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Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.
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BACKGROUND: Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma. METHODS: We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS: Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Rituximab/efeitos adversosRESUMO
PURPOSE: Currently, there is no approved therapy for cancer cachexia. According to European and American regulatory agencies, physical function improvements would be approvable co-primary endpoints of new anti-cachexia medications. As physical functioning is in part dependent on cardiac functioning, we aimed to explore the cardiac status of a group of patients meeting current criteria for inclusion in cachexia clinical trials. METHODS: Seventy treatment-naive patients with metastatic NSCLC [36 (51.4%) male; 96% ECOG 0-1; eligible for carboplatin-based therapy and meeting eligibility criteria for cachexia clinical trials] were recruited before the start of first-line carboplatin-based chemotherapy. Patients were evaluated by echocardiography, electrocardiography, and scales for fatigue and dyspnea. Computed tomography cross-sectional images were utilized for body composition analysis. RESULTS: In 9/70 patients (12.8%), echocardiography allowed discovery of clinically relevant cardiac disorders [seven patients with left ventricular ejection fraction (LVEF) 32%-47%; one patient with severe right ventricular dilation and severe pulmonary hypertension and one patient with severe pericardial effusion warranted hospitalization and drainage]. Another 10/70 (14.3%) patients had diastolic dysfunction with preserved LVEF. The cardiac conditions were associated with aggravated fatigue (p < 0.05), dyspnea (p < 0.05), and anemia (p = 0.06). Five out of seven patients with LVEF < 50% were sarcopenic and one was borderline sarcopenic. CONCLUSION: Baseline cardiac status of the metastatic NSCLC patients adds potential heterogeneity for anti-cachexia clinical trials. Detailed cardiac screening data might be useful for inclusion/exclusion criteria, randomization, and post hoc analysis.
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Caquexia/prevenção & controle , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Cardiopatias/epidemiologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Idoso , Idoso de 80 Anos ou mais , Caquexia/epidemiologia , Caquexia/etiologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Ensaios Clínicos como Assunto/estatística & dados numéricos , Estudos Transversais , Diagnóstico Tardio/estatística & dados numéricos , Feminino , Cardiopatias/complicações , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3â+â3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.
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Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antígenos CD79/imunologia , Imunoconjugados/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Antígenos CD79/biossíntese , Esquema de Medicação , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RituximabRESUMO
Purpose Preclinical evidence suggests dichloroacetate (DCA) can reverse the Warburg effect and inhibit growth in cancer models. This phase 1 study was undertaken to assess the safety, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of oral DCA in patients with advanced solid tumors. Patients and Methods Twenty-four patients with advanced solid malignancies were enrolled using a standard 3 + 3 protocol at a starting dose of 6.25 mg/kg twice daily (BID). Treatment on 28 days cycles was continued until progression, toxicity, or consent withdrawal. PK samples were collected on days 1 and 15 of cycle 1, and day 1 of subsequent cycles. PET imaging ((18) F-FDG uptake) was investigated as a potential biomarker of response. Results Twenty-three evaluable patients were treated with DCA at two doses: 6.25 mg/kg and 12.5 mg/kg BID (median of 2 cycles each). No DLTs occurred in the 6.25 mg/kg BID cohort so the dose was escalated. Three of seven patients had DLTs (fatigue, vomiting, diarrhea) at 12.5 mg/kg BID. Thirteen additional patients were treated at 6.25 mg/kg BID. Most toxicities were grade 1-2 with the most common being fatigue, neuropathy and nausea. No responses were observed and eight patients had stable disease. The DCA PK profile in cancer patients was consistent with previously published data. There was high variability in PK values and neuropathy among patients. Progressive increase in DCA trough levels and a trend towards decreased (18) F-FDG uptake with length of DCA therapy was observed. Conclusions The RP2D of oral DCA is 6.25 mg/kg BID. Toxicities will require careful monitoring in future trials.
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Ácido Dicloroacético/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estudos de Coortes , Ácido Dicloroacético/efeitos adversos , Ácido Dicloroacético/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/metabolismoRESUMO
BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas/genética , Quinazolinonas/administração & dosagem , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Efeito Placebo , Proteínas Proto-Oncogênicas p21(ras) , Quinazolinonas/efeitos adversosRESUMO
INTRODUCTION: Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. METHODS: In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. RESULTS: Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. CONCLUSIONS: Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Guanina/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Pemetrexede , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
Importance: Immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined. Objective: To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs. Design, Setting, and Participants: This retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line. Exposure: Developing an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs). Main Outcomes and Measures: The primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS. Results: Among the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001). Conclusions and Relevance: In this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alberta/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Pacientes Ambulatoriais , Estudos Retrospectivos , Adolescente , AdultoRESUMO
BACKGROUND: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in non-small cell lung cancer (NSCLC). Based on preclinical demonstration of additive cytotoxicity, we evaluated the safety and efficacy of combining pemetrexed and nanoparticle albumin bound (nab) paclitaxel with a focus on NSCLC for phase II expansion. METHODS: A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: pemetrexed 500 mg/m(2) day 1 and nab-paclitaxel day 1 at 180, 220, & 260 mg/m(2) every 21 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. RESULTS: Planned dose escalation was completed without reaching the MTD. The RP2D was pemetrexed 500 mg/m(2) and nab-paclitaxel 260 mg/m(2). The phase II portion accrued 37 pts before early closure due to increasing first-line pemetrexed/platinum doublet use in non-squamous NSCLC. In 31 assessable phase II patients there were 5 partial responses, 12 stable disease, 14 progressive disease. The median overall survival was 8.8 months; progressive disease 4.4 months and disease control 15.6 months. CONCLUSIONS: Pemetrexed 500 mg/m(2) day 1 with nab-paclitaxel 260 mg/m(2) was feasible and well tolerated. The phase II component demonstrated activity in second/third-line therapy of advanced NSCLC; response rate 14% and disease control rate 46%. Treatment practice patterns of advanced NSCLC have evolved; further trials of this regimen are not planned.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Idoso , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , PemetrexedeRESUMO
INTRODUCTION/BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized non-small cell lung cancer (NSCLC). We aimed to identify baseline characteristics, that are prognostic factors for overall survival (OS) in patients with NSCLC treated with ICI monotherapy, in order to derive the Lung Immune Therapy Evaluation (LITE) risk, a prognostic model. MATERIALS AND METHODS: Multi-center observational cohort study of patients with advanced NSCLC that received ≥1 dose of ICI monotherapy. The training set (n=342) consisted of patients with NSCLC who received first line ICI. The test set (n=153) used for external validation was a discrete cohort of patients who received second line ICI. 20 candidate prognostic factors were examined. Penalized Cox regression was used for variable selection. Multiple imputation was used to address missingness. RESULTS: Three baseline characteristics populated the final model: ECOG (0, 1 or ≥2), lactate dehydrogenase>upper limit of normal, and derived neutrophil to lymphocyte ratio ≥3. Patients were parsed into 3 risk groups; favorable (n=146, risk score 0-1), intermediate (n=101, risk score 2) and poor (n=95, risk score ≥3). The c-statistic of the training cohort was 0.702 and 0.694 after bootstrapping. The test cohort c-statistic was 0.664. The median OS for favorable, intermediate and poor LITE risk were; 28.3 months, 9.1 months and 2.1 months respectively. Improving LITE risk group was associated with improved OS, intermediate vs favorable HR 2.08 (95%CI 1.46-2.97, P < .001); poor vs favorable HR 5.21 (95%CI 3.69-7.34, P < .001). CONCLUSION: A simple prognostic model, utilizing accessible clinical data, can discriminate survival outcomes in patients with advanced NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Prognóstico , Neoplasias Pulmonares/tratamento farmacológico , Pulmão , Estudos RetrospectivosRESUMO
PURPOSE: We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS: Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS: At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION: With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Ipilimumab , Neoplasias Pulmonares , Nivolumabe , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Ipilimumab/uso terapêutico , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/uso terapêutico , Qualidade de VidaRESUMO
Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.
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Linfoma Difuso de Grandes Células B , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológicoRESUMO
Introduction: The expensive modern therapeutic regimens for advanced lung cancer (LC) stages have been recently approved. We evaluated whether low-dose computed tomography (LDCT) LC screening of high-risk Albertans is cost saving. Methods: We used a decision analytical modeling technique with a health system perspective and a time horizon of 3 years to compare benefits associated with reduced health service utilization (HSU) from earlier diagnosis to the costs of screening. Using patient-level data, HSU costs by stage of disease were estimated for patients with LC, including inpatient, outpatient, and physician services, and costs for prescription drugs and cancer treatments. Results: Of 101,000 people aged 55 to 74 years eligible for screening, an estimated 88,476 scans would be performed in Alberta in 3 years. Given LDCT sensitivity and specificity of 90.5% and 93.1%, respectively, we estimated that a stage shift toward earlier diagnosis would be expected whereby 43% more patients would be identified at stage 1 or 2 as compared with without screening. The estimated cost of screening is $35.6 million (M), whereas the stage shift associated with screening would avoid $42M in HSU costs. The net cost avoidance associated with screening is therefore $6.65M. The probability for the screening to be cost saving is estimated at 72%. Conclusions: This study has revealed that LDCT LC screening is likely to be cost saving in Alberta. Adoption of this program into the provincial health care system is worth considering provided constraints in the system related to surgical capacity and CT wait times could be addressed.
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The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014-2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Canadá , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/uso terapêutico , Rearranjo Gênico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pemetrexede/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Estudos RetrospectivosRESUMO
The multicenter, phase Ib CC-122-DLBCL-001 dose-expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [n = 27], FL [n = 41; 31 lenalidomide-naïve, 10 lenalidomide-treated]). Median age was 62 years (range, 33-84 years), and patients had received a median of 3 (range, 1-8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab-refractory at study entry and 10.0% were lenalidomide-refractory. The most common any-grade avadomide-related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide-related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide-naïve and -treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL.
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There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.
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INTRODUCTION: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up. METHODS: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs). RESULTS: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population. CONCLUSIONS: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.
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Neoplasias Pulmonares , Nivolumabe , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Ipilimumab/efeitos adversos , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/efeitos adversosRESUMO
BACKGROUND: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m² intravenously (IV) followed by a weekly maintenance dose of 250 mg/m². It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods Four dose levels were tested: Cetuximab 400 mg/m² IV loading dose and 250, 300, 350, 400 mg/m² weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. RESULTS: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m²). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m²) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. CONCLUSIONS: Cetuximab administered at 400 mg/m² IV as a loading dose with weekly maintenance dose of 400 mg/m² is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.
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Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Pele/efeitos dos fármacos , Acne Vulgar/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Cetuximab , Quimiocinas/sangue , Demografia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: This study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK-rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada. METHODS: Demographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK-rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis. RESULTS: A total of 92 patients with ALK-rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK-rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK-wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement (ALK-rearranged versus ALK-wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p = 0.04). CONCLUSIONS: Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer.