RESUMO
Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Imunoglobulina G/administração & dosagem , Mesotelioma Maligno/tratamento farmacológico , Proteínas de Fusão Oncogênica/administração & dosagem , Pemetrexede/administração & dosagem , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Imunoglobulina G/efeitos adversos , Ligantes , Masculino , Mesotelioma Maligno/metabolismo , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/efeitos adversos , Proteínas de Fusão Oncogênica/farmacocinética , Pemetrexede/efeitos adversos , Proteínas Recombinantes de Fusão , Resultado do TratamentoRESUMO
BACKGROUND: Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. FINDINGS: Between Oct 18, 2007, and July 17, 2012, we screened 13â849 patients for MAGE-A3 expression; 12â820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). INTERPRETATION: Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.
Assuntos
Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoconjugados/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/imunologia , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Two separate multinational surveys of oncologists and patients with cancer were conducted to assess the awareness and use of biomarkers in clinical practice. These data explore the self-reported and physician-assessed levels of patient cancer literacy and factors affecting physicians' choice to use biomarkers in treatment decisions. PATIENTS AND METHODS: Interviews were conducted via telephone with patients and online with physicians. Physicians had 3-35 years of experience; were treating more than 15 patients/month; and specialized in breast, lung, or colorectal cancer. Patients had received treatment for breast, lung, or colorectal cancer within the previous 5 years. RESULTS: Interviews with 895 physicians and 811 patients were completed. Most patients and physicians reported that patients understood that a tumor could be tested to determine what treatment would be most effective (78% and 73%, respectively) and that patients would be willing to participate in a personalized treatment plan. Whereas 85% of patients felt that they understood their treatment when it was explained to them, only 23% of doctors felt that their patients were always fully informed. Most physicians (90%) reported using biomarkers; among the 10% not performing biomarker analysis, the most cited obstacles were local availability, speed of obtaining results, and cost. CONCLUSION: These data demonstrate wide global use of biomarker testing but with regional variations reflecting cultural and local practice. Self-reported and physician-assessed cancer literacy, although generally high, highlighted important regional variations and the need to provide patients with additional information.
Assuntos
Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Letramento em Saúde , Pacientes/estatística & dados numéricos , Médicos/estatística & dados numéricos , Medicina de Precisão/estatística & dados numéricos , Adulto , Biomarcadores Tumorais , Neoplasias da Mama/terapia , Neoplasias Colorretais/terapia , Tomada de Decisões , Feminino , Humanos , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.
Assuntos
Neoplasias Pulmonares/terapia , Qualidade da Assistência à Saúde , Benchmarking , Coleta de Dados , Europa (Continente) , Disparidades em Assistência à Saúde , Humanos , Cooperação Internacional , Neoplasias Pulmonares/diagnóstico , Análise Multivariada , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Guias de Prática Clínica como Assunto , Encaminhamento e Consulta , Literatura de Revisão como AssuntoRESUMO
The anaplastic lymphoma kinase (ALK) gene plays a key role in the pathogenesis of selected tumors, including non-small-cell lung cancer (NSCLC). Patients with ALK-rearranged NSCLC are initially sensitive to the ALK inhibitor crizotinib but eventually become resistant, limiting its therapeutic potential. Ceritinib is an oral second-generation ALK inhibitor with greater preclinical antitumor potency than crizotinib in ALK-positive NSCLC. A Phase I trial of ceritinib in ALK-positive tumors demonstrated good activity in patients with advanced NSCLC, including those who had progressed on crizotinib. Adverse events are similar to those seen with other ALK tyrosine kinase inhibitors and are generally manageable. Ongoing trials are evaluating ceritinib in patients with ALK-rearranged NSCLC treated with prior chemotherapy and/or crizotinib.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/genética , Receptores Proteína Tirosina QuinasesRESUMO
Introduction: In the placebo-controlled, phase 3 PACIFIC trial, durvalumab significantly prolonged progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p = 0.00251) in patients with unresectable stage III NSCLC and no progression after platinum-based concurrent chemoradiotherapy (cCRT). Pneumonitis or radiation pneumonitis (PRP) was common in both arms. We report exploratory analyses evaluating the association of symptomatic (grade ≥2) PRP (G2+PRP) with baseline factors and clinical outcomes. Methods: Patients with WHO performance status of 0 or 1 were randomized (2:1) to 12 months of durvalumab or placebo, 1 to 42 days after cCRT. Associations between baseline factors and on-study G2+PRP in durvalumab-treated patients were investigated using univariate and multivariate logistic regression. PFS and OS were analyzed using Cox proportional hazards models adjusted for time-dependent G2+PRP plus covariates for randomization stratification factors without and with additional baseline factors. Results: On-study G2+PRP occurred in 94 of 475 (19.8%) and 33 of 234 patients (14.1%) on durvalumab and placebo, respectively (median follow-up, 25.2 mo); grade greater than or equal to 3 PRP was uncommon (4.6% and 4.7%, respectively). Time to onset and resolution of G2+PRP was similar with durvalumab and placebo. Univariate and multivariate analyses identified patients treated in Asia, those with stage IIIA disease, those with performance status of 1, and those who had not received induction chemotherapy as having a higher risk of G2+PRP. PFS and OS benefit favoring durvalumab versus placebo was maintained regardless of time-dependent G2+PRP. Conclusions: Factors associated with higher risk of G2+PRP with durvalumab after cCRT were identified. Clinical benefit was maintained regardless of on-study G2+PRP, suggesting the risk of this event should not deter the use of durvalumab in eligible patients with unresectable stage III NSCLC.
RESUMO
INTRODUCTION: Immune-mediated adverse events (imAEs), including all-cause immune-mediated pneumonitis, were reported in approximately 25% of patients in the placebo-controlled, phase III PACIFIC trial of durvalumab monotherapy (for up to 12 months) in patients with unresectable, stage III NSCLC and no disease progression after concurrent chemoradiotherapy; only 3.4% of patients experienced grade 3/4 imAEs. With broad application of the PACIFIC regimen (consolidation durvalumab after chemoradiotherapy), now standard-of-care in this setting, there is a need to better characterize the occurrence of imAEs with this regimen. METHODS: We performed descriptive, post-hoc, exploratory analyses to characterize the occurrence of imAEs (pneumonitis and non-pneumonitis) in PACIFIC in terms of: incidence, severity, and timing; clinical management and outcomes; and associations between the occurrence of imAEs and (1) all-cause AEs and (2) baseline patient, disease, and treatment characteristics. RESULTS: Any-grade immune-mediated pneumonitis (9.4%) and non-pneumonitis imAEs (10.7%) occurred infrequently and were more common with durvalumab versus placebo. Grade 3/4 immune-mediated pneumonitis (1.9%) and non-pneumonitis imAEs (1.7%) were uncommon with durvalumab, as were fatal imAEs (0.8%; all pneumonitis). The most common non-pneumonitis imAEs with durvalumab were thyroid disorders, dermatitis/rash, and diarrhea/colitis. Dermatitis/rash had the shortest time to onset (from durvalumab initiation), followed by pneumonitis; dermatitis/rash had the longest time to resolution, followed by thyroid disorders. Most patients with immune-mediated pneumonitis (78.4%) and non-pneumonitis imAEs (56.3%) had these events occur ≤ 3 months after initiating durvalumab. ImAEs were well managed with administration of systemic corticosteroids, administration of endocrine replacement therapy, and interruption/discontinuation of durvalumab. Time elapsed from completion of prior radiotherapy to trial randomization (<14 vs. ≥ 14 days) did not impact either incidence or severity of imAEs. Durvalumab had a manageable safety profile broadly irrespective of whether patients experienced imAEs. CONCLUSION: The risk of imAEs should not deter use of the PACIFIC regimen in eligible patients, as these events are generally well managed through appropriate clinical intervention.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Dermatite , Exantema , Neoplasias Pulmonares , Pneumonia , Anticorpos Monoclonais , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/efeitos adversos , Dermatite/tratamento farmacológico , Dermatite/etiologia , Exantema/etiologia , Humanos , Neoplasias Pulmonares/terapia , Pneumonia/diagnóstico , Pneumonia/epidemiologia , Pneumonia/etiologiaRESUMO
PURPOSE: The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non-small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. METHODS: Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method. RESULTS: Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS. CONCLUSION: These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia , Progressão da Doença , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Objectives: The aim of ASTRIS, a real-world study, was to assess the safety and efficacy of osimertinib in patients with locally advanced or metastatic (stage IIIB-IV) epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who had received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. Here, we describe the Belgian subset of the global ASTRIS study.Methods: Patients received osimertinib orally as one 80 mg tablet once daily until disease progression or unacceptable toxicity. Socio-demographic data, medical history, disease progression and survival status were collected and molecular testing for EGFR status was performed. Safety was also assessed. All collected data were summarized using descriptive statistics.Results: Of the 31 Belgian patients enrolled in the study, 9 (29.0%) discontinued treatment for disease progression and 5 (16.1%) due to other reasons. Among the 31 patients treated with osimertinib, 16 (51.6%, 95% CI 33.1-69.8) had a clinical response and 13 (41.9%) had stable disease as best response assessed by the investigator, with a disease control rate of 93.5%. The clinical response rate was 66.7% (6/9) in patients with brain/leptomeningeal metastases and 50.0% (4/8) in patients without brain/leptomeningeal metastases. About one third of the patients (11/31) reported at least one adverse event (AE) (35.5%) or serious AE (10/31; 32.3%) and 3/31 (9.7%) patients discontinued treatment due to AEs.Conclusion: We here demonstrate the effectiveness of osimertinib in a real-world setting in Belgian patients with locally advanced or metastatic T790M-positive NSCLC who had received previous EGFR-TKI treatment. No new safety signals were identified.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Bélgica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized. METHODS: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method. RESULTS: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively. CONCLUSION: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Lung cancer remains one of the greatest medical challenges with nearly 1.5 million new cases worldwide each year and a growing tobacco epidemic in the developing world. This review summarizes briefly the current status in growing areas of clinical research. The value of screening for early disease is not yet established and trials to see if mortality can be improved as a result are in progress. Better and more accurate staging will both streamline investigation and prove cost-effective once ultrasound-guided biopsy and aspiration of mediastinal nodes become universally accepted. This, allied to the new staging classification, will improve selection of cases for surgery, intensive multimodality therapy and for adjuvant treatment postoperatively. Much still needs to be done to refine staging as within a particular stage group, the outcome shows great variation. More information is needed on the genetic make-up in some groups of tumours and not just their size; that is, more biological data on tumour growth patterns are likely to be at least as discriminating. The place of the stem cell theory of tumorigenesis is also explored in this paper. Finally, targeted therapy for advanced non-small-cell lung cancer is highlighted as a development with early promise, but still much clarification is required, before it can be considered as a universal approach in late disease.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Transportadores de Cassetes de Ligação de ATP/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/patologia , Programas de Rastreamento , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/patologiaRESUMO
Tumor infiltrating lymphocytes (TIL), programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) expression are important prognostic markers. This study aimed to investigate these markers in lung adenocarcinoma (ADC) biopsies from patients with stage IIIB or IV ADC with little or no smoking history, to investigate their prognostic value and to correlate these results with the presence of driver mutations in the tumors. TIL were retrospectively evaluated on hematoxylin and eosin stained slides from 152 tumor samples. PD-1/PD-L1 expression was retrospectively evaluated with PD-1/PD-L1 immunohistochemistry (IHC) double staining on 74 tumor samples with sufficient residual tissue. PD-L1 expression was analysed on stromal cells of the tumor compartment, the tumor cells and TIL and PD-1 on TIL. Median overall survival (OS) was longer in patients with high stromal TIL infiltration compared to patients with low stromal TIL infiltration (68 weeks vs. 35 weeks respectively; p = 0.003). This was observed most prominently in KRAS mutant tumors (95 weeks vs. 12 weeks; p = 0.003). Only PD-L1 expression on tumor stromal cells influenced OS and indicated a worse prognosis (77 weeks vs 25 weeks; p = 0.013). Stromal TIL counts nor PD-1/PD-L1 expression levels were associated with the presence of driver mutations. The results of the current study reinforce the prognostic role of TIL in lung ADC, which is most prominent in KRAS mutant cancers. The results of the PD-1/PD-L1 analysis suggest that stromal cells can effectively suppress the anti-tumor immune response via the PD-L1 pathway.
Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Antígeno B7-H1/biossíntese , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
INTRODUCTION: In the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42-65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53-0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study. METHODS: Patients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method. RESULTS: As of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55-0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses. CONCLUSIONS: Updated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Neoplasias Pulmonares , Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estadiamento de NeoplasiasRESUMO
INTRODUCTION: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. METHODS: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. RESULTS: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Nivolumabe , Pirimidinas , SulfonasRESUMO
PURPOSE: Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non-small cell lung cancer (NSCLC) tumor samples from two phase III studies. EXPERIMENTAL DESIGN: The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were used as "training set"; the remaining two thirds, constituting the "test set," were used for the prospective validation of the GS. RESULTS: In the melanoma training set, the expression level of eight Th1/IFNγ-related genes in tumor-positive lymph node tissue predicted the duration of disease-free survival (DFS) and overall survival (OS) in the placebo arm. This GS was prospectively and independently validated as prognostic in the test set. Building a multivariate Cox model in the test set placebo patients from clinical covariates and the GS score, an increased number of melanoma-involved lymph nodes and the GS were associated with DFS and OS. This GS was not associated with DFS in NSCLC, although expression of the Th1/IFNγ-related genes was associated with the presence of lymphocytes in tumor samples in both indications. CONCLUSIONS: These findings provide evidence that expression of Th1/IFNγ genes in the TME, as measured by this GS, is associated with clinical outcome in melanoma. This suggests that, using this GS, patients with stage IIIB/C melanoma can be classified into different risk groups.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Interferon gama/imunologia , Melanoma/patologia , Células Th1/imunologia , Microambiente Tumoral/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Interferon gama/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Melanoma/tratamento farmacológico , Melanoma/genética , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Células Th1/metabolismo , TranscriptomaRESUMO
PURPOSE: MET dysregulation occurs in up to 26% of non-small-cell lung cancers (NSCLCs) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Capmatinib (INC280) is a potent and selective MET inhibitor with preclinical activity in combination with gefitinib in EGFR-mutant, MET-amplified/overexpressing models of acquired EGFR-TKI resistance. This phase Ib/II study investigated the safety and efficacy of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who experienced disease progression while receiving EGFR-TKI treatment. METHODS: Patients in phase Ib received capmatinib 100- to 800-mg capsules once per day or 200- to 600-mg capsules or tablets twice per day, plus gefitinib 250 mg once per day. Patients in phase II received the recommended phase II dose. The primary end point was the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: Sixty-one patients were treated in phase Ib, and 100 were treated in phase II. The recommended phase II dose was capmatinib 400 mg twice per day plus gefitinib 250 mg once per day. Preliminary clinical activity was observed, with an ORR across phase Ib/II of 27%. Increased activity was seen in patients with high MET-amplified tumors, with a phase II ORR of 47% in patients with a MET gene copy number ≥ 6. Across phases Ib and II, the most common drug-related adverse events were nausea (28%), peripheral edema (22%), decreased appetite (21%), and rash (20%); the most common drug-related grade 3/4 adverse events were increased amylase and lipase levels (both 6%). No significant drug-drug interactions between capmatinib and gefitinib were evident. CONCLUSION: This study, focused on a predominant EGFR-TKI resistance mechanism in patients with EGFR-mutated NSCLC, shows that the combination of capmatinib with gefitinib is a promising treatment for patients with EGFR-mutated, MET-dysregulated NSCLC, particularly MET-amplified disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Benzamidas , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/genética , Feminino , Gefitinibe/administração & dosagem , Gefitinibe/efeitos adversos , Gefitinibe/farmacocinética , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-met/metabolismo , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Triazinas/farmacocinéticaRESUMO
Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Humanos , Imunoterapia/tendências , Terapia de Alvo Molecular/tendênciasRESUMO
The advent of erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin (rHuEPO) and darbepoetin alfa for the treatment of chemotherapy-induced anaemia was associated with decreased requirements for red blood cell (RBC) transfusions and improved quality of life in cancer patients. Dosing of rHuEPO three times per week is the originally approved regimen, although in some countries weekly dosing is approved in some settings. Darbepoetin alfa was the first ESA to be developed with an extended dosing interval, offering the potential for less frequent administration and greater convenience for patients and healthcare professionals. In a placebo-controlled study of once-weekly darbepoetin alfa treatment in anaemic cancer patients undergoing chemotherapy, significantly fewer treated patients required RBC transfusions, regardless of initial haemoglobin levels. A subsequent dose-finding study of once-every-3-week darbepoetin alfa treatment showed that the drug was effective and well-tolerated in anaemic cancer patients and reduced the need for transfusions at all doses compared with placebo. Timing of ESA administration may be crucial to achieve maximum erythropoietic responses, thus synchronous dosing with 3-weekly chemotherapy cycles may improve efficacy and convenience. Recent trials have shown that synchronous dosing is equally effective, with improved convenience, compared with asynchronous dosing, and that fixed-dose (500 microg) treatment achieves similar efficacy and tolerability as administration by weight.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/análogos & derivados , Hematínicos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ensaios Clínicos como Assunto , Darbepoetina alfa , Esquema de Medicação , Transfusão de Eritrócitos , Eritropoetina/administração & dosagem , Hemoglobinas/análise , Humanos , Neoplasias/tratamento farmacológico , Placebos , Qualidade de Vida , Proteínas RecombinantesRESUMO
Advanced-stage non-small cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a survival benefit, although it is small. We now know that anti-PD-1/PD-L1 has substantial clinical activity in both of these diseases, with an overall response rate (ORR) of 15%-20%. These responses are frequently rapid and durable, increase median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant results, many patients do not benefit from anti-PD-1/PD-L1. This is because of the potential for malignancies to co-opt myriad immunosuppressive mechanisms other than aberrant expression of PD-L1. Conceptually, these can be divided into three categories. First, for some patients there is likely a failure to generate sufficient functional tumor antigen-specific T cells. Second, for others, tumor antigen-specific T cells may be generated but fail to enter into the tumor parenchyma. Finally, there are a large number of immunosuppressive mechanisms that have the potential to be operational within the tumor microenvironment: surface membrane immune checkpoint proteins PD-1, CTLA-4, LAG3, TIM3, BTLA, and adenosine A2AR; soluble factors and metabolic alterations interleukin (IL)-10, transforming growth factor (TGF)-ß, adenosine, IDO, and arginase; and inhibitory cells, cancer-associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages. In this article, we discuss three strategies to generate more tumor-reactive T cells for patients: anti-CTLA-4, therapeutic tumor vaccination, and adoptive cellular therapy, with T cells redirected to tumor antigens using T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene modification. We also review some of the various strategies in development to thwart tumor microenvironment immunosuppressive mechanisms. Strategies to drive more T cells into tumors remain a significant challenge.
Assuntos
Antígeno B7-H1/uso terapêutico , Antígeno CTLA-4/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/uso terapêutico , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Antígeno CTLA-4/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/imunologiaRESUMO
INTRODUCTION: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor. METHODS: Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease. RESULTS: Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung. CONCLUSION: The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00339586.