , Oligopéptidos/farmacología , Técnicas de Placa-Clamp/métodos , Sustancia Gris Periacueductal/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Receptores Opioides mu/deficiencia , Estricnina/farmacología , Sulfonamidas/farmacología , Transmisión Sináptica/efectos de los fármacos , Factores de Tiempo , Xantinas/farmacología , Arrestina beta 2 , beta-Arrestinas , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms.
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Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Neuronas/metabolismo , Trastornos Relacionados con Opioides/metabolismo , Sustancia Gris Periacueductal/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/fisiología , Animales , Canales de Cloruro/efectos de los fármacos , Canales de Cloruro/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Proteínas Transportadoras de GABA en la Membrana Plasmática , Masculino , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/efectos de los fármacos , Trastornos Relacionados con Opioides/fisiopatología , Técnicas de Cultivo de Órganos , Sustancia Gris Periacueductal/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The dorsal raphe nucleus (DRN) projects serotonergic axons throughout the brain and is involved in a variety of physiological functions. However, it also includes a large population of cells that contain other neurotransmitters. To clarify the physiological and pharmacological differences between the serotonergic and nonserotonergic neurons of the DRN, their postsynaptic responses to 5-hydroxytryptamine (5-HT, serotonin) and to selective activation of 5-HT1A or 5-HT2A/C receptors and their action potential characteristics were determined using in vitro patch-clamp recordings. The slices containing these neurons were then immunostained for tryptophan hydroxylase (TPH), a marker of serotonergic neurons. It was found that subpopulations of both serotonergic and nonserotonergic neurons responded to 5-HT with outward (i.e., inhibitory) and inward (i.e., excitatory) currents, responded to both 5-HT1A and 5-HT2A/C receptor activation with outward and inward currents, respectively, and displayed overlapping action potential characteristics. These findings suggest that serotonergic and nonserotonergic neurons in the DRN are both heterogeneous with respect to their individual pharmacological and electrophysiological characteristics. The findings also suggest that the activity of the different populations of DRN neurons will display heterogeneous changes when the serotonergic tone in the DRN is altered by neurological disorders or by drug treatment.
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Neuronas/fisiología , Núcleos del Rafe/citología , Núcleos del Rafe/fisiología , Serotonina/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Inmunohistoquímica , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Serotonina/farmacología , Triptófano Hidroxilasa/metabolismoRESUMEN
Chronic treatment with opioids induces adaptations in neurons leading to tolerance and dependence. Studies have implicated the midbrain periaqueductal gray (PAG) in the expression of many signs of withdrawal. Patch-clamp recording techniques were used to examine whether augmentation of adenylyl cyclase signalling produces hyperexcitation in GABAergic nerve terminals within the mouse PAG. Both the rate of mIPSCs and the amplitude of evoked IPSCs during naloxone-precipitated withdrawal was profoundly enhanced in chronically morphine treated mice, compared to vehicle treated controls, in the presence but not the absence an adenosine A(1) receptor antagonist DPCPX. Enhanced GABAergic transmission in the presence of DPCPX was abolished by blocking protein kinase A. Inhibitors of cAMP transport, phosphodiesterase and nucleotide transport mimicked the effect of DPCPX. Coupling efficacy of micro-receptors to presynaptic inhibition of GABA release was increased in dependent mice in the presence of DPCPX. The increased coupling efficacy was abolished by blocking protein kinase A, which unmasked an underlying micro-receptor tolerance. These findings indicate that enhanced adenylyl cyclase signalling following chronic morphine treatment produces (1) GABAergic terminal hyperexcitability during withdrawal that is retarded by a concomitant increase in endogenous adenosine, and (2) enhanced micro-receptor coupling to presynaptic inhibition that overcomes an underlying tolerance.
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Adenosina/análogos & derivados , AMP Cíclico/análogos & derivados , Mesencéfalo/citología , Dependencia de Morfina/metabolismo , Neuronas/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/metabolismo , Sulfonamidas , Tioinosina/análogos & derivados , Ácido gamma-Aminobutírico/metabolismo , Potenciales de Acción/efectos de los fármacos , Adenosina/farmacología , Marcadores de Afinidad/farmacología , Animales , Colforsina/farmacología , AMP Cíclico/farmacología , Dipiridamol/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Encefalinas/farmacología , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Isoquinolinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Naloxona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Narcóticos/administración & dosificación , Inhibición Neural/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Probenecid/farmacología , Agonistas del Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Transmisión Sináptica/efectos de los fármacos , Tioinosina/farmacología , Factores de Tiempo , Uricosúricos/farmacología , Vasodilatadores/farmacología , Xantinas/farmacologíaRESUMEN
1 Patch clamp recordings were made from periaqueductal grey (PAG) neurons in vitro to investigate the cellular actions of opioids in wild-type C57B16/J mice and mutant mice lacking the first exon of the micro -opioid (MOP) receptor. 2 In wild-type mice, the kappa-(KOP) agonist U-69593 (300 nM) and the mixed micro /delta-opioid agonist met-enkephalin (10 micro M), but not the delta-(DOP) agonist deltorphin (300 nM), reduced the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs). Met-enkephalin and U-69593 also reduced the rate of spontaneous miniature IPSCs, but had no effect on their amplitude and kinetics. In micro -receptor-deleted mice, only U-69593 (300 nM) reduced the amplitude of evoked IPSCs. 3 In wild-type mice, the MOP agonist DAMGO (3 micro M) produced an outward current in 76% of the neurons. Deltorphin and U-69593 produced outward currents in 24 and 32% of the neurons, respectively. In micro -receptor-deleted mice, deltorphin and U-69593 produced similar outward currents in 32 and 27% of the neurons, respectively, while DAMGO was without effect. All neurons in both the wild-type and micro -receptor-deleted mice responded with similar outward currents to either the GABA(B) receptor agonist baclofen (10 micro M), or the opioid-like receptor ORL1 (NOP) agonist nociceptin (300 nM). 4 The DAMGO-, deltorphin-, U-69593-, baclofen- and nociceptin-induced currents displayed inward rectification and reversed polarity at -109 to -116 mV. 5 These findings indicate that micro -, delta- and kappa-opioid receptor activation has complex pre- and postsynaptic actions within the mouse PAG. This differs to the rat PAG where only micro -opioid receptor actions have been observed.