RESUMEN
Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Melanoma/terapia , Viroterapia Oncolítica/efectos adversos , Terapia Combinada , Herpesviridae/genética , Humanos , Inmunoterapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente TumoralRESUMEN
BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Biomarcadores/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Piperazinas/efectos adversos , Supervivencia sin Progresión , Piridinas/efectos adversos , Pirimidinas/efectos adversosRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Piperazinas , Piridinas , Pirimidinas , Adulto , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Lenguaje , MutaciónRESUMEN
Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 µg/day blinatumomab during week 1 and 28 µg/day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 µg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL.
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Anticuerpos Biespecíficos/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/sangre , Anticuerpos Biespecíficos/farmacocinética , Antígenos CD19/genética , Antígenos CD19/inmunología , Linfocitos B/patología , Complejo CD3/genética , Complejo CD3/inmunología , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interferón gamma/sangre , Estimación de Kaplan-Meier , Linfoma de Células B/sangre , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Neoplasia Residual/sangre , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión , Linfocitos T/inmunologíaRESUMEN
Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.
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Aurora Quinasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Ftalazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Administración Oral , Anciano , Biomarcadores , Progresión de la Enfermedad , Esquema de Medicación , Monitoreo de Drogas , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Ftalazinas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Retratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer. METHODS: We recruited patients (≥18 years old) with unresectable locally advanced or metastatic gastric or oesophagogastric junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who had not received previous systemic therapy, from 43 sites worldwide. Phase 1b was an open-label, dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m(2) intravenously on day 1, cisplatin 60 mg/m(2) intravenously on day 1, capecitabine 625 mg/m(2) twice a day orally on days 1-21, respectively), administered every 3 weeks. The phase 1b primary endpoint was the incidence of dose-limiting toxicities in all phase 1b patients who received at least one dose of rilotumumab and completed the dose-limiting toxicity assessment window (first cycle of therapy). Phase 2 was a double-blind study that randomly assigned patients (1:1:1) using an interactive voice response system to receive rilotumumab 15 mg/kg, rilotumumab 7·5 mg/kg, or placebo, plus ECX (doses as above), stratified by ECOG performance status and disease extent. The phase 2 primary endpoint was progression-free survival (PFS), analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00719550. FINDINGS: Seven of the nine patients enrolled in the phase 1b study received at least one dose of rilotumumab 15 mg/kg, only two of whom had three dose-limiting toxicities: palmar-plantar erythrodysesthesia, cerebral ischaemia, and deep-vein thrombosis. In phase 2, 121 patients were randomly assigned (40 to rilotumumab 15 mg/kg; 42 to rilotumumab 7·5 mg/kg; 39 to placebo). Median PFS was 5·1 months (95% CI 2·9-7·0) in the rilotumumab 15 mg/kg group, 6·8 months (4·5-7·5) in the rilotumumab 7·5 mg/kg group, 5·7 months (4·5-7·0) in both rilotumumab groups combined, and 4·2 months (2·9-4·9) in the placebo group. The hazard ratio for PFS events compared with placebo was 0·69 (80% CI 0·49-0·97; p=0·164) for rilotumumab 15 mg/kg, 0·53 (80% CI 0·38-0·73; p=0·009) for rilotumumab 7·5 mg/kg, and 0·60 (80% CI 0·45-0·79; p=0·016) for combined rilotumumab. Any grade adverse events more common in the combined rilotumumab group than in the placebo group included haematological adverse events (neutropenia in 44 [54%] of 81 patients vs 13 [33%] of 39 patients; anaemia in 32 [40%] vs 11 [28%]; and thrombocytopenia in nine [11%] vs none), peripheral oedema (22 [27%] vs three [8%]), and venous thromboembolism (16 [20%] vs five [13%]). Grade 3-4 adverse events more common with rilotumumab included neutropenia (36 [44%] vs 11 [28%]) and venous thromboembolism (16 [20%] vs four [10%]). Serious adverse events were balanced between groups except for anaemia, which occurred more frequently in the combined rilotumumab group (ten [12%] vs none). INTERPRETATION: Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress. FUNDING: Amgen Inc.
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Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Unión Esofagogástrica/patología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Intervalos de Confianza , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Epirrubicina/efectos adversos , Epirrubicina/uso terapéutico , Unión Esofagogástrica/efectos de los fármacos , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
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Neoplasias Colorrectales , Piperazinas , Proteínas Proto-Oncogénicas p21(ras) , Piridinas , Pirimidinas , Humanos , Panitumumab/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Anticuerpos Monoclonales/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Receptores ErbB , Mutación/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Factor 2 Relacionado con NF-E2 , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
OBJECTIVES: Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS: KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS: Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION: Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutación , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas , PirimidinasRESUMEN
This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3-5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma.
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Anticuerpos Biespecíficos , Linfoma de Células B Grandes Difuso , Adulto , Anticuerpos Biespecíficos/efectos adversos , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2 , Inducción de RemisiónRESUMEN
Part- and whole-task conditions were created by manipulating the presence of certain components of the Space Fortress video game. A cognitive model was created for two-part games that could be combined into a model that performed the whole game. The model generated predictions both for behavioral patterns and activation patterns in various brain regions. The activation predictions concerned both tonic activation that was constant in these regions during performance of the game and phasic activation that occurred when there was resource competition. The model's predictions were confirmed about how tonic and phasic activation in different regions would vary with condition. These results support the Decomposition Hypothesis that the execution of a complex task can be decomposed into a set of information-processing components and that these components combine unchanged in different task conditions. In addition, individual differences in learning gains were predicted by individual differences in phasic activation in those regions that displayed highest tonic activity. This individual difference pattern suggests that the rate of learning of a complex skill is determined by capacity limits.
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Atención/fisiología , Mapeo Encefálico/métodos , Encéfalo/fisiología , Modelos Psicológicos , Desempeño Psicomotor/fisiología , Juegos de Video , Adolescente , Adulto , Femenino , Humanos , Masculino , Tiempo de Reacción/fisiología , Juegos de Video/psicología , Adulto JovenRESUMEN
OBJECTIVE: ⢠To evaluate the efficacy and safety of single-agent AMG 102, an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), in renal cell carcinoma (RCC). PATIENTS AND METHODS: ⢠This open-label phase II study included patients ≥ 18 years old with histologically confirmed, advanced or metastatic RCC (mRCC) and Eastern Cooperative Oncology Group performance status 0 to 2. AMG 102 was administered i.v. at 10 or 20 mg/kg once every 2 weeks. ⢠A two-stage design was used at each dose level and the primary endpoint was objective best confirmed response (by Response Evaluation Criteria in Solid Tumours) at any time. RESULTS: ⢠Sixty-one patients with mRCC enrolled and received AMG 102 (40 at 10 mg/kg; 21 at 20 mg/kg). Overall, 70.5% were men, median age was 59 years (range, 39 to 84 years), and 92% had received previous anti-vascular endothelial growth factor therapy. RCC histologies were: clear cell (75.4%), papillary (11.5%), chromophobe (4.9%) and unclassified (8.2%). ⢠One confirmed partial response occurred at 10 mg/kg, maintained for over 2.5 years; 26 patients (43%) had stable disease, 10 (16%) for ≥ 32 weeks. The median profression-free survival was 3.7 months at 10 mg/kg and 2.0 months at 20 mg/kg. The commonest adverse events were oedema (45.9%), fatigue (37.7%) and nausea (27.9%). Grade 3 or 4 adverse events occurred in 33% of patients, the most common being oedema (9.8%). ⢠Baseline levels of plasma HGF/SF and soluble c-Met as well as archival-tumour c-Met did not correlate with measures of efficacy. CONCLUSION: ⢠Single-agent AMG 102 was tolerable, but it is unclear if AMG 102 was growth inhibitory in this population of patients with mRCC.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Relación Dosis-Respuesta a Droga , Femenino , Factor de Crecimiento de Hepatocito/sangre , Humanos , Infusiones Intravenosas , Neoplasias Renales/mortalidad , Neoplasias Renales/secundario , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
This study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE® therapy, for 4 weeks (9 µg/day cycle 1 week 1, 28 µg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood samples were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival; lower tumor burden was prognostic for hematologic remission; and a higher percentage of CD3+ T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45+ CD3+ CD8+ T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.
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Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response. METHODS: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8+ T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response. RESULTS: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8+ T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8+ T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8+ T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8+ T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions. CONCLUSIONS: This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy. TRIAL REGISTRATION NUMBER: NCT02366195.
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Productos Biológicos/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Herpesvirus Humano 1/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/terapia , Viroterapia Oncolítica , Virus Oncolíticos/inmunología , Neoplasias Cutáneas/terapia , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Productos Biológicos/efectos adversos , Europa (Continente) , Femenino , Herpesvirus Humano 1/patogenicidad , Humanos , Masculino , Melanoma/inmunología , Melanoma/patología , Melanoma/virología , Persona de Mediana Edad , Estadificación de Neoplasias , Viroterapia Oncolítica/efectos adversos , Virus Oncolíticos/patogenicidad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/virología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Novel therapies are needed for children with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific T-cell engager immunotherapy that simultaneously binds to CD3-positive cytotoxic T cells and CD19-positive B cells and redirects the patient's T cells to lyse malignant and normal B cells. We conducted an open-label phase 1b study to determine the safety, pharmacokinetics, efficacy, and recommended dose of blinatumomab in Japanese children with R/R B-cell precursor ALL. Patients received induction blinatumomab for 4 weeks (5 µg/m2/day week 1; 15 µg/m2/day weeks 2-4), followed by a 2-week treatment-free interval (6-week cycle). In subsequent cycles, patients received blinatumomab 15 µg/m2/day. The primary end point was the incidence of dose-limiting toxicities. Nine patients received blinatumomab. Since no dose-limiting toxicities were reported, the maximum tolerated dose was 5 µg/m2/day for week 1, followed by 15 µg/m2/day weeks 2-4 (5-15 µg/m2/day, the global recommended dose of blinatumomab). All patients had ≥ 1 grade ≥ 3 adverse events; 89% had grade ≥ 3 treatment-related adverse events. M1 remission rate within the first two cycles of treatment was 56%; one patient had a minimal residual disease response. Consistent with global studies, blinatumomab appeared to be safe with preliminary evidence of efficacy in Japanese children with R/R B-cell precursor ALL.
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Anticuerpos Biespecíficos/administración & dosificación , Antineoplásicos/administración & dosificación , Linfocitos B , Inmunoterapia , Linfocitos T , Adolescente , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Pueblo Asiatico , Linfocitos B/metabolismo , Niño , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Inducción de Remisión , Seguridad , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
This open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.
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Acetatos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Piperidonas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Recurrencia , Resultado del TratamientoRESUMEN
PURPOSE: Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma. METHODS: In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety. RESULTS: Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%. CONCLUSION: T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.
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Anticuerpos Monoclonales/administración & dosificación , Melanoma/terapia , Virus Oncolíticos , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Ipilimumab , Masculino , Persona de Mediana Edad , Viroterapia Oncolítica/efectos adversos , Viroterapia Oncolítica/métodos , Subgrupos de Linfocitos T/inmunología , Carga TumoralRESUMEN
BACKGROUND: In order to identify rice genes involved in nutrient partitioning, microarray experiments have been done to quantify genomic scale gene expression. Genes involved in nutrient partitioning, specifically grain filling, will be used to identify other co-regulated genes, and DNA binding proteins. Proper identification of the initial set of bait genes used for further investigation is critical. Hierarchical clustering is useful for grouping genes with similar expression profiles, but decreases in utility as data complexity and systematic noise increases. Also, its rigid classification of genes is not consistent with our belief that some genes exhibit multifaceted, context dependent regulation. RESULTS: Singular value decomposition (SVD) of microarray data was investigated as a method to complement current techniques for gene expression pattern recognition. SVD's usefulness, in finding likely participants in grain filling, was measured by comparison with results obtained previously via clustering. 84 percent of these known grain-filling genes were re-identified after detailed SVD analysis. An additional set of 28 genes exhibited a stronger grain-filling pattern than those grain-filling genes that were unselected. They also had upstream sequence containing motifs over-represented among grain filling genes. CONCLUSIONS: The pattern-based perspective that SVD provides complements to widely used clustering methods. The singular vectors provide information about patterns that exist in the data. Other aspects of the decomposition indicate the extent to which a gene exhibits a pattern similar to those provided by the singular vectors. Thus, once a set of interesting patterns has been identified, genes can be ranked by their relationship with said patterns.