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BACKGROUND: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine. METHODS: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL). RESULTS: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen. CONCLUSIONS: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Cooperação do Paciente , Qualidade de Vida , Análise de Sobrevida , Tegafur/efeitos adversosRESUMO
BACKGROUND: The toxicity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is less than that of cytotoxic agents. The reports of dramatic response and improvement in performance status with the use of EGFR TKIs may influence a physician's decision-making for patients with non-squamous non-small cell lung cancer (NSCLC) and life-threatening respiratory distress. The aim of this study was to evaluate the outcome of rescue or maintenance therapy with EGFR TKI for stage IIIb-IV non-squamous NSCLC patients requiring mechanical ventilation. METHODS: Eighty-three Asian patients with stage IIIb-IV non-squamous NSCLC and who required mechanical ventilation between June 2005 and January 2010 were evaluated. RESULTS: Of the 83 patients, 16 (19%) were successfully weaned from the ventilator. The use of EGFR TKI as rescue or maintenance therapy during respiratory failure did not improve the rate of successful weaning (standard care 18% vs. with EGFR TKI, 22%; p = 0.81) in univariate and multivariate analyses. CONCLUSIONS: Rescue or maintenance therapy with EGFR TKI for stage IIIb-IV non-squamous NSCLC patients requiring mechanical ventilation was not associated with better outcome. An end-of-life discussion should be an important aspect in the care of this group of patients, since only 19% were successfully weaned from mechanical ventilation.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Respiração Artificial , Estudos Retrospectivos , Resultado do Tratamento , Desmame do RespiradorRESUMO
BACKGROUND: STK11/LKB1 mutations have been associated with primary resistance to PD-1 axis inhibitors and poor prognosis in advanced KRAS-mutant lung adenocarcinoma. This study aimed to assess the prognostic significance of STK11/LKB1 alterations in localized non-squamous non-small cell lung carcinoma (non-sq NSCLC). PATIENTS AND METHODS: Surgical samples from patients undergoing complete resection for stage IIa, IIb, or IIIa (N2 excluded) non-sq NSCLC in the randomized adjuvant phase II trial (NCT00775385 IFCT-1801 TASTE trial) were examined. Patients received either standard chemotherapy (Pemetrexed Cisplatin) or personalized treatment based on EGFR mutation (Erlotinib) and ERCC1 expression. Tumor molecular profiles were analyzed using targeted NGS and correlated with overall survival (OS) and disease-free survival (DFS), adjusting for relevant clinical variables. Additionally, interactions between treatment groups and molecular alterations on OS, PD-L1 expression, and tumor-circulating DNA in post-operative plasma samples were evaluated. RESULTS: Among 134 patients (predominantly male smokers with adenocarcinoma), KRAS mutations were associated with shorter DFS (HR: 1.95, 95 % CI: 1.1-3.4, p = 0.02) and OS (HR: 2.32, 95 % CI: 1.2-4.6, p = 0.014). Isolated STK11/LKB1 mutations (n = 18) did not significantly impact DFS or OS. However, within KRAS-mutated samples (n = 53), patients with concurrent STK11/LKB1 mutations (n = 10) exhibited significantly shorter DFS (HR: 3.85, CI: 1.5-10.2, p = 0.006) and a trend towards shorter OS (HR: 1.80, CI: 0.6-5.3, p = 0.28). No associations were found between PD-L1 expression, other gene mutations, progression-free survival (PFS), or OS. CONCLUSION: This analysis reinforces KRAS mutations as predictive factors for relapse and poor survival in localized non-sq NSCLC. Furthermore, the presence of concomitant STK11/LKB1 mutations exacerbated the prognosis within the KRAS-mutated subset. These findings emphasize the clinical relevance of these molecular markers and their potential impact on treatment strategies in non-sq NSCLC.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Adenocarcinoma de Pulmão/genética , Quinases Proteína-Quinases Ativadas por AMP , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
BACKGROUND: This was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The six symptom items' [average symptom burden index (ASBI)] mean at baseline was calculated using the lung cancer symptom scale (LCSS). Low and high symptom burden (LSB, ASBI < 25; HSB, ASBI ≥ 25) and performance status (PS: 0, 1) subgroups were analyzed for treatment effect on progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models adjusted for demographic/clinical factors. RESULTS: Significantly longer PFS and OS for pemetrexed versus placebo occurred in LSB patients [PFS: median 5.1 versus 2.4 months, hazard ratio (HR) 0.49, P < 0.0001; OS: median 17.5 versus 11.0 months, HR 0.63, P = 0.0012] and PS 0 patients (PFS: median 5.5 versus 1.7 months, HR 0.36, P < 0.0001; OS: median 17.7 versus 10.3 months, HR 0.54, P = 0.0019). Significantly longer PFS, but not OS, occurred in HSB patients (median 3.7 versus 2.8 months, HR 0.50, P = 0.0033) and PS 1 patients (median 4.4 versus 2.8 months, HR 0.60, P = 0.0002). CONCLUSIONS: ASBI and PS are associated with survival for non-squamous NSCLC patients, suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction.
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Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Feminino , Guanina/administração & dosagem , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Pemetrexede , Resultado do TratamentoRESUMO
Background: The addition of bevacizumab was found to be associated with prolonged survival whether in combination with chemotherapy, tyrosine kinase inhibitors or immune checkpoint inhibitors in the treatment landscape of advanced non-small cell lung cancer (NSCLC) patients. However, the biomarkers for efficacy of bevacizumab were still largely unknown. This study aimed to develop a deep learning model to provide individual assessment of survival in advanced NSCLC patients receiving bevacizumab. Methods: All data were retrospectively collected from a cohort of 272 radiological and pathological proven advanced non-squamous NSCLC patients. A novel multi-dimensional deep neural network (DNN) models were trained based on clinicopathological, inflammatory and radiomics features using DeepSurv and N-MTLR algorithm. And concordance index (C-index) and bier score was used to demonstrate the discriminatory and predictive capacity of the model. Results: The integration of clinicopathologic, inflammatory and radiomics features representation was performed using DeepSurv and N-MTLR with the C-index of 0.712 and 0.701 in testing cohort. And Cox proportional hazard (CPH) and random survival forest (RSF) models were also developed after data pre-processing and feature selection with the C-index of 0.665 and 0.679 respectively. DeepSurv prognostic model, indicated with best performance, was used for individual prognosis prediction. And patients divided in high-risk group were significantly associated with inferior PFS (median PFS: 5.4 vs 13.1 months, P<0.0001) and OS (median OS: 16.4 vs 21.3 months, P<0.0001). Conclusions: The integration of clinicopathologic, inflammatory and radiomics features representation based on DeepSurv model exhibited superior predictive accuracy as non-invasive method to assist in patients counseling and guidance of optimal treatment strategies.
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BACKGROUND: This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224-0.634; p < .001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p = .033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1-2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. CONCLUSIONS: First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC.
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Bevacizumab , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Estudos Retrospectivos , Neoplasias Encefálicas/secundárioRESUMO
PURPOSE: The relationship between mutant KRAS and the risk of disease progression and death in advanced non-squamous non-small cell lung cancer (NSCLC) is still controversial among current studies, and the effects of distinct KRAS mutations on prognosis may be different. This study aimed to further investigate the association between them. PATIENTS AND METHODS: Of the 184 patients eventually included in the study, 108 had KRAS wild type (WT) and 76 had KRAS mutant type (MT). Kaplan-Meier curves were plotted to describe the survival for patients among groups, while log-rank tests were conducted to evaluate the survival differences. The univariate and multivariate Cox regression were performed to identify predictors, and subgroup analysis was used to verify the interaction effect. RESULTS: Similar efficacy of first-line therapy was observed for KRAS MT and WT patients (p = 0.830). The association between KRAS mutation and progression-free survival (PFS) was not significant in univariate analysis (hazard ratio [HR] = 0.94; 95% CI, 0.66-1.35), and no KRAS mutation subtype significantly affected PFS. However, KRAS mutation and KRAS non-G12C were associated with increased risk of death compared to KRAS WT in univariate and multivariate analysis. Univariate and multivariate analysis also confirmed that chemotherapy combined with antiangiogenesis or immunotherapy in the KRAS mutation group was associated with decreased risk of disease progression. However, the overall survival (OS) among KRAS mutant patients received different first-line treatments did not significantly differ. CONCLUSION: KRAS mutations and their subtypes are not independent negative predictors of PFS, while KRAS mutation and KRAS non-G12C were independent prognostic factors for OS. Chemotherapy combined with antiangiogenesis or immunotherapy conferred decreased risk of disease progression to KRAS mutation patients compared to single chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , População do Leste Asiático , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Non-small cell lung cancer (NSCLC) is one of the most malignant tumors. The study was carried out to investigate the prognostic value of Beclin 1, EGFR and ALK for this cancer. Patients diagnosed with non-squamous NSCLC and admitted to our hospital from January 2011 to September 2016 were analyzed. Expression of Beclin 1 and mutation of EGFR and ALK were assessed using polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) and analyzed for their relationship with demographic and clinical characteristics of the patients. Multivariate Cox regression models were applied to analyze the risk factors associated with survival and receiver response curves (ROC) were plotted to determine the prognostic value of Beclin 1, EGFR and ALK for patients with non-squamous NSCLC. Compared with adjacent normal tissue, Beclin 1 expression was elevated in the cancer tissue significantly; assessments of EGFR and ALK mutations showed that out of the 480 patients, 233 (48.5%) and 75 (12.6%) patients had EGFR and ALK mutations. Univariate analysis revealed that Beclin 1 level, EGFR and ALK mutations were associated with lymph node metastasis, TNM stage, tumor differentiation and prognosis, but not with gender, age and smoking status. The Kaplan-Meier survival analysis indicated that low Beclin 1 expression and positive EGFR and ALK rearrangements were associated with higher survival rate and longer progress-free survival (PFS). Multivariate Cox regression analysis showed that Beclin 1, EGFR, ALK mutations, tumor differentiation grade, TNM stage and lymph node metastasis were independently associated with PFS. ROC analysis showed that Beclin 1, EGFR and ALK were significant predictors for PFS; the areas under curve (AUC) for Beclin 1, EGFR and ALK were 0.812 (P = 0.018, cut-off value: 1.2), 0.781 (P = 0.011, cut-off value: 15%) and 0.722 (P = 0.010, cut-off value: 11%), respectively, suggesting that they have significant prognostic value for lung cancer patients. Our data indicate that Beclin 1, EGFR and ALK genes are associated with the prognosis of patients with non-squamous NSCLC. High Beclin 1 expression and negative EGFR and ALK mutations predict a poor prognosis with PFS.
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Aim: The objective of our study was to assess the efficacy of immune checkpoint inhibitors (ICIs) on patients with non-small-cell lung cancer (NSCLC) harboring oncogenic alterations. Methods: We retrospectively enrolled patients with advanced non-squamous NSCLC who were treated with anti-PD-1-based monotherapy or combined immunotherapy. Major characteristics including PD-L1 expression, treatment, and survival were analyzed. Results: In total, 309 non-squamous NSCLC patients with a median age of 61 years (range 20-88 years) including 70.9% male were retrospectively enrolled. The molecular alterations involved epidermal growth factor receptor (EGFR) (n = 81), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (n = 31), anaplastic lymphoma kinase (ALK) (n = 1), human epidermal growth factor receptor 2 (HER2) (n = 12), V-raf murine sarcoma viral oncogene homolog (BRAF) (n = 2), rearranged during transfection (n = 4), and c-ros oncogene 1 (ROS1) (n = 3). In the EGFR subset, the ORR was 30.9% (n = 81) and PFS was significantly shorter than WT group (median PFS: 5.7 months vs. 7.1 months; P = 0.0061). In subgroup analyses, ICI combined therapy was significantly correlated with a longer PFS compared with ICI monotherapy (median PFS: 7.7 months vs. 4.7 months; P = 0.0112). In KRAS patients, ORR was 51.6% (n = 31). No significant difference was found in subgroup analyses. The ORR and PFS were 16.7% (n = 12) and 28.6% (n = 7), 7.8 months and 9.0 months for HER2 and EGFR Exon20 insertion patients, respectively. Three ROS1 patients were enrolled with a PFS of 16.0, 34.2, and 45.0 months individually, and one ALK patient with PFS of 4.4 months was identified. No response was found in two BRAF patients. Conclusion: ICI-based combination therapy can bring benefit to patients with EGFR-mutant NSCLC. ICI-based combination therapy could be considered for patients with ROS1 rearrangement, HER2 mutation and EGFR Exon20 insertion NSCLC.
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Background: Bevacizumab (Avastin®), a monoclonal antibody targeting vascular endothelial growth factor (VEGF)-A, is widely used in treating a variety of malignant tumors. Several biosimilars of bevacizumab have been developed and marketed with the expiration of bevacizumab's patent. The objective of this study was to collate available data from head-to-head randomized controlled trials (RCTs) and evaluate the efficacy and safety of biosimilar bevacizumab compared with the bevacizumab (Avastin®) in patients with non-squamous non-small cell lung cancer (NSCLC). Methods: Literature search of Web of Science, PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov was performed from inception until October 15, 2021. The efficacy outcome indicators were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The occurrence of adverse events (AEs) was evaluated for safety outcome. Results: Ten RCTs recruiting 6,416 patients with non-squamous NSCLC were included. All RCTs studies included the biosimilar bevacizumab group as the experimental group and the original bevacizumab group as the control group. The patients in the experimental group and control group received the same dose and duration of chemotherapy combined with carboplatin and paclitaxel. The results of meta-analysis showed that there were no significant differences in ORR [risk ratio (RR): 0.97, 95% confidence interval (95% CI): 0.93-1.02. P=0.841, I2=0], PFS (RR: 1.04, 95% CI: 0.98-1.10, P=0.235, I2=0) and OS (RR: 1.05, 95% CI: 1.00-1.10, P=0.692, I2=0) between the biomarker and original groups. The P values of ORR, PFS and OS were 0.533, 0.970 and 0.916 respectively as shown by Egger's test, suggesting that there was no publication bias. Subgroup analysis showed no significant differences in ORR, PFS, and OS between the Chinese and multicenter trials. The pooled incidence rate of AEs between two groups was similar, and there was also no significant difference between the two groups. Discussion: This is the first study to independently report biosimilar bevacizumab in a meta-analysis on NSCLC treatment. The results showed that biosimilar bevacizumab had similar efficacy and safety compared with the original bevacizumab. Trial Registration: PROSPERO registration No. CRD42021276991.
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BACKGROUND: We compared the efficacy, safety, and immunogenicity of MIL60 with reference bevacizumab as first-line treatment in patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) in this phase 3, randomized, double-blind study. METHODS: Patients with untreated advanced or recurrent NSCLC were randomized (1:1 ratio) to receive either MIL60 or bevacizumab in combination with paclitaxel/carboplatin. Patients with non-progressive disease continued maintenance single-agent MIL60 until disease progression, or intolerable toxicity. The primary endpoint was the 12-week objective response rates (ORR12) by independent review committee (IRC) using RECIST 1.1. Bioequivalence was established if the ORR ratio located between 0.75 and 1/0.75. The trial was registered with clinicaltrials.gov (NCT03196986). FINDINGS: Between Aug 23, 2017, and May 8, 2019, 517 patients were randomly assigned to MIL60 group (n=257) and bevacizumab group (n=260). In the full analysis set (FAS) population including all randomized and evaluable patients who received at least one dose of MIL60 or bevacizumab, the ORR12 in MIL60 group and bevacizumab group were 48.6% and 43.1%, respectively. The ORR ratio of these two groups were 1.14 (90% CI 0.97-1.33), which fell within the pre-specified equivalence boundaries (0.75-1/0.75). The median DOR was 5.7 months (95% CI 4.5-6.2) for MIL60 and 5.6 months (95% CI 4.3-6.4) for bevacizumab. No significant difference was noted in median PFS (7.2 vs. 8.1 months; HR 1.01, 95% CI 0.78-1.30, p=0.9606) and OS (19.3 vs. 16.3 months; HR 0.81, 95% CI 0.64-1.02, p=0.0755). Safety and tolerability profiles were similar between the two groups. No patient detected positive for Anti-drug antibody (ADA). INTERPRETATION: The efficacy, safety and immunogenicity of MIL60 were similar with bevacizumab, providing an alternative treatment option for advanced or recurrent non-squamous NSCLC. FUNDING: This study was sponsored by Betta Pharmaceutical Co., Ltd.
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OBJECTIVE: This phase 3 study aimed to test equivalence in efficacy and safety for QL1101, a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab, 15 mg/kg every 3-week for 6 cycles. This was followed by maintenance treatment with single agent QL1101 every 3-week. The primary end-point was objective response rate (ORR), with secondary end-points being progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). RESULTS: Of 675 patients, 535 eligible patients were randomized to the QL1101 group (n = 269) and bevacizumab group (n = 266). ORRs were 52.8% and 56.8%, respectively, for the QL1101 and bevacizumab groups, with an ORR hazard ratio 0.93 (95% confidence interval: 0.8-0131.1). The PFS, OS, DCR, and AEs were comparable between the 2 groups, which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history. CONCLUSIONS: QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.
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BACKGROUND: Circular RNAs (circRNAs) are covalently closed RNAs and are implicated in the development of non-small cell lung cancer (NSCLC). Here, we identified the precise actions of circRNA LIM domain binding 2 (circLDB2, hsa_circ_0069244) in non-squamous NSCLC development and drug sensitivity. METHODS: CircLDB2, microRNA (miR)-346, and LIM and calponin-homology domains 1 (LIMCH1) were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Ribonuclease R (RNase R), actinomycin D, and subcellular localization assays were used to characterize circLDB2. Cell proliferation and viability, colony formation, apoptosis, migration, and invasion were gauged by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound-healing, and transwell assays, respectively. RNA immunoprecipitation (RIP), RNA pull-down, and dual-luciferase reporter assays were used to verify the direct relationship between miR-346 and circLDB2 or LIMCH1. Animal studies were performed to evaluate the impact of circLDB2 in vivo. RESULTS: CircLDB2 was underexpressed in non-squamous NSCLC and was identified as a bona fide circular transcript. Overexpression of circLDB2 impeded cell proliferation, migration, invasion, and enhanced apoptosis and cisplatin sensitivity in vitro, as well as promoted the antitumor effect of cisplatin in vivo. CircLDB2 regulated cell functional behaviors and cisplatin sensitivity by sponging miR-346. LIMCH1 was a direct and functional target of miR-346. Furthermore, circLDB2 acted as a competing endogenous RNA (ceRNA) for miR-346 to induce LIMCH1 expression. CONCLUSION: Our findings demonstrated that circLDB2 impeded non-squamous NSCLC development and enhanced cisplatin sensitivity partially by acting as a ceRNA, highlighting circLDB2 as a promising candidate for the development of novel antitumor therapies.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Pulmonares/metabolismo , MicroRNAs/fisiologia , RNA Circular/fisiologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Although concurrent chemoradiotherapy is the standard therapy for unresectable stage III non-small cell lung cancer (NSCLC), no optimal concurrent chemoradiotherapy regimen has been identified in non-squamous NSCLC. We conducted an open-label, multicenter phase I trial to assess the safety of carboplatin (CBDCA) plus pemetrexed (PEM) with concurrent thoracic radiotherapy (TRT) of 60 Gy. The primary endpoint was determination of the maximum tolerated dose. In total, 6 patients were registered during the period from February 2012 through January 2014. Dose-limiting toxicities (DLTs) were observed in 2 patients (one case each of prolonged neutropenia and pneumonitis). The overall response rate was 83.3%, and median progression-free survival was 20.1 months. Since only two DLTs were observed in the phase I cohort, we concluded that CBDCA plus PEM with concurrent TRT was feasible in Japanese patients with unresectable stage III non-squamous NSCLCs. We will recommend the dose of CBDCA area under the curve 5 plus PEM 500 mg/m2 for the next phase II trial.
Assuntos
Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia/métodos , Pemetrexede/uso terapêutico , Adulto , Idoso , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Japão/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To analyze the prognostic effect for patients with non-squamous non-small cell lung cancer (NSCLC) harbored STK11 or KEAP1 (STK11/KEAP1) mutations receiving atezolizumab and docetaxel. METHODS: Data from OAK and POPLAR clinical trials was firstly applied to analyze genomic alteration frequency and the correlation between STK11/KEAP1 mutations and blood-based tumor mutational burden (bTMB)/PD-L1 expression. Univariate and multivariate Cox regression hazard models were preformed to analyze the influence of prognostic factors on survival. Survival difference was compared by Kaplan-Meier and log-rank test. RESULTS: Most STK11/KEAP1 mutations (7.33 %/10.76 %) were found in non-squamous NSCLC compared with squamous lung cancer. Interestingly, only 1.56 % STK11 mutation or 3.13 % KEAP1 mutation occurred in EGFR mutant non-squamous NSCLC. Compared with wild type, patients with STK11/KEAP1 mutations had higher bTMB (both, P < 0.001). Moreover, compared with wild type, patients harbored KEAP1 mutation had higher PD-L1 expression (TC3/IC3: 25.00 % vs. 14.54 %), while patients harbored STK11 mutation had lower PD-L1 expression (TC3/IC3: 7.89 % vs. 15.90 %). Univariate and multivariate analyses revealed that STK11/KEAP1 mutations were independent and significant prognostic factors on overall survival (OS) (both, P < 0.05) and progression-free survival (PFS) (both, P < 0.05). Importantly, patients harbored STK11/KEAP1 mutations had a relatively worse OS than wild type both in those receiving atezolizumab and docetaxel (all, P < 0.05). In addition, for STK11 mutant subset, atezolizumab did not improve OS compared with docetaxel (HR = 0.669; 95 %CI: 0.380-1.179; P = 0.669); while cox-regression analysis showed the improved survival of patients with KEAP1 mutation who receiving atezolizumab compared with docetaxel (HR = 0.610; 95 %CI: 0.384-0.969; P = 0.036). CONCLUSION: Compared with wild type, non-squamous NSCLC patients with STK11/KEAP1 mutations may not benefit more from both atezolizumab and docetaxel. However, patients with mere KEAP1 mutations and without STK11 mutations may have a better response to atezolizumab than docetaxel.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinases Proteína-Quinases Ativadas por AMP , Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Fator 2 Relacionado a NF-E2 , Proteínas Serina-Treonina Quinases , Análise de SobrevidaRESUMO
INTRODUCTION: We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis. METHODS: Sixty-seven chemonaïve patients with advanced non-squamous NSCLC were screened, enrolling 21 ASS1-deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m2 ) with Pem (500 mg/m2 ) and Cis (75 mg/m2 ), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next-generation sequencing and PD-L1 immunohistochemistry. RESULTS: ADIPemCis was well-tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%-97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%-70.2%). The median progression-free and overall survivals were 4.2 (95% CI 2.9-4.8) and 7.2 (95% CI 5.1-18.4) months, respectively. Two PD-L1-expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1-proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD-L1 (<1%) expression (55.6%). Re-expression of tumoral ASS1 was detected in one patient at progression (n = 1/3). CONCLUSIONS: ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Hidrolases/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Cisplatino/farmacologia , Estudos de Coortes , Feminino , Humanos , Hidrolases/farmacologia , Masculino , Pessoa de Meia-Idade , Pemetrexede/farmacologia , Polietilenoglicóis/farmacologiaRESUMO
BACKGROUND: Recently, several clinical studies have evaluated the first-line use of immune checkpoint inhibitors (ICIs) combined with platinum-doublet chemotherapy in patients with non-squamous non-small cell lung cancer (NSCLC), however, the differences in safety and efficacy between the various types of ICIs still require investigation. In this study, we evaluated the efficacy and safety of the first-line use of ICIs combined with platinum-doublet chemotherapy in patients with non-squamous NSCLC by meta-analysis and indirect comparison. METHODS: Literature searches were performed using PubMed, the Cochrane Library, Embase, China Knowledge Resource Integrated Database, and Wanfang Data to identify all relevant randomized clinical trials for non-squamous NSCLC after 2010. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) were pooled for meta-analysis and indirect comparison. Subgroup analyses were conducted to examine the factors associated with PFS. RESULTS: The meta-analysis showed that the additional use of ICIs could significantly improve PFS and OS. The indirect comparison showed no significant difference in pembrolizumab + chemotherapy and atezolizumab + chemotherapy in the reducing of disease progression, while a significant difference in restricted mean survival time (RMST) was found between pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy. A significant increase in grade ≥3 AEs was observed with the additional use of atezolizumab combined with chemotherapy. Subgroups including PD-1 status [high (>50%), intermediate (1-49%), and negative (<1%) expression], sex (male and female), smoking status (current or former smoker, and never smoked), liver metastases (with and without), age (>65 and ≤65) and Eastern Cooperative Oncology Group (ECOG) score (ECOG=0 and ECOG=1) were all associated with better PFS. CONCLUSIONS: This meta-analysis confirmed the treatment effects of ICIs combined with chemotherapy for non-squamous NSCLC. The pembrolizumab combination group had a greater RMST benefit compared with the atezolizumab combination group. Furthermore, our study also demonstrated a PFS advantage for non-squamous NSCLC using ICIs combined with chemotherapy irrespective of programmed death-ligand 1 (PD-L1) expression level, smoking status, liver metastasis status, sex, age and ECOG score. Due to the significant increase in AEs (> grade 3), more attention should be paid to the additional use of atezolizumab.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , China , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , MasculinoRESUMO
BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.
Assuntos
Adenocarcinoma/mortalidade , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , SobreviventesRESUMO
Lung cancer is still considered a big killer among cancer diseases, due to high incidence and mortality rates. The newer frontiers of therapeutic development regard the discovery of oncogene driven tumours: however, the majority of NSCLC patients are wild type and they cannot be treated with targeted based agents. The recent positive results obtained with immunotherapy and with the combination of angiogenesis inhibitors and docetaxel, changed the therapeutic scenario of the second line therapy of non squamous NSCLC without actionable mutations. A major issue is currently the lack of predictive biomarkers that could help the oncologists in the choice of the best second-line treatment. Aim of this project was to define an optimal therapeutic pathway for patients with non-squamous NSCLC, through a working group of a large number of Italian lung cancer oncologists. Panellists have identified and discussed the more significant criteria in the second-line setting for a therapeutic decision between the combination of angiogenesis inhibitors plus chemotherapy or immunotherapy. Finally, they expressed their preference on each criterion, building a proposal of a decision-making tree for a second-line treatment of non-squamous NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Docetaxel , Humanos , Indóis/administração & dosagem , Itália , Nivolumabe , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxoides/administração & dosagem , RamucirumabRESUMO
OBJECTIVES: This single-arm multicenter Phase II study investigated the efficacy and safety of pemetrexed (Pem) and cisplatin (Cis) induction chemotherapy (CT) followed by full-dose Pem-Cis plus concurrent radiotherapy (RT) in patients with locally advanced non-squamous NSCLC. MATERIALS AND METHODS: Patients with unresectable Stage III non-squamous NSCLC received two 21-day cycles of Pem 500 mg/m(2) (vitamin/folic acid supplementation and dexamethasone prophylaxis per Pem-label)+Cis 75 mg/m(2) on Day 1. Eligible patients who had not progressed continued with 2 further cycles of full-dose Pem-Cis plus concurrent RT (2 Gy/fraction, 5 days/week, 66 Gy total). Primary endpoint was the 1-year progression-free survival (PFS) rate. RESULTS: Of 90 patients enrolled (all treated; median age 61 years, male/female 57%/43%, ECOG performance status 0/1 66%/34%, adenocarcinoma 90%, Stage III 36%/62%), 75 (83%) completed induction CT and started concurrent CT+RT. 64 (71%) patients received all 4 CT cycles and an RT dose ≥60 Gy. The 1-year PFS rate was 51.3% (95%CI: 42.0, 60.5). Median PFS was 10.6 months (95%CI: 8.6, 17.3), median OS was 26.2 months (95%CI: 16.7, not estimable). One patient died from enteritis (treatment-related) during Cycle 4. Four patients discontinued due to treatment-related adverse events, 1 on induction CT (renal failure), 3 on concurrent CT+RT (1 hypoacusis, 2 acute esophagitis). During induction CT, 18.9% of patients reported Grade 3/4 CTCAEs, only neutropenia (2.2%) and syncope (2.2%) were reported by >1 patient. During concurrent CT+RT, 41.3% of patients reported G3/4 CTCAEs, mainly esophagitis (12.0%), neutropenia (10.7%), and leukopenia (9.3%). CONCLUSION: In this study of Pem-Cis induction CT followed by full-dose Pem-Cis with concurrent RT, median PFS was 10.6 months and toxicity was manageable, in line with previous data on Pem-Cis plus RT.