RESUMO
BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events. CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Cisplatino , Neoplasias Pulmonares , Humanos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Terapia CombinadaRESUMO
BACKGROUND: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC. METHODS: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C. RESULTS: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C. CONCLUSIONS: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination. TRIAL REGISTRATION: NCT03322566. Registered October 26, 2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Método Duplo-Cego , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Adulto , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , OximasRESUMO
BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses. METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability. RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group. CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sulfonamidas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Método Duplo-Cego , Antígeno B7-H1/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Adulto , Oximas/administração & dosagem , Oximas/uso terapêutico , Oximas/efeitos adversos , Idoso de 80 Anos ou mais , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Real-world data regarding patient characteristics, adjuvant treatment patterns, and long-term survival outcomes are needed to better understand unmet needs among patients with completely resected early-stage non-small cell lung cancer (NSCLC). METHODS: Electronic medical records from the U.S.-based ConcertAI Patient360™ database were analyzed in patients with stage IB-IIIA NSCLC who underwent complete resection prior to March 1, 2016. Patients were followed until death or July 1, 2021. This study evaluated adjuvant chemotherapy use, and overall survival (OS) and real-world disease-free survival (rwDFS) outcomes using the Kaplan-Meier method. The correlation between OS and rwDFS was assessed using the Kendall rank test. Among patients who did not recur 5 years following surgery, landmark analyses of OS and rwDFS were conducted to understand the subsequent survival impact of remaining disease-free for at least 5 years. RESULTS: Data from 441 patients with completely resected stage IB-IIIA NSCLC were included. About 35% of patients received adjuvant chemotherapy post-resection. Median OS and rwDFS from resection were 83.1 months and 42.4 months, respectively. The 5-year OS and rwDFS rates were 65.7% and 42.1%, respectively. OS and rwDFS were positively correlated (Kendall rank correlation coefficient = 0.67; p < 0.0001). Among patients without recurrence within 5 years after resection, the subsequent 5-year OS and rwDFS survival rates were 52.9% and 36.6%, respectively. CONCLUSIONS: Use of adjuvant chemotherapy was low, and the overall 5-year OS rate remained low despite all patients having undergone complete resection. Patients who remained non-recurrent over time had favorable subsequent long-term survival.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Estadiamento de Neoplasias , Humanos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Feminino , Masculino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Intervalo Livre de Doença , Pneumonectomia , Estimativa de Kaplan-Meier , Idoso de 80 Anos ou mais , Estados Unidos/epidemiologia , AdultoRESUMO
Aim: Real-world data on outcomes for early-stage non-small-cell lung cancer (NSCLC) are needed to better understand the benefits of new therapies. Methods: In this retrospective study using the ConcertAI Patient360™ database, overall survival and healthcare resource utilization were compared among patients with recurrent and non-recurrent completely resected stage IB-IIIA NSCLC. Results: Recurrence was associated with a shorter median overall survival compared with non-recurrence (31.5 months vs 75.6 months, respectively), lower survival probability 5-years post-resection, and higher healthcare resource utilization. Patients with late recurrence had a longer restricted mean survival time versus patients with early recurrence. Conclusion: Results from this real-world study highlight the potential value of preventing or delaying recurrence in patients with early-stage NSCLC.
This study looked at how people with early-stage non-small-cell lung cancer did after surgery to completely remove the disease. It compared two groups of patients: those whose disease came back after surgery and those whose disease did not come back after surgery. The group of people whose disease came back after surgery did not live as long as those whose disease did not come back after surgery (31.5 months vs 75.6 months). Patients whose disease came back had a lower chance of living at least 5 years after surgery and they had more hospital visits and doctor's office visits. In addition, those whose disease came back within 1 year did not live as long as those whose disease came back between 1 and 5 years after surgery. Preventing or delaying the return of disease after surgery is important for improving the lives of patients with early-stage non-small-cell lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Quimioterapia Adjuvante , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC. METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting. FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo. INTERPRETATION: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Hipertensão , Neoplasias Pulmonares , Miocardite , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Hipertensão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgiaRESUMO
PURPOSE: Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors. METHODS: Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab. RESULTS: Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis-a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data. CONCLUSION: Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Oximas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Relação Dose-Resposta a Droga , Humanos , Japão , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oximas/administração & dosagem , Oximas/efeitos adversos , Oximas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinéticaRESUMO
Primary central nervous system lymphoma (PCNSL) is rare in children with immunocompromise as an important risk factor. A 7-year-old girl with unspecified T-cell immunodeficiency presented with left-sided weakness and was found to have a right-sided frontal lobe mass on imaging. The mass was resected; histopathology and molecular studies evidenced diffuse large B-cell lymphoma. Prior chest imaging had revealed left upper lobe mass, and repeat chest imaging revealed multiple pulmonary nodules, initially concerning for metastasis. Video-assisted thoracoscopic surgical wedge resection of the lung mass was performed; the molecular profile was distinct from the PCNSL, suggesting synchronous de novo lymphomagenesis of brain and pulmonary primaries.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Criança , Diagnóstico Diferencial , Feminino , Lobo Frontal , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/cirurgia , Imageamento por Ressonância Magnética , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Cirurgia Torácica Vídeoassistida/métodosRESUMO
Central nervous system (CNS) tumors exhibiting dual features of malignant glioma (MG) and primitive neuroectodermal tumor (PNET) are rare and diagnostically challenging. Previous studies have shown that MG-PNET carry MYCN or MYC gene amplifications within the PNET component concomitant with glioma-associated alterations, most commonly 10q loss, in both components [9]. Here we confirm and extend the profile of molecular genetic findings in a MG-PNET involving the left frontal lobe of a 12-year-old male. Histologically, the PNET-like component showed morphological features akin to anaplastic medulloblastoma highlighted by widespread immunoreactivity for ßIII-tubulin (TUBB3) and nonphosphorylated neurofilament protein, and to a lesser degree, Neu-N, synaptophysin, and CD99, whereas the gliomatous component was demarcated by glial fibrillary acidic protein (GFAP) labeling. Immunohistochemical labeling with an anti-H3K27M mutant-specific antibody was not detectable in either gliomatous and/or PNET-like areas. Interphase fluorescent in situ hybridization (FISH) study on touch preparations from frozen tumor and formaldehyde-fixed, paraffin-embedded histological sections showed amplification of MYC in both PNET-like and gliomatous areas. Single nucleotide polymorphism (SNP) microarray analysis revealed that the tumor carried gains of multiple chromosomes and chromosome arms, losses of multiple chromosomes and chromosome arms, gains of multiple chromosomal segments (not limited to amplification of chromosomal segments 4q12 including PDGFRA, and 8q24.21 including MYC), and a hitherto unreported chromothripsis-like abnormality on chromosome 8. No mutations were identified for IDH1, IDH2, or BRAF genes by sequence analysis. The molecular genetic findings support the presence of a CNS-PNET as an integral part of the tumor coupled with overlapping genetic alterations found in both adult and pediatric high-grade gliomas/glioblastoma. Collectively, microarray data point to a complex underpinning of genetic alterations associated with the MG-PNET tumor phenotype.â©.
Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Tumores Neuroectodérmicos Primitivos/patologia , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/genética , Criança , Glioma/genética , Humanos , Imuno-Histoquímica , Masculino , Análise de Sequência com Séries de OligonucleotídeosRESUMO
BACKGROUND: Novel neoadjuvant chemoimmunotherapy treatments are being investigated for locally advanced non-small-cell lung cancer (NSCLC), but real-world outcomes for neoadjuvant treatments are poorly understood. This study examined neoadjuvant treatment patterns, real-world event-free survival (rwEFS) and overall survival (OS) in patients with resected, stage II-III NSCLC in the United States (US). METHODS: This retrospective study identified patients in the SEER-Medicare database (2007-2019) with newly diagnosed stage II, IIIA, and IIIB (N2) NSCLC (AJCC 8th edition) treated with neoadjuvant chemo/chemoradiotherapy and resection (index date: neoadjuvant therapy initiation). Neoadjuvant treatment regimens were described. rwEFS (time from index to first recurrence or death, whichever occurred first) and OS (time from index to death) were summarized by Kaplan-Meier analysis for overall population, by disease stage at diagnosis, and by neoadjuvant treatment modality. RESULTS: 221 patients (stage II, N=70; stage III, N=151) met eligibility criteria. The median follow-up from index was 32.7 months. All patients received neoadjuvant chemotherapy (51%) or chemoradiotherapy (49%) prior to surgery; 97% of patients received platinum-based regimens, among which carboplatin+paclitaxel was the most frequent (45%). In all patients, median rwEFS was 17.6 months and 5-year rwEFS was 20.9%; median OS was 48.5 months and 5-year OS was 44.9%. 71% of patients had disease recurrence during follow-up; among them, 28% developed locoregional recurrence as the first recurrence event. CONCLUSIONS: Patients with resected, stage II-III NSCLC who received neoadjuvant chemo/chemoradiotherapy have high rates of disease recurrence and poor survival outcomes, highlighting need for more effective treatments to improve survival rates.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidade , Terapia Neoadjuvante/mortalidade , Terapia Neoadjuvante/métodos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Taxa de Sobrevida , Estadiamento de Neoplasias , Estados Unidos , Pneumonectomia , Resultado do Tratamento , Programa de SEER , Seguimentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
INTRODUCTION: Lenvatinib plus pembrolizumab was found to have antitumor activity and acceptable safety in previously treated metastatic NSCLC. We evaluated first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab in metastatic NSCLC in the LEAP-007 study (NCT03829332/NCT04676412). METHODS: Patients with previously untreated stage IV NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1% without targetable EGFR/ROS1/ALK aberrations were randomized 1:1 to lenvatinib 20 mg or placebo once daily; all patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary end points were progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival (OS). We report results from a prespecified nonbinding futility analysis of OS performed at the fourth independent data and safety monitoring committee review (futility bound: one-sided p < 0.4960). RESULTS: A total of 623 patients were randomized. At median follow-up of 15.9 months, median (95% confidence interval [CI]) OS was 14.1 (11.4â19.0) months in the lenvatinib plus pembrolizumab group versus 16.4 (12.6â20.6) months in the placebo plus pembrolizumab group (hazard ratio = 1.10 [95% CI: 0.87â1.39], p = 0.79744 [futility criterion met]). Median (95% CI) PFS was 6.6 (6.1â8.2) months versus 4.2 (4.1â6.2) months, respectively (hazard ratio = 0.78 [95% CI: 0.64â0.95]). Grade 3 to 5 treatment-related adverse events occurred in 57.9% of patients (179 of 309) versus 24.4% (76 of 312). Per data and safety monitoring committee recommendation, the study was unblinded and lenvatinib and placebo were discontinued. CONCLUSIONS: Lenvatinib plus pembrolizumab did not have a favorable benefitârisk profile versus placebo plus pembrolizumab. Pembrolizumab monotherapy remains an approved treatment option in many regions for first-line metastatic NSCLC with programmed cell death-ligand 1 tumor proportion score of at least 1% without EGFR/ALK alterations.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Feminino , Método Duplo-Cego , Compostos de Fenilureia/uso terapêutico , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials. METHODS: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year. Adverse events (AEs) were summarized for patients who received ≥ 1 dose of treatment. RESULTS: Data were pooled from 4125 patients treated with pembrolizumab (n = 2060) or placebo (n = 2065). Median (range) duration of treatment was 11.1 months (0.0-18.9) with pembrolizumab and 11.2 months (0.0-18.1) with placebo. Treatment-related AEs occurred in 78.6 % (1620/2060) of patients in the pembrolizumab group (grade 3-5, 16.3 % [336/2060]) and 58.7 % (1212/2065) in the placebo group (grade 3-5, 3.5 % [72/2065]). Immune-mediated AEs (e.g. adrenal insufficiency, hypophysitis, and thyroiditis) occurred in 36.2 % (746/2060) of patients in the pembrolizumab group (grade 3-5, 8.6 % [177/2060]) and 8.4 % (174/2065) in the placebo group (grade 3-5, 1.1 % [23/2065]). Of patients with ≥ 1 immune-mediated AE or infusion reaction, systemic corticosteroids were required for 35.2 % (268/761) and 20.2 % (39/193) of patients in the pembrolizumab and placebo groups, respectively. CONCLUSIONS: Adjuvant pembrolizumab demonstrated a manageable safety profile that was comparable to prior reports in advanced disease.
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Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Renais , Ensaios Clínicos Fase III como Assunto , Neoplasias Renais , Neoplasias Pulmonares , Melanoma , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quimioterapia Adjuvante , Idoso , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Adulto , Adulto Jovem , Idoso de 80 Anos ou mais , AdolescenteRESUMO
BACKGROUND: As the non-small cell lung cancer (NSCLC) adjuvant treatment landscape evolves, an evaluation of treatment patterns and outcomes of patients with early-stage, resected NSCLC eligible for adjuvant treatment in routine clinical practice is needed to better understand the unmet needs in this patient population. MATERIALS AND METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2007-2019) were used to identify patients with newly diagnosed stage IB (tumor size ≥4cm)-IIIA (AJCC 7th edition) NSCLC who received primary surgery (index date). We assessed adjuvant treatment patterns, real-world disease-free survival (rwDFS; time from index date to first recurrence or death) and overall survival (OS; time from index date to death), and loco-regional recurrence pattern and treatment distribution. RESULTS: Among 1761 patients with primary surgery, mean age was 73.8 years; 47.9% were male; and 83.9% were white. Approximately 41% of patients received adjuvant chemotherapy; median time from surgery to adjuvant chemotherapy initiation was 48 days, and the most frequently observed adjuvant chemotherapy regimen was carboplatin+paclitaxel (24.5%). In the overall population, median rwDFS was 24.8 months and OS was 76.7 months; 5-year rwDFS and OS rates were 29.3% and 57.5%, respectively. Among 392 patients with loco-regional recurrence, the most frequently observed treatment was curative radiation monotherapy (28.2%). CONCLUSION: Despite clinical guideline recommendations, rate of adjuvant chemotherapy among patients with resected early-stage NSCLC was low in clinical practice. Overall, among patients with early-stage NSCLC treated with conventional primary surgery, poor survival outcomes were observed, highlighting the need for and importance of more effective adjuvant treatments.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Idoso , Estados Unidos/epidemiologia , Feminino , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medicare , Carboplatina , Carcinoma de Pequenas Células do Pulmão/patologia , Quimioterapia Adjuvante , Estadiamento de NeoplasiasRESUMO
OBJECTIVES: Event-free survival has replaced overall survival as a primary end point in many recent and ongoing clinical trials. This study aims to examine the correlation between real-world event-free survival and overall survival and to assess the clinical and economic burden associated with disease recurrence among patients with resected stage II to III non-small cell lung cancer who received neoadjuvant therapy in the United States. METHODS: This retrospective study used the Surveillance, Epidemiology, and End Results Medicare database (2007-2019) to identify patients with newly diagnosed, resected, stage II to IIIB (N2) non-small cell lung cancer who received neoadjuvant therapy. The correlation between real-world event-free survival and overall survival was assessed using the normal scores rank correlation and landmark analysis. Overall survival, all-cause health care resource use and costs, and non-small cell lung cancer-related health care resource use and costs were compared between patients with and without recurrence. RESULTS: A total of 221 patients met the eligibility criteria (median follow-up time from neoadjuvant treatment initiation: 32.7 months). The mean age was 72.1 years, and 57.0% of patients were male. Real-world, event-free survival and overall survival are positively and significantly correlated (0.68; 95% CI, 0.52-0.79). Patients with recurrence had significantly shorter median overall survival (19.3 vs 116.9 months), 4.59 times increased risk of death (95% CI, 2.56-8.26), and significantly higher all-cause and non-small cell lung cancer-related health care resource use and costs (adjusted mean monthly costs per patient difference: $5758 and $3187, respectively [all P < .001]). CONCLUSIONS: These findings help validate event-free survival as a clinically meaningful end point and strong predictor for overall survival and highlight the need for additional novel therapies that may delay or prevent recurrence in resectable stage II and III non-small cell lung cancer.
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BACKGROUND: Intermediate endpoints, such as disease-free survival (DFS), have shown good correlation with overall survival (OS) in early-stage non-small cell lung cancer (NSCLC) clinical trials. However, real-world data are limited, and no previous real-world study has quantified the clinical and economic burden of disease recurrence. OBJECTIVE: To examine the association between real-world DFS (rwDFS) and OS and quantify the association between NSCLC recurrence and health care resource utilization (HCRU), health care costs, and OS in patients with resected early-stage NSCLC in the United States. METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare database (2007-2019) for patients with newly diagnosed stage IB (tumor size ≥ 4 cm) to IIIA (American Joint Committee on Cancer 7th edition) NSCLC who underwent surgery for primary NSCLC were analyzed in this retrospective observational study. Baseline patient demographic and clinical characteristics were described. rwDFS and OS were compared between patients with vs without recurrence using Kaplan-Meier curves and the log-rank test; their correlation was assessed using normal scores rank correlation. All-cause and NSCLC-related HCRU and health care costs were summarized, and mean monthly allcause and NSCLC-related health care costs were compared between cohorts using generalized linear models. RESULTS: Of the 1,761 patients who underwent surgery, 1,182 (67.1%) had disease recurrence; these patients had shorter OS from the index date and shorter subsequent OS at each postsurgery landmark (ie, 1, 3, and 5 years) than those without recurrence (all P < 0.001). OS and rwDFS were significantly correlated (0.57; P < 0.001). Patients with recurrence also had significantly higher all-cause and NSCLC-related HCRU and mean monthly all-cause and NSCLC-related health care costs during the study period. CONCLUSIONS: Postsurgery rwDFS was significantly correlated with OS in patients with early-stage NSCLC. Patients with postsurgery recurrence had a higher risk of death and incurred higher HCRU and health care costs than those without recurrence. These findings highlight the importance of preventing or delaying recurrence in patients with resected NSCLC. DISCLOSURES: Dr West is Senior Medical Director at AccessHope and an Associate Professor at City of Hope. He also serves on the advisory board for Amgen, AstraZeneca, Genentech/Roche, Gilead, Merck, Mirati Therapeutics, Regeneron, Summit Therapeutics, and Takeda and as a speaker for AstraZeneca and Merck. Drs Hu, Chirovsky, and Samkari are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and own stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Drs Zhang, Song, Gao, and Signorovitch, Mr Lerner, and Ms Jiang are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, which funded the development and conduct of this study and article. This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention's National Program of Cancer Registries, under cooperative agreement 5NU58DP006344; the National Cancer Institute's SEER Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Idoso , Estados Unidos/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Intervalo Livre de Doença , Medicare , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia , Custos de Cuidados de Saúde , Estudos Retrospectivos , Efeitos Psicossociais da DoençaRESUMO
Introduction: The NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ) was developed to assess NSCLC symptom severity in accordance with Food and Drug Administration evidentiary expectations leading to Food and Drug Administration qualification in 2018. This study evaluated the NSCLC-SAQ's measurement properties within a clinical trial. Methods: The KEYNOTE-598 phase 3 study of participants with stage IV metastatic NSCLC with programmed death-ligand 1 tumor proportion score greater than or equal to 50% was used to assess the NSCLC-SAQ's reliability, construct validity, responsiveness, and estimate clinically meaningful within-person change. Other patient-reported outcome measures included patient global impression items of severity and change in lung cancer symptoms, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and lung cancer module, LC13. Results: Participants (N = 560) were mostly men (70%), had a mean age of 64 years, and had Eastern Cooperative Oncology Group performance status of 1 (64%) or 0 (36%). Internal consistency at baseline (Cronbach's α = 0.74) and test-retest reliability after 3 weeks (intraclass correlation coefficient = 0.79) were satisfactory. NSCLC-SAQ items, domains, and total score correlated moderately to highly with patient-reported outcome measures capturing similar content, and the total score differentiated among patient global impression of severity groups (p < 0.001). The total score detected improvement over time and the estimated clinically meaningful within-person change threshold for improvement ranged from three to five points on the 0 to 20 scale. Few participants exhibited symptom worsening (n = 38), limiting inferences in this group. Conclusions: The NSCLC-SAQ was found to be reliable, valid, responsive, and interpretable for assessing symptom improvement in NSCLC. Further evaluation is recommended in trial participants whose symptoms worsen over time.
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INTRODUCTION: High-grade pneumonitis is a severe and potentially life-threatening adverse event associated with concurrent chemoradiation (cCRT) in patients with non-small cell lung cancer (NSCLC). The aim of this study was to summarize and quantify the incidence of severe (grade 3-5) cCRT-induced pneumonitis in unresectable stage III NSCLC patients. METHODS: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. Published literature was searched for randomized controlled trials (RCTs), observational studies, and non-randomized trials from 2014 to April 2020. The primary outcome of interest was incidence of grade 3-5 pneumonitis. RESULTS: Included were 17 studies for the review and 11 for the meta-analysis (1,788 participants); all studies examined radiation-related pneumonitis (RP). The pooled incidence of cCRT-induced grade 3-5 RP in unresectable stage III NSCLC patients was estimated to be 3.62% [95% confidence interval (CI): 1.65-6.21] in RCTs, 5.98% [95% CI: 2.26-12.91] in observational studies, and 7.85% [95% CI: 4.08-13.10] in observational studies using platinum-based doublet chemotherapies. CONCLUSION: These results suggest the incidence of severe and fatal RP in patients with unresectable stage III NSCLC treated with cCRT ranges from 3.62% to 7.85%, with incidence varying by study design and chemotherapy regimen. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Pneumonite por Radiação , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Pneumonite por Radiação/diagnóstico , Pneumonite por Radiação/epidemiologia , Pneumonite por Radiação/etiologia , Pneumonia/etiologia , Pneumonia/induzido quimicamenteRESUMO
The multiple functions of the oncofetal protein survivin are dependent on its selective expression patterns within immunochemically distinct subcellular pools. The mechanism by which survivin localizes to these compartments, however, is only partly understood. Here we show that nuclear accumulation of survivin is promoted by CREB-binding protein (CBP)-dependent acetylation on lysine 129 (129K, Lys-129). We demonstrate a mechanism by which survivin acetylation at this position results in its homodimerization, while deacetylation promotes the formation of survivin monomers that heterodimerize with CRM1 and facilitate its nuclear export. Using proteomic analysis, we identified the oncogenic transcription factor STAT3 as a binding partner of nuclear survivin. We show that acetylated survivin binds to the N-terminal transcriptional activation domain of the STAT3 dimer and represses STAT3 transactivation of target gene promoters. Using multiplex PCR and DNA sequencing, we identified a single-nucleotide polymorphism (A â G) at Lys-129 that exists as a homozygous mutation in a neuroblastoma cell line and corresponds with a defect in survivin nuclear localization. Our results demonstrate that the dynamic equilibrium between survivin acetylation and deacetylation at amino acid 129 determines its interaction with CRM1, its subsequent subcellular localization, and its ability to inhibit STAT3 transactivation, providing a potential route for therapeutic intervention in STAT3-dependent tumors.
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Núcleo Celular/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Acetilação , Transporte Ativo do Núcleo Celular , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Tumoral , Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Immunoblotting , Proteínas Inibidoras de Apoptose , Carioferinas/metabolismo , Lisina/genética , Lisina/metabolismo , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/genética , Mutação , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Multimerização Proteica , Receptores Citoplasmáticos e Nucleares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/química , Fator de Transcrição STAT3/genética , Survivina , Ativação Transcricional , Proteína Exportina 1RESUMO
INTRODUCTION: We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)-positive non-small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. METHODS: We pooled data for patients with previously treated or untreated PD-L1âpositive (tumor proportion score [TPS], ≥1%) advanced or metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases. RESULTS: A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1â43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS ≥50% (0.67 [95% confidence intervals (CI): 0.44â1.02] and 0.66 [95% CI: 0.58â0.76], respectively) and PD-L1 TPS ≥1% (0.83 [95% CI: 0.62â1.10] and 0.78 [95% CI: 0.71â0.85], respectively). Progression-free survival was improved, objective response rates were higher, and duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without. CONCLUSIONS: Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1âpositive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.
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INTRODUCTION: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study. METHODS: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m2 once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis. RESULTS: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0â77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44â0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61â0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (â¼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab. CONCLUSIONS: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.