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INTRODUCTION: Established biomarkers for predicting chemoradiotherapy efficacy for limited-disease small cell lung cancer (LD-SCLC) are lacking. The inflammation-based Glasgow Prognostic Score (GPS), comprising serum C-reactive protein (CRP) and albumin levels, can predict survival in advanced cancer. This study investigated whether metabolic and inflammatory markers, including the GPS, can predict the efficacy of chemoradiotherapy in patients with LD-SCLC. METHODS: We retrospectively analyzed 124 patients who underwent chemoradiotherapy for LD-SCLC at two institutions between April 2007 and June 2021, and assessed the prognostic significance of various metabolic and inflammatory markers. The GPS was calculated using the CRP and albumin concentrations, and categorized as follows: 0, CRP<1.0 mg/dL and albumin≥3.5 mg/dL; 1, elevated CRP or decreased albumin; and 2, CRP≥1.0 mg/dL and albumin<3.5 mg/dL. Differences in progression-free survival (PFS) and overall survival (OS) were examined using Kaplan-Meier curves and Cox proportional-hazard models. RESULTS: The overall response rate was 95.1% (95% confidence interval [CI]: 89.6-97.9%). The median PFS and OS from chemoradiotherapy initiation were 12.6 (95% CI: 9.9-15.4) and 29.0 (95% CI: 24.8-45.5) months, respectively. The GPS demonstrated independent predictive ability for the effectiveness of chemoradiotherapy, wherein favorable scores (GPS 0-1) were significantly correlated with superior PFS and OS compared to unfavorable scores (GPS 2: PFS: 14.8 vs. 6.7 months, p=0.0001; OS: 35.4 vs. 11.0 months, p<0.0001). CONCLUSION: This preliminary examination revealed that the GPS was significantly associated with PFS and OS in patients undergoing chemoradiotherapy for LD-SCLC, indicating its potential utility in assessing the therapeutic outcomes in LD-SCLC.
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BACKGROUND: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established. PATIENTS AND METHODS: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan. RESULTS: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006). CONCLUSIONS: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID.
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Doenças Autoimunes , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Estudos Retrospectivos , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Idoso , Doenças Autoimunes/mortalidade , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/complicações , Pessoa de Meia-Idade , Análise de Sobrevida , Japão/epidemiologia , Idoso de 80 Anos ou mais , Taxa de Sobrevida , AdultoRESUMO
Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.
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OBJECTIVE: Cancer is a well-known risk factor for venous thromboembolism. The D-dimer level is used to predict venous thromboembolism; however, reports on an appropriate D-dimer cut-off value in Japanese patients with advanced lung cancer are lacking. Therefore, this study aimed to calculate the D-dimer cut-off value for venous thromboembolism at the time of lung cancer diagnosis. METHODS: The Rising-venous thromboembolism/NEJ037 study was a multicenter, prospective observational study. Patients with lung cancer who were contraindicated for radical resection or radiation were enrolled and followed up for 2 years. In the present study (jRCT no. 061180025), a receiver operating characteristic curve for D-dimer levels was created using the dataset of the Rising-venous thromboembolism/NEJ037 study. RESULTS: The Rising-venous thromboembolism/NEJ037 study included a total of 1008 patients, of whom 976, whose D-dimer levels had been measured at the time of cancer diagnosis, were included in the present study. At the time of lung cancer diagnosis, 62 (6.3%) and 914 (93.7%) patients presented with and without venous thromboembolism, respectively. The D-dimer values ranged from 0.1 to 180.1 µg/ml and from 0.1 to 257.2 µg/ml in patients with and without venous thromboembolism, respectively. The receiver operating characteristic curve was discriminative with a cut-off value of 3.3 µg/ml and an area under the curve of 0.794 (sensitivity, 0.742; specificity, 0.782; 95% confidence interval, 0.725-0.863). CONCLUSIONS: This is the first study to calculate the D-dimer cut-off value in Japanese patients with advanced lung cancer. Patients with D-dimer levels ≥3.3 µg/ml at the time of initial diagnosis may have coexisting venous thromboembolism.
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Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7-7.7) and 18.5 months (95% CI: 3.5-33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8-64.5) and 36.4% (95% CI: 19.0-53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.
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BACKGROUND/AIM: Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker. PATIENTS AND METHODS: Forty-six patients with ES-SCLC who received 18F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated. RESULTS: PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUVmax, MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were significant predictors of OS. SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs. CONCLUSION: MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Carga Tumoral , Antígeno B7-H1/metabolismo , Prognóstico , Albuminas/metabolismo , Estudos Retrospectivos , Glicólise , Compostos RadiofarmacêuticosRESUMO
Importance: Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. Objective: To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. Design, Setting, and Participants: This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. Exposures: Systemic therapy. Main Outcomes and Measures: The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). Conclusions and Relevance: In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Idoso , Feminino , Antígeno B7-H1 , Estudos Retrospectivos , Recidiva Local de Neoplasia , ImunoterapiaRESUMO
Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.
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Carcinoma Pulmonar de Células não Pequenas , Neutropenia Febril , Filgrastim , Leucopenia , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/etiologia , Ramucirumab , Docetaxel , Neoplasias Pulmonares/etiologia , Polietilenoglicóis/uso terapêutico , Leucopenia/induzido quimicamente , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/prevenção & controle , Neutropenia Febril/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêuticoRESUMO
The aim of the present study was to explore the relationship between tumor metabolic glycolysis and inflammatory or nutritional status in patients with advanced non-small cell lung cancer (NSCLC) who received programmed death-1 (PD-1) blockade. A total of 186 patients were registered in the present study. All of patients underwent 18F-FDG PET imaging before initial PD-1 blockade, and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed as indicators of 18F-FDG uptake. As inflammatory and nutritional index, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ration (PLR), systemic immune inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI) and Glasgow prognostic score (GPS) were evaluated based on previous assessment. 18F-FDG uptake by MTV and TLG significantly correlated with the scores of NLR, PLR, SII, PNI and ALI, in addition to the level of albumin, lactate dehydrogenase, C-reactive protein, white blood cells, neutrophils, lymphocytes and body mass index. The count of NLR, PLR and SII was significantly higher in patients with <1 year overall survival (OS) compared with in those with ≥1 year OS, and that of PNI and ALI was significantly lower in those with <1 year OS compared with those with ≥1 year OS. High MTV under the high PLR, SII and low ALI were identified as significant factors for predicting the decreased PFS and OS after PD-1 blockade in a first-line setting. In second or more lines, high MTV was identified as a significant prognostic predictor regardless of the levels of PLR, SII, ALI and GPS. In conclusion, metabolic tumor glycolysis determined by MTV was identified as a predictor for the outcome of PD-1 blockade under the high inflammatory and low nutritional conditions, in particular, when treated with a first-line PD-1 blockade. A high MTV under high PLR and SII and low ALI in the first-line setting could be more predictive of ICI treatment than other combinations.
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Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Receptores ErbB/genéticaRESUMO
Despite the occurrence of various hemorrhagic events during advanced lung cancer treatment, few researchers have reported on their risk factors. Moreover, the development of cancer-related thromboembolism indicates anticoagulant use. However, adverse events such as bleeding should be monitored. In this study, we aimed to identify factors that influence the onset of hemorrhagic events in patients with lung cancer. The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study. A total of 1008 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Multivariate analysis using a Cox proportional hazard model was performed to compare the outcomes of the time to the onset of hemorrhagic events for 2 years after registration. Hemorrhagic events occurred in 115 patients (11.4%), with 35 (30.4%) experiencing major bleeding. Significant risk factors included venous thromboembolism (VTE) (hazard ratio [HR]: 4.003, p < 0.001) and an Eastern Cooperative Oncology Group Performance Status score of 1 (HR: 2.476, p < 0.001). Factors that significantly reduced hemorrhagic event risk were female sex (HR: 0.454, p = 0.002) and M1a status (HR: 0.542, p = 0.038). VTE is a risk factor for hemorrhagic events in patients with advanced lung cancer, and risks associated with anticoagulant therapy should be considered.
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INTRODUCTION: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi. METHODS: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). RESULTS: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of <1% and ≥1%, respectively. CONCLUSION: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Nivolumabe , Ipilimumab/uso terapêutico , Estudos Retrospectivos , Contagem de Linfócitos , Prognóstico , Inflamação/tratamento farmacológico , Neutrófilos/patologiaRESUMO
BACKGROUND: A prospective evaluation of non-alcoholic fatty liver disease (NAFLD) during induction therapy for acute lymphoblastic leukemia (ALL) has not been performed. Herein, we prospectively investigated the frequency, risk factors, and outcomes of NAFLD during induction therapy in children and adolescents with B-cell precursor ALL (BCP-ALL). METHODS: This study enrolled 74 newly diagnosed BCP-ALL cases aged 1 year and older who were admitted to our department between January 2011 and December 2020. Median age was 6.6 years (1.3-17.5 years). Plain computed tomography (CT) of the upper abdomen was performed before induction therapy, and on days 15 and 29 after initiation of induction therapy. Patients with a liver/spleen CT ratio <0.9 were defined as having NAFLD. RESULTS: The frequency of NAFLD was 73%. Patients with NAFLD had a higher rate of hypertriglyceridemia. There was no significant difference in 5-year overall survival and event-free survival (EFS) between patients with and without NAFLD. However, after restricting the target age to 10 years and older, 5-year EFS was significantly higher in patients with NAFLD than in those without (88.5 vs. 42.9%, respectively, P = 0.037). Similarly, 5-year cumulative incidence of relapse (CIR) was significantly lower in patients with NAFLD than in those without it (5-year CIR, 6.3 vs. 57.1%, respectively, P = 0.013). CONCLUSION: Patients with NAFLD exhibit better outcomes including 5-year EFS and CIR. Further studies are necessary.
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Hepatopatia Gordurosa não Alcoólica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adolescente , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Intervalo Livre de Doença , Prognóstico , Quimioterapia de Indução , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , RecidivaRESUMO
PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.
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Acrilamidas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Sistema Nervoso Central , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Pemetrexede/uso terapêutico , Platina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carboplatina , Bevacizumab , Paclitaxel , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptores ErbB/genética , Falha de Tratamento , Neoplasias Hepáticas/etiologia , Neoplasias Encefálicas/etiologia , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
BACKGROUND: The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. RESULTS: Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. CONCLUSION: Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ramucirumab , Docetaxel/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
BACKGROUND: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade. METHODS: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed. RESULTS: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA. CONCLUSIONS: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/metabolismo , Anticorpos Antinucleares/uso terapêutico , Prognóstico , Estudos Retrospectivos , Receptor de Morte Celular Programada 1 , Relevância Clínica , Fatores de Transcrição Forkhead/uso terapêuticoRESUMO
BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Compostos de Anilina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Pemetrexede/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) has been identified as one of the resistant mechanisms to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the relationship between the efficacy of osimertinib and protein expression of VEGF family members in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations remains unclear. METHODS: A total of 76 patients with advanced NSCLC with EGFR major mutations (del19 or L858R) receiving first-line osimertinib were eligible as the osimertinib (Osi) group, whereas 43 patients receiving first- or second-generation EGFR-TKIs were compared with the control group. The expression of vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor C (VEGF-C) in the tumor specimens was analyzed using immunohistochemistry. RESULTS: VEGFR2 and VEGF-C were highly expressed in 65.8% and 51.3% of patients, respectively, in the Osi group, and 69.7% and 76.7%, respectively, in the control group. High VEGFR2 and VEGF-C levels were significantly associated with poor performance status (PS) and female sex, respectively. In the Osi group, patients with co-high expression of VEGFR2 and VEGF-C showed significantly worse progression-free survival (PFS) and overall survival (OS) than those without co-high expression. In del19, VEGFR2 was a significant predictor of PFS and OS and independent predictor of OS in multivariate analysis. In L858R, co-high expression of VEGFR2 and VEGF-C was identified as a significant predictor of PFS and OS and independent predictor of PFS. CONCLUSION: VEGFR2 and VEGF-C are highly expressed in EGFR-mutant NSCLC cells. Increased expression of VEGFR2 was identified as a significant prognostic factor in patients with EGFR del19 mutation who received osimertinib, whereas co-high expression of VEGFR2 and VEGF-C was a significant predictor for those with EGFR L858R mutation.