RESUMO
BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Método Duplo-Cego , Etoposídeo/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Carcinoma de Pequenas Células do Pulmão/mortalidadeRESUMO
BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS: In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS: The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .).
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Quinase do Linfoma Anaplásico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/administração & dosagem , Receptores Proteína Tirosina Quinases/genética , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non-small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG. MATERIALS AND METHODS: Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. RESULTS: One hundred twenty-nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression-free survival (PFS) in the unselected intent-to-treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37-1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16-0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97-4.76; p = .059, HRG-by-treatment interaction, p value = .0016). CONCLUSION: The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). IMPLICATIONS FOR PRACTICE: The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neuregulina-1/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Feminino , Seguimentos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neuregulina-1/antagonistas & inibidores , Seleção de Pacientes , Intervalo Livre de Progressão , Receptor ErbB-3/análise , Receptor ErbB-3/antagonistas & inibidores , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. FUNDING: Bristol-Myers Squibb.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Comorbidade , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nivolumabe , Receptor de Morte Celular Programada 1/metabolismo , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by molecular profiling analysis to be associated with higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance. Survivin's differential expression in cancer compared to normal tissue and its role as a nodal protein in a number of cellular pathways make it a highly flexible therapeutic target, suitable for small-molecule inhibitiors, molecular antagonists, and vaccination-based therapies. By targeting survivin it is hoped that multiple tumor signaling circuitries may be simultaneously disabled. This effect may be applicable to many tumor histologies irrespective of specific genetic makeup. To date, survivin inhibitors have shown modest activity as single agents, but it is anticipated that when given in combination with cytotoxic chemotherapy or monoclonal antibodies they may exhibit enhanced efficacy. This review discusses the complex circuitry of survivin in human cancers and highlights clinical trials involving novel agents that target this important protein.
Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias/terapia , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Ensaios Clínicos como Assunto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia/métodos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/imunologia , Neoplasias/genética , Neoplasias/imunologia , Survivina , Vacinação/métodosAssuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transtorno Depressivo/complicações , Neoplasias Pulmonares/tratamento farmacológico , Negro ou Afro-Americano/estatística & dados numéricos , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Fumar , Veteranos/estatística & dados numéricos , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC. MATERIALS AND METHODS: Patients received up to six 21-day cycles of P 200mg/m2 and C AUC 6 (day 1)±olaratumab 15mg/kg (days 1 and 8). Primary endpoint was PFS. Olaratumab was continued in the olaratumab+P/C arm until disease progression. RESULTS: 131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive. CONCLUSIONS: The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Terapia Combinada , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Epidermal growth factor receptor (EGFR) mutations confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). There are limited and conflicting reports on the frequency of EGFR mutations in Latinos. PATIENTS AND METHODS: Samples from 642 patients with NSCLC from seven institutions in the United States and Latin America were assessed for EGFR mutations (exons 18 to 21) at Clinical Laboratory Improvement Amendments-certified central laboratories. RESULTS: EGFR mutation analysis was successfully performed in 480 (75%) of 642 patients; 90 (19%) were Latinos, 318 (66%) were non-Latino whites, 35 (7%) were non-Latino Asians, 30 (6%) were non-Latino blacks, and seven (2%) were of other races or ethnicities. EGFR mutations were found in 21 (23%) of 90 Latinos with varying frequencies according to the country of origin; Latinos from Peru (37%), followed by the United States (23%), Mexico (18%), Venezuela (10%), and Bolivia (8%). In never-smoker Latinos and Latinos with adenocarcinoma histology, EGFR mutation frequencies were 38% and 30%, respectively. There was a significant difference in the frequency of EGFR mutations among the different racial and ethnic subgroups analyzed (P < .001), with non-Latino Asians having the highest frequency (57%) followed by Latinos (23%), non-Latino whites (19%), and non-Latino blacks (10%). There was no difference between Latinos (23%) and non-Latinos (22%; P = .78) and Latinos and non-Latino whites (P = .37). Patients from Peru had an overall higher frequency of mutations (37%) than all other Latinos (17%), but this difference only exhibited a trend toward significance (P = .058). CONCLUSION: There was no significant difference between the frequency of EGFR mutations in NSCLC in Latinos and non-Latinos.
RESUMO
GABA(C) receptors were first described as a non-desensitizing, bicuculline- and baclofen-insensitive component in Xenopus oocytes expressing bovine retina mRNA. However, the expression, tissue distribution and functional properties of GABA(C) receptors from other areas of the CNS still remain controversial. In previous experiments, the injection of rat cerebellum mRNA into Xenopus oocytes induced the expression of receptors that generated currents with both GABA(A) and GABA(C) characteristics; the latter component apparently being given by the rho2 subunit, suggesting the expression of GABA(C) receptors in the CNS and the formation of homooligomeric receptors. In this study, using RT-PCR, we found that the rho1 and rho2 subunits are widely expressed in the CNS including areas where they have not been previously described such as the bulb, pons and the caudate nucleus. To determine if the GABA(C) component of the GABA-currents elicited by oocytes expressing cerebellum mRNA was caused by activation of homomeric GABA rho2 receptors, we cloned the corresponding cDNA and expressed it in Xenopus oocytes. It was found that oocytes injected with rho2 cDNA, efficiently formed GABA-gated homooligomeric receptors. The GABA-dose-current response gave an EC50=1.19muM and the currents were resistant to bicuculline and reversibly antagonized by the specific GABA(C) receptor antagonist TPMPA. Altogether, our results indicate a widespread distribution of both rho1 and rho2 subunits in the bovine CNS and show further that the rho2 subunit cDNA isolated from cerebellum, forms fully functional receptors when expressed in Xenopus oocytes.
Assuntos
Encéfalo/metabolismo , Receptores de GABA/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Bovinos , Clonagem Molecular , Hibridização In Situ , Dados de Sequência Molecular , Oócitos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de GABA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , XenopusRESUMO
PURPOSE: We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. PATIENTS AND METHODS: We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. RESULTS: Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). CONCLUSION: This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Adolescente , Adulto , Idoso , Benzimidazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Classe I de Fosfatidilinositol 3-Quinases , Receptores ErbB/genética , Cloridrato de Erlotinib , Feminino , Genes ras/genética , Humanos , Indóis/uso terapêutico , Lapatinib , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Pirróis/uso terapêutico , Quinazolinas/uso terapêutico , Reprodutibilidade dos Testes , Carcinoma de Pequenas Células do Pulmão/genética , Sunitinibe , Neoplasias do Timo/genética , Resultado do Tratamento , Adulto Jovem , Proteínas ras/genéticaRESUMO
Improved understanding of the molecular mechanisms involved in development, growth and spread of cancer have led to develpment of targeted therapies for many cancers. Based on their superior tolerability and efficacy, targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or crizotinib are preferred first-line treatments over platinum-based chemotherapies in patients whose tumours harbour EGFR-activating mutations and anaplastic lymphoma kinase (ALK) translocations, respectively. Active areas of research in EGFR-mutant and ALK-translocated NSCLC include identification of mechanisms of resistance and overcoming them. Therapeutic targeting of several other targets including ROS, RET and discoidin domain receptor 2 (DDR2) tyrosine kinases are in early phases of clinical evaluation. Despite the advances in tumour genomic sequencing, a substantial fraction of patients with non-small cell lung cancer (NSCLC) do not have any targetable genetic alteration. Ongoing research is focused on identifying mechanisms of carcinogenesis in these patients. Targeted therapies in small cell lung cancer (SCLC) and thymic malignancies have not yielded meaningful clinical benefits, and platinum-based therapies remain the cornerstone of treating patients with advanced disease.
Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Compostos Organoplatínicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/química , Neoplasias Torácicas/tratamento farmacológico , Animais , Humanos , Prognóstico , Neoplasias Torácicas/enzimologiaRESUMO
PURPOSE: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. EXPERIMENTAL DESIGN: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. RESULTS: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m(2) belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m(2) with chemotherapy (P, 50 mg/m(2) on day 2; A, 25 mg/m(2) on days 2 and 3; C, 500 mg/m(2) on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%-50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8(+) T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3(+) CD8(+) T cells were larger in responders than nonresponders (P = 0.049). CONCLUSION: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3(+) CD8(+) T cells warrant further study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/metabolismo , Sulfonamidas/administração & dosagem , Neoplasias do Timo/metabolismo , Pesquisa Translacional Biomédica/métodos , Adulto JovemRESUMO
The hepatocyte growth factor (HGF)/c-Met signaling pathway mediates angiogenesis. We have previously reported that airway expression of a human HGF transgene (HGF TG) produced mice that were more susceptible to lung tumorigenesis induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK). Here we show untreated HGF TG mice display enhanced vascularization (40 wks) and enhanced lymph vessel formation (20 wks) in the lungs compared to wild-type (WT) littermates, as ascertained by microvessel density. We profiled mRNA expression from HGF TG and WT mice for genes involved in angiogenesis. We consistently found significant decreases in expression of the VEGF family of angiogenic genes, including Vegfa, Vegfb, Vegfc, and Vegfd / Figf. Decreases were confirmed in whole lung protein extracts by immunoblot. Similar patterns of down-regulation were observed at 10, 20, and 40 wks of age. Vandetanib, an inhibitor of VEGFR2 and VEGFR3, did not prevent the increase in microvessel density observed in HGF TG mice. Reduction in VEGF pathway genes was also detected in lung tumors derived from NNK-treated HGF TG mice. HGF TG lung tumors also showed increased expression of five Cxcl family genes including Cxcl1 and Cxcl2 (murine forms of IL8). These results suggest increased vascularization produced by airway over-expression of HGF occurs through direct activation of c-Met on endothelial cells, rather than induction of VEGF pathways. Elevated HGF may also increase expression of inflammatory mediators that contribute to lung tumor progression.
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INTRODUCTION: The Eastern Cooperative Oncology Group (ECOG) 4599 study showed a significant survival benefit with the use of bevacizumab (BV) in combination with carboplatin and paclitaxel (CP) in comparison with CP chemotherapy alone in patients with previously untreated advanced, metastatic or recurrent non-small-cell lung cancer (NSCLC). Such results were achieved using BV as maintenance therapy until progressive disease. Because current data on single-agent BV maintenance in non-small-cell lung cancer are limited, we present a retrospective analysis of safety and efficacy outcomes for patients who received maintenance BV after induction treatment and the maintenance-eligible population of the control arm in ECOG 4599. METHODS: Landmark analyses were conducted in patients in both the CP and CP+BV groups who were alive and progression free through the completion of six cycles + 21 days. The BV maintenance population consisted of patients in the CP+BV arm, who were alive without progressive disease before the start of maintenance (maintenance-nonprogressor population). CP nonprogressors were those patients in the CP-alone arm without progressive disease after six cycles of CP + 21 days. RESULTS: Two hundred and seventeen patients (51%) were alive, progression free, and eligible for maintenance therapy six cycles + 21 days after induction CP+ BV compared with 134 patients (30%) in the CP-alone arm. Postinduction progression-free survival was significantly longer in the BV maintenance group relative to CP nonprogressors (4.4 versus 2.8 months; hazards ratio [HR] 0.64; p < 0.001). One-year overall survival rates were 75% for the BV maintenance group versus 69% in the CP nonprogressor group. Two-year overall survival rates were 34% for the BV maintenance group versus 25% in the CP nonprogressor group. Median postinduction overall survival (OS) was also significantly longer for the BV-maintenance group compared with CP nonprogressors (12.8 versus 11.4 months; HR 0.75; p = 0.030). Within the subgroup having complete response or partial response after induction, the progression-free survival and OS hazard ratio estimates were 0.59 (95% [confidence interval] CI: 0.41-0.84) and 0.78 (95% CI: 0.53-1.14), respectively. In the maintenance setting, BV was associated with a less-than 1% rate of grade 3 or 4 hematological toxicities, no grade 3 or 4 nausea, vomiting or diarrhea, and no grade 5 toxicities. CONCLUSIONS: In this retrospective analysis of patients in the ECOG 4599 study, who were alive, progression free, and on-study 21 days after six cycles of induction therapy, significant reductions in HRs for progression (0.64, p < 0.001) and survival (0.75, p = 0.03) were associated with BV treatment during induction and maintenance compared with CP induction therapy alone and suggestive of possible benefit because of bevacizumab maintenance.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Gerenciamento Clínico , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
CONTEXT: ACTH-producing neuroendocrine tumor (NET) of the thymus is a rare cause of Cushing's syndrome (CS). The literature consists mainly of isolated case reports. PATIENTS: We studied 12 cases (eight males and four females) diagnosed between 1986 and 2010 with CS and thymic NET who underwent surgical resection. MAIN OUTCOME MEASURES: We measured time from onset of CS to diagnosis of thymic NET, tumor size, histological grade, time to recurrence, and survival and performed a meta-analysis of other published cases of CS associated with thymic NET. RESULTS: Eleven of 12 patients presented with classic features of CS at a median age of 21 yr (range, 7-51). Four were children. The 24-h urine free cortisol was greater than 16-fold of normal, and biochemical testing was consistent with ectopic ACTH production in all 11. Another patient presenting with pulmonary embolus had a thymic mass and was later diagnosed with CS. All patients underwent thymectomy, and nine of 10 tumors exhibited positive ACTH immunochemistry. Median tumor diameter was 5 cm (range, 1-11.5). Six patients recurred 20-28 months after surgery with metastases to mediastinal lymph nodes (n = 5), bone (n = 5), liver (n = 1), parotid gland (n = 1), and breast (n = 1). Four of five patients treated with radiation therapy also received chemotherapy. All recurrent patients received ketoconazole; four later underwent bilateral adrenalectomy. Six recurrent patients died 22-90 months (median, 57) after thymectomy. At last review, six patients were alive 14-90 months (median, 49) after thymectomy. These data are similar to those from the meta-analysis. CONCLUSIONS: Thymic ACTH-producing NET is an aggressive disease that should be considered in CS with ectopic ACTH secretion, particularly in younger patients.
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Síndrome de ACTH Ectópico/cirurgia , Tumores Neuroendócrinos/cirurgia , Neoplasias do Timo/cirurgia , Síndrome de ACTH Ectópico/diagnóstico , Adolescente , Adulto , Criança , Estudos de Coortes , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiologia , Síndrome de Cushing/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/metabolismo , Estudos Retrospectivos , Timectomia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/metabolismo , Fatores de Tempo , Adulto JovemRESUMO
Preclinical models and data from clinical trials suggest that cancer is a preventable disease. However, demonstration of a preventive effect requires large phase III clinical trials of long duration and involves many thousands of participants. The decision to proceed with phase III studies therefore must be informed by robust efficacy and safety data. This requires a systematic review of all available preclinical, epidemiological, and clinical data, along with a mechanistic understanding of the biology of the disease under study. In this review we identify the issues that are critical to decision-making prior to embarking on late phase prevention clinical trials and provide a framework for making such decisions.
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Anticarcinógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Quimioprevenção/tendências , Neoplasias/prevenção & controle , Animais , Anticarcinógenos/efeitos adversos , Antineoplásicos/efeitos adversos , Quimioprevenção/métodos , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Medicina Baseada em Evidências , Humanos , Neoplasias/epidemiologia , Medição de Risco , Resultado do TratamentoRESUMO
PURPOSE: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. EXPERIMENTAL DESIGN: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters K(trans), K(ep), and V(e) were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. RESULTS: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. K(ep), was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028). CONCLUSIONS: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.
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Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Genes ras , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Piridinas/uso terapêutico , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Citocinas/análise , Citocinas/metabolismo , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Neovascularização Patológica , Niacinamida/análogos & derivados , Compostos de Fenilureia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , SorafenibeRESUMO
PURPOSE: Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat. PATIENTS AND METHODS: Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had failed were eligible for this study. Other eligibility criteria included adequate organ function and good performance status. Belinostat was administered intravenously at 1 g/m(2) on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance. The primary objective was response rate in patients with thymoma. RESULTS: Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of two previous systemic regimens (range, one to 10 regimens). Treatment was well tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects. Two patients achieved partial response (both had thymoma; response rate, 8%; 95% CI, 2.2% to 25%), 25 had stable disease, and 13 had progressive disease; there were no responses among patients with thymic carcinoma. Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached v 12.4 months; P = .001). Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome. CONCLUSION: Belinostat has modest antitumor activity in this group of heavily pretreated thymic malignancies. However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.