RESUMO
The recent discovery of relevant biomarkers has reshaped our approach to therapy selection for patients with non-small cell lung cancer. The unprecedented outcomes demonstrated with tyrosine kinase inhibitors in molecularly defined cohorts of patients has underscored the importance of genetic profiling in this disease. Despite published guidelines on biomarker testing, successful tumor genotyping faces significant hurdles at both academic and community-based practices. Oncologists are now faced with interpreting large-scale genomic data from multiple tumor types, possibly making it difficult to stay current with practice standards in lung cancer. In addition, physicians' lack of time, resources, and face-to-face opportunities can interfere with the multidisciplinary approach that is essential to delivery of care. Finally, several challenges exist in optimizing the amount and quality of tissue for molecular testing. Recognizing the importance of biomarker testing, a series of advisory boards were recently convened to address these hurdles and clarify best practices. We reviewed these challenges and established recommendations to help optimize tissue acquisition, processing, and testing within the framework of a multidisciplinary approach.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Medicina Baseada em Evidências/métodos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Técnicas de Diagnóstico Molecular , Patologia Molecular/educação , Médicos , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. METHODS: In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m(2)) or docetaxel (75 mg/m(2)) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m(2) at first dose and 250 mg/m(2) weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. FINDINGS: Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7-3·2) versus 2·8 months (2·5-3·3) with pemetrexed (HR 1·03, 95% CI 0·87-1·21; p=0·76). The most common grade 3-4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. INTERPRETATION: The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. FUNDING: Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Canadá , Cetuximab , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede , Compostos de Platina/administração & dosagem , Índice de Gravidade de Doença , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Falha de Tratamento , Estados UnidosRESUMO
BACKGROUND: Some elderly patients may have reduced tolerance the standard therapy (chemotherapy doublets) for stage III/IV non-small cell lung cancer (NSCLC). Sunitinib malate (S), an oral, multitargeted kinase inhibitor, shows promise as 2nd-line NSCLC treatment. This study explored the safety/efficacy of S in elderly patients with previously untreated NSCLC. PRIMARY OBJECTIVE: disease control rate (DCR) at six-weeks. SECONDARY OBJECTIVES: overall response (OR, CR+PR), progression-free survival (PFS), time to progression (TTP), one-yr survival, quality of life (QOL), and safety. TREATMENT: S 37.5 mg daily/42-day cycle until PD or intolerable toxicity. Key inclusion: chemo-naïve stage IIIB/IV NSCLC (nonsquamous histology); ECOG PS=0-1; ≥ 70 years; normal organ function. Exclusion: hemoptysis, anticoagulation, or clotting diathesis. Other standard S-specific criteria applied. RESULTS: 63 patients enrolled/60 treated. DEMOGRAPHICS: 51 % male, 95 % white, median age 78 years (range, 70-88), 73 % ECOG=1, 97 % Stage IV, 83 % adenocarcinoma, 44 % prior surgery, 19 % prior radiation. With a median of 2 cycles (range, 1-16), DCR=63 %, OR=7 % (0 CR, 4 PR). Median follow-up=5.8 months (all; 15.9 months survivors), median PFS =3.0 months (range, <1-25.1), median TTP=4.5 months (range, <1-25.1), and 1-year survival=26.4 % [95 % CI: 15.9, 38.2]. QOL declined initially, but improved over time. TREATMENT-related adverse events included: fatigue (48.3 %); diarrhea (38.3 %); thrombocytopenia (33.3 %), anorexia (26.7 %), mucositis (25.0 %); nausea (25.0 %), dysgeusia (20.0 %), and neutropenia (20.0 %). Conclusions The study met its primary endpoint. S produced acceptable DCR and QOL improved; however, OR was disappointing (7 %) and toxicity was greater than expected. A biomarker to identify patients more likely to benefit from S is needed.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Qualidade de Vida , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: Uncontrolled studies comparing pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR) to fludarabine plus C+R (FCR) suggest similar efficacy with fewer infectious complications with PCR. We compared FCR and PCR in previously-untreated or minimally-treated B-cell chronic lymphocytic leukemia (CLL). TREATMENT: FCR (F 20 mg/m(2) Days 1-5, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (28-day cycles) or PCR (P 4 mg/m(2) Day 1, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (21-day cycles). Dose 1 of R: 100 mg/m(2) was given on Day 8 Cycle 1 and the remainder on Day 9; in subsequent cycles the entire dose was given on Day 1. RESULTS: Ninety-two patients were randomly assigned to each group (N = 184). Groups were balanced; ~20% had received prior chemotherapy. The infection rate (FCR/PCR) was 31%/36%, the infective event rate was 38%/45%; 30 (35%)/37 (44%) patients were hospitalized; total hospitalization days was 271/404. 12 (14%)/6 (7%) patients achieved complete remissions (CR); the overall response rate (ORR) including CR+nodular PR (nPR)+PR was 59%/49%. Grade 3-4 treatment related AEs: neutropenia (69%/57%), leukopenia (34%/17%), thrombocytopenia (13%/6%). Grade 3-4 infections: febrile neutropenia (8%/6%), fever (2%/6%), infection (1%/3%), urinary tract infection (1%/0%), pneumonia (3%/1%), and sepsis (1%/2%); 5 deaths (1 FCR/4 PCR) were treatment-related. CONCLUSIONS: PCR and FCR have significant activity in CLL and can be given safely in the community setting despite significant toxicity. ORRs were lower than expected; the CR rate was higher (NS) with FCR. This trial did not demonstrate a lower infection rate with PCR.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentostatina/administração & dosagem , Pentostatina/efeitos adversos , Rituximab , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosRESUMO
The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell-dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody-based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4(+) and CD8(+) antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses.
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Linfócitos B/fisiologia , Vacinas Anticâncer , Linfoma de Célula do Manto/imunologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Idiótipos de Imunoglobulinas/imunologia , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
PURPOSE: Limited data exist on the optimal duration of immunotherapy, including for non-small-cell lung cancer (NSCLC). We present an exploratory analysis of CheckMate 153, a largely community-based phase IIIb/IV study, to evaluate the impact of 1-year fixed-duration versus continuous therapy on the efficacy and safety of nivolumab. METHODS: Patients with previously treated advanced NSCLC received nivolumab monotherapy (3 mg/kg every 2 weeks). Those still receiving treatment at 1 year, including patients perceived to be deriving benefit despite radiographic progression, were randomly assigned to continue nivolumab until disease progression or unacceptable toxicity or to stop nivolumab with the option of on-study retreatment after disease progression (1-year fixed duration). RESULTS: Of 1,428 patients treated, 252 were randomly assigned to continuous (n = 127) or 1-year fixed-duration (n = 125) treatment (intent-to-treat [ITT] population). Of these, 89 and 85 patients in the continuous and 1-year fixed-duration arms, respectively, had not progressed (progression-free survival [PFS] population). With minimum post-random assignment follow-up of 13.5 months, median PFS was longer with continuous versus 1-year fixed-duration treatment (PFS population: 24.7 months v 9.4 months; hazard ratio [HR], 0.56 [95% CI, 0.37 to 0.84]). Median overall survival from random assignment was longer with continuous versus 1-year fixed-duration treatment in the PFS (not reached v 32.5 months; HR, 0.61 [95% CI, 0.37 to 0.99]) and ITT (not reached v 28.8 months; HR, 0.62 [95% CI, 0.42 to 0.92]) populations. Few new-onset treatment-related adverse events occurred. No new safety signals were identified. CONCLUSION: To our knowledge, these findings from an exploratory analysis represent the first randomized data on continuous versus fixed-duration immunotherapy in previously treated advanced NSCLC and suggest that continuing nivolumab beyond 1 year improves outcomes.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversosRESUMO
PURPOSE: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. PATIENTS AND METHODS: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined. RESULTS: The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. CONCLUSIONS: Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Mostardas de Fosforamida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/mortalidade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Nitroimidazóis/administração & dosagem , Nitroimidazóis/efeitos adversos , Mostardas de Fosforamida/administração & dosagem , Mostardas de Fosforamida/efeitos adversos , Retratamento , Resultado do TratamentoRESUMO
INTRODUCTION: Around 3â»5% of non-small cell lung cancers (NSCLC) are ALK-positive. Crizotinib was the first approved ALK inhibitor from clinical trials. However, there are less data on the utilization and patient outcomes associated with crizotinib in real-world clinical practice. METHODS: This was a retrospective, observational study of adult crizotinib-treated ALK-positive metastatic NSCLC patients who received treatment between 1 September 2011 and 31 October 2014, with follow up through 31 December 2015. Data were obtained via programmatic queries of the US Oncology Network/McKesson Specialty Health electronic health record database, supplemented with chart abstraction. Overall survival (OS) and time to treatment failure (TTF) were estimated from crizotinib initiation using the Kaplanâ»Meier (KM) method. RESULTS: Of the n = 199 ALK-positive crizotinib-treated patients meeting eligibility criteria, crizotinib was prescribed as first line (1 L) in n = 123 (61.8%). The majority (88.9%) had confirmed adenocarcinoma histology and 32.2% had brain metastases at initial diagnosis. Median age at crizotinib initiation was 60.2 years (range 27.1â»88.2); 54.8% were never smokers, 33.7% were former smokers. Treatment of 250 mg, twice daily, was most commonly prescribed (89.5%) with the dose unchanged from an initial dose in 79.4% of patients. The primary discontinuation reason was progression (n = 91, 58.7%). Patients (3.2%) were identified as discontinuing crizotinib as a result of treatment-related toxicity. With median follow-up time of 13.0 months (minâ»max = 0.03â»46.6), median OS from crizotinib initiation was 33.8 months (95% CI = 24.3â»38.8). Median TTF was 10.4 months. CONCLUSIONS: Crizotinib usage evaluated within the real-world setting is consistent with prior phase III clinical trial data, and illustrates the real-world effectiveness of crizotinib.
RESUMO
INTRODUCTION: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation-positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation-positive NSCLC. METHODS: Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation-positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. RESULTS: Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response. CONCLUSIONS: These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Crizotinibe/administração & dosagem , Crizotinibe/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Translocação GenéticaRESUMO
PURPOSE: Nivolumab has been administered using a 60-min infusion time. Reducing this time to 30 min would benefit both patients and infusion facilities. This analysis compared the safety of 30- and 60-min infusions of nivolumab in patients with previously treated advanced non-small cell lung cancer. METHODS: CheckMate 153 is an open-label, phase 3b/4, predominantly community-based study ongoing in the United States and Canada. Patients with stage IIIB/IV disease with progression/recurrence after at least one prior systemic therapy received nivolumab 3 mg/kg every 2 weeks over 30 or 60 min for 1 year or until disease progression. The primary outcome overall was to estimate the incidence of grade 3-5 treatment-related select adverse events; a retrospective objective was to estimate the incidence of hypersensitivity/infusion-related reactions (IRRs) with the 30-min infusion. Exploratory pharmacokinetic analyses were performed using a population pharmacokinetics model. RESULTS: Of 1420 patients enrolled, 369 received only 30-min infusions and 368 received only 60-min infusions. Similar frequencies of hypersensitivity/IRRs were noted in patients receiving 30-min [2% (n = 8)] and 60-min [2% (n = 7)] infusions. Grade 3-4 treatment-related hypersensitivity/IRRs led to treatment discontinuation in < 1% of patients in each group; < 1% of patients in each group received systemic corticosteroids. Hypersensitivity/IRRs were managed by dosing interruptions, with minimal impact on total dose received. Nivolumab pharmacokinetics were predicted to be similar in the two groups. CONCLUSIONS: Nivolumab infused over 30 min had a comparable safety profile to the 60-min infusion, including a low incidence of IRRs.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Nivolumabe/farmacocinética , Prognóstico , Estudos Retrospectivos , Segurança , Distribuição TecidualRESUMO
Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/patologiaRESUMO
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.
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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 management of advanced lung cancer is changing rapidly, with new drug approvals occurring almost monthly. The average age of a newly diagnosed patient with advanced lung cancer remains around age 70. Caring for the older adult with advanced cancer differs from the care of younger adults. Chronologic age often does not accurately reflect the physiologic and functional status of older adults. Selecting treatment based on age alone results in undertreatment and overtreatment of many older adults. Addressing issues such as multiple chronic conditions, polypharmacy, geriatric syndromes, and heterogeneity in functional status among an expanding menu of treatment options for advanced disease is increasingly difficult, particularly among older adults historically underrepresented in clinical trials. In this article, we highlight key issues in caring for the older adult with advanced non-small cell lung cancer and the continued need for data supporting current and emerging treatment options. Key issues include the unique challenges of managing advanced lung cancer and a summary of the current treatment evidence as they apply to the elderly lung cancer population including supportive care strategies, risk stratification, and patient-reported outcomes.
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Gerenciamento Clínico , Avaliação Geriátrica , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/terapia , Adulto , Fatores Etários , Idoso , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/patologia , Seleção de PacientesRESUMO
Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk-to-benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs.
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Carcinoma de Células Escamosas/terapia , Neoplasias Pulmonares/terapia , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/patologiaRESUMO
Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/patologia , Comorbidade , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Fumar/efeitos adversosRESUMO
This trial was designed to determine the 1-year survival rate, efficacy, progression-free survival (PFS), and toxicity with gemcitabine in patients with stage IIIB (with pleural effusion) or stage IV non-small-cell lung cancer (NSCLC) with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. Gemcitabine 1250 mg/m2 was administered intravenously on days 1 and 8 of each 21-day cycle. Treatment consisted of 6 cycles; patients who responded with complete response or partial response received < or = 2 additional cycles. Forty-two patients were enrolled at 31 community-based centers between March and November 2002. Most patients had stage IV disease (74%). The median age was 73 years (range, 58-84 years), and 19% had received prior palliative radiation therapy. Patients received a median of 3 cycles (range, 1-8 cycles). The median survival was 4.8 months (range, < 1 to 19.2 months), and the estimated 1-year survival was 20%. Median PFS was 2.5 months (range, < 1 to 19.2 months), and PFS at 1 year was 11.1%. Thirty-one patients died of disease progression, and 1 each died of myocardial infarction, brain herniation, pneumonia, and respiratory failure. Seven patients were not evaluable for response; 4 refused or received no treatment, treatment in 2 failed (myocardial infarction and pneumonia), and 1 was lost to follow-up. Among 35 evaluable patients, there were 5 partial responses (14%), 10 with stable disease (29%), and 20 with disease progression (57%). Drug-related grade > or = 3 toxicities included neutropenia (18%), anemia (8%), and dyspnea (2.6%). These results suggest that patients with NSCLC with an ECOG PS of 2 may benefit from single-agent chemotherapy gemcitabine. General toxicity, including myelotoxicity, was relatively low. Further studies comparing single-agent chemotherapy with combination chemotherapy for patients with a PS of 2 are warranted.
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Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Ribonucleotídeo Redutases/antagonistas & inibidores , Resultado do Tratamento , GencitabinaRESUMO
Although there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced lung cancer has multiple treatment pathways that depend on multiple factors, including histology and molecular subtype of disease. New molecular targets, targeted agents, and modes of therapy for patients, including immunotherapy, are being identified at an accelerating pace. These advances are changing outcomes and the treatment landscape, but they also highlight situations with inadequate data to support the use of cytotoxic chemotherapy. In this article, we provide an overview of data regarding cytotoxic chemotherapy and targeted therapy and their value after second line, review the critical role of supportive care and palliative care, and emphasize the importance of advance care planning with our patients. Although this article focuses primarily on NSCLC, the comments about palliative care and advanced care planning also apply to patients with small cell lung cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Cuidados PaliativosRESUMO
INTRODUCTION: Treatment impact on quality of life (QoL) informs treatment management decisions in advanced nonsquamous non-small-cell lung cancer (NS NSCLC). QoL outcomes from the phase III PointBreak trial are reported. METHODS: Chemonaive patients (n = 939) with stage IIIB/IV nonsquamous non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status 0 to 1 were randomized (1:1) to pemetrexed-carboplatin-bevacizumab (pemetrexed arm) or paclitaxel-carboplatin-bevacizumab (paclitaxel arm). Patients without progressive disease received maintenance pemetrexed-bevacizumab (pemetrexed arm) or bevacizumab (paclitaxel arm). QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-General (FACT-G), FACT-Lung (FACT-L), and FACT/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) instruments. Subscale scores, total scores, and trial outcome indices were analyzed using linear mixed-effects models. Post hoc analyses examined the association between baseline FACT scores and overall survival (OS). RESULTS: Mean score differences in change from baseline significantly favored the pemetrexed arm for the neurotoxicity subscale score, FACT-Ntx total scores, and FACT-Ntx trial outcome index. They occurred at cycle 2 (p < 0.001) and persisted through induction cycles 2 to 4 and six maintenance cycles. Investigator-assessed, qualitative, drug-related differences in grade 2 (1.6% versus 10.6%) and grade 3 (0.0% versus 4.1%) sensory neuropathy and grade 3/4 fatigue (10.9% versus 5.0%, p = 0.0012) were observed between the pemetrexed and paclitaxel arms. Baseline FACT-G, FACT-L, and FACT-Ntx scores were significant prognostic factors for OS (p < 0.001). CONCLUSIONS: Randomized patients reported similar changes in QoL, except for less change from baseline in neurotoxicity on the pemetrexed arm; investigators reported greater neurotoxicity on the paclitaxel arm and greater fatigue on the pemetrexed arm. Higher baseline FACT scores were favorable prognostic factors for OS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Pemetrexede , Qualidade de Vida , Resultado do TratamentoRESUMO
INTRODUCTION: African Americans have a greater incidence of lung cancer than whites and have been underrepresented in clinical trials. In the PointBreak trial (pemetrexed-carboplatin-bevacizumab and maintenance pemetrexed-bevacizumab [PemCBev] vs. paclitaxel-carboplatin-bevacizumab and maintenance bevacizumab [PacCBev]), 10% of the patients were African American. PointBreak had negative findings; PemCBev did not demonstrate superior overall survival (OS). MATERIALS AND METHODS: PointBreak subgroup efficacy and safety data were retrospectively analyzed: African Americans versus whites for PemCBev; PemCBev versus PacCBev in African Americans; and academic versus community settings for African Americans. Hazard ratios (HRs) and P values were derived from a multivariate Cox proportional hazards model after adjusting for covariates. RESULTS: Of 939 intent-to-treat (ITT) patients, 94 were African American and 805 were white. African-American enrollment was uniform across the study sites (median, 1 African American per site). In the PemCBev arm, OS (HR, 1.125; P = .525), progression-free survival (PFS) (HR, 1.229; P = .251), response (P = .607), and toxicity profiles were similar in African Americans versus whites. For African Americans, OS (HR, 1.375; P = .209), PFS (HR, 0.902; P = .670), response (P = 1.000), and toxicity profiles were similar in the PemCBev versus PacCBev arm. For African Americans, no significant differences were seen in OS (HR, 0.661; P = .191) or PFS (HR, 0.969; P = .915) in academic versus community practice settings. CONCLUSION: In the PemCBev arm, this exploratory analysis showed no significant differences between African Americans and whites for the efficacy outcomes or toxicity profiles. Consistent with the ITT population negative trial result, for African Americans, the median OS was not superior for either arm. For African Americans, PFS and OS were similar in the academic and community settings. Additional outcomes data for African Americans should be collected in lung cancer studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Negro ou Afro-Americano/etnologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/etnologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
This manuscript describes the early history of NK cell discovery, with emphasis on the events in the first decade of NK cell studies, 1972-1982. The authors highlight some of the earliest and most important observations that would later prove to be milestones in the study of NK cells and their activity.