Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-...Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-NSCLC).Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching(PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified.Results: The median duration of follow-up was 15.8 months. The median progression-free survival(PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall(9.8 vs. 7.8 months, P=0.006) and PSM pairs(9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed(12.3 vs. 4.8 vs. 8.6 months;P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy.Conclusions: First-line induction and maintenance therapy with Bev(7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.展开更多
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).Method...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.展开更多
Background: Pemetrexed (PEM) is an efficacious multi-targeted antifolate with acceptable toxicities for non-squamous non-small cell lung cancer (non-Sq NSCLC). However, in the clinical setting, PEM has more severe adv...Background: Pemetrexed (PEM) is an efficacious multi-targeted antifolate with acceptable toxicities for non-squamous non-small cell lung cancer (non-Sq NSCLC). However, in the clinical setting, PEM has more severe adverse effects than those reported. The aim of this study was to identify the factors for the toxicities of PEM-containing chemotherapy in non-Sq NSCLC patients in the clinical setting. Patients and Methods: We retrospectively evaluated the factors related to PEM toxicities in chemotherapy-naive patients with non-Sq NSCLC from September 2009 to July 2013 at our hospital. Logistic regression model was used in the univariate and multivariate analyses. Results: In total, 104 patients were analyzed. Grades 3 to 5 hematologic toxicities were frequent and included neutropenia (42%), febrile neutropenia (7%), anemia (18%), thrombocytopenia (17%), and disseminated intravascular coagulation (2%). On multivariate analyses, the predictors were poor performance status (PS) [odds ratio (OR): 4.89, 95% confidence interval (CI): 1.22 - 19.4] and low body mass index (OR: 1.44, 95% CI: 1.05 - 1.98) for febrile neutropenia;concomitant chronic infectious disease (OR: 6.63, 95% CI: 1.59 - 27.5) and bevacizumab use (OR: 3.57, 95% CI: 1.36 - 9.32) for neutropenia;poor PS (OR: 3.02, 95% CI: 1.33 - 6.85) for thrombocytopenia;and low serum albumin level (OR: 0.22, 95% CI: 0.08 - 0.63) for non-hematologic toxicities. Conclusions: In addition to the previously reported predictors of PEM toxicities, the presence of concomitant chronic infectious disease was associated with hematologic toxicities. Patient groups who are not sufficiently evaluated in clinical trials should be carefully monitored for the development of more toxicities than expected.展开更多
Objective:To explore effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase (MMPs), vascular esandothelial growth factor (VEGF), NK cells and immune function in patients with non-squa...Objective:To explore effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase (MMPs), vascular esandothelial growth factor (VEGF), NK cells and immune function in patients with non-squamous non-small cell lung cancer.Method:A total of86 cases of non-squamous non-small cell lung cancer patients were divided into control group (n=44) and observation group (n=42), control group was given docetaxel combined cis-platinum chemotherapy, pemetrexed combined cis-platinum chemotherapy, was applied for observation group. Compared MMP-2, MMP-9, VEGF, NK cells and immune function level before and after treatment in both groups.Results: MMP-2, MMP-9, VEGF, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups before treatment was no significant difference. After treatment, MMP-2, MMP-9, VEGF, CD8+level in both groups was significant lower than before treatment intra-group, and observation was lower than control group, there was significant difference. After treatment, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups was increased dramatically than before treatment of intra-group, moreover, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+level in observation group after treatment was obvious higher than in control group after treatment, there was significant difference.Conclusion:Pemetrexed combined with cis-platinum chemotherapy for non-squamous non-small cell lung cancer could effectively decrease serum MMPs, VEGF level and increase NK cell level, regulate immune function, with definite clinical significance.展开更多
Lung cancer is the most widespread type of cancer and the primary cause of cancer-related death in the world.In this study,we aimed to analyze the cost-effectiveness of second-line chemotherapy strategies based on gem...Lung cancer is the most widespread type of cancer and the primary cause of cancer-related death in the world.In this study,we aimed to analyze the cost-effectiveness of second-line chemotherapy strategies based on gemcitabine,pemetrexed,and docetaxel for advanced non-squamous non-small cell lung cancer patients in China.A Markov model based on three states,progression-free survival,progressed survival and death,was constructed to simulate the progression of the disease in a 6-year horizon.Sensitivity analysis was performed to evaluate the robustness of the model.The primary outcome of the model was the incremental cost-effectiveness ratio at a willingness-to-pay threshold of 3×per capita GDP of China in 2018($29383).The baseline model results showed that the quality-adjusted life years over the course of the disease associated with second-line chemotherapy strategies were 0.233,0.417 and 0.272 for gemcitabine,pemetrexed and docetaxel,respectively,and the corresponding total costs were$5321.02,$12143.94,and$9479.42.Gemcitabine,pemetrexed and docetaxel resulted in the incremental cost-effectiveness ratios of$37081.09 and$106625.64 per quality-adjusted life year gained.The incremental cost-effectiveness ratio of pemetrexed and docetaxel compared with gemcitabine exceeded the willingness-to-pay threshold.One-way sensitivity analysis showed that the utility value of gemcitabine in the progressed survival state was the most influential parameter.展开更多
Lung carcinoma is associated with a high mortality worldwide,being the leading cause of cancer death.It is mainly classified into squamous non-small cell lung cancer(NSCLC),non-squamous NSCLC,and small cell lung cance...Lung carcinoma is associated with a high mortality worldwide,being the leading cause of cancer death.It is mainly classified into squamous non-small cell lung cancer(NSCLC),non-squamous NSCLC,and small cell lung cancer.However,such malignancy has been increasingly subdivided into histological and molecular subtypes to guide treatment.Therapies can be used in adjuvant and palliative settings.Regarding immunotherapy,it has been widely tested in both first or subsequent palliative lines.In this sense,drugs such as pembrolizumab,nivolumab,atezolizumab,ipilimumab,avelumab,and durvalumab have been assessed in large studies.Some of these trials have also studied these medicines in adjuvant and in maintenance therapy.In recent years,advances in immunotherapy have raised the hope that the unfavorable prognosis observed in several affected individuals can be changed.Immunotherapy has increased the overall survival in squamous NSCLC,non-squamous NSCLC,and small cell lung cancer.However,it has added to the oncology practice some side effects that are unusual in standard chemotherapy and require special clinical support.In order to show how immunotherapy is being applied in the treatment of lung carcinoma,we reviewed the main studies in adjuvant and palliative scenarios.What is the better scheme?What is the better combination?What is the better dose?When should we use immunotherapy?Does programmed cell death ligand 1 expression significantly interfere in immunotherapy efficiency?Some of these questions have already been answered,while others require more investigations.展开更多
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 pati...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.展开更多
Aim:Our study aimed to explore the prognostic predictive potential of a novel RNA-based signature called ImmuneScore in advanced non-squamous NSCLC patients receiving combined immune checkpoint inhibitor(ICI)treatment...Aim:Our study aimed to explore the prognostic predictive potential of a novel RNA-based signature called ImmuneScore in advanced non-squamous NSCLC patients receiving combined immune checkpoint inhibitor(ICI)treatment and chemotherapy.Methods:RNA-sequencing data of 113 patients screened out from ORIENT-11 trial were retrospectively analyzed.ImmuneScore was calculated by the ESTIMATE algorithm.The association of ImmuneScore with early tumor progression,progression-free survival(PFS),and overall survival(OS)was analyzed using chi-square test,Cox regression test,and log-rank test.Receiver operating characteristic(ROC)curves were generated,with higher values of area under the ROC curves(AUCs)indicating better prediction ability.Results:ImmuneScore was negatively correlated with early tumor progression rate(4.3%vs.18.6%,P=0.013)while positively correlated with PFS(HR=0.29,95%CI:0.16-0.53,P<0.001)and OS(HR=0.32,95%CI:0.18-0.58,P<0.001),demonstrating higher AUCs than that of Programmed death-ligand 1(PD-L1)tumor proportion score(TPS)(early tumor progression:0.64 vs.0.68;PFS:0.67 vs.0.58;OS:0.73 vs.0.63).Nomograms integrating ImmuneScore and other significant variables(age and T-stage for PFS,gender and T-stage for OS)yielded good performance in PFS and OS prediction.Conclusion:ImmuneScore serves as a novel RNA-based prognostic signature superior to PD-L1 in advanced non-squamous NSCLC patients receiving chemotherapy combined with ICI therapy.Higher ImmuneScore indicates lower early tumor progression rate,longer PFS,and longer OS.展开更多
In non-small cell lung cancers,the non-squamous and squamous subtypes(nsqNSCLC and sqNSCLC)exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpo...In non-small cell lung cancers,the non-squamous and squamous subtypes(nsqNSCLC and sqNSCLC)exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor(ICI)-based treatments.In our inhouse training cohort(n=85),the presence of the LRP1B deleterious mutation(LRP1B-del)was associated with longer and shorter progression-free survival(PFS)on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteraction<0.001).Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs(P=0.040)and sqNSCLCs(P=0.014),respectively.In the POPLAR/OAK cohort,nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel(hazard ratio(HR)=0.70,P=0.046),whereas this benefit was negligible in those without LRP1B-del(HR=1.05,P=0.64).Conversely,sqNSCLCs without LRP1Bdel benefited more from atezolizumab(HR=0.60,P=0.002)than those with LRP1B-del(HR=1.30,P=0.31).Consistent results were observed in the in-house CHOICE-01 cohort,in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone(Pinteraction=0.008).This multi-cohort study delineates the antithetical impacts of LRP1Bdel in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy alone.Our findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs,emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.展开更多
基金supported by Wu Jieping Fund (No. 320.6750.14266)
文摘Objective: To evaluate the efficacy and safety profile of first-line bevacizumab(Bev)-containing pemetrexedplatinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer(NS-NSCLC).Methods: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching(PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified.Results: The median duration of follow-up was 15.8 months. The median progression-free survival(PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall(9.8 vs. 7.8 months, P=0.006) and PSM pairs(9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed(12.3 vs. 4.8 vs. 8.6 months;P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy.Conclusions: First-line induction and maintenance therapy with Bev(7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.
文摘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.
文摘Background: Pemetrexed (PEM) is an efficacious multi-targeted antifolate with acceptable toxicities for non-squamous non-small cell lung cancer (non-Sq NSCLC). However, in the clinical setting, PEM has more severe adverse effects than those reported. The aim of this study was to identify the factors for the toxicities of PEM-containing chemotherapy in non-Sq NSCLC patients in the clinical setting. Patients and Methods: We retrospectively evaluated the factors related to PEM toxicities in chemotherapy-naive patients with non-Sq NSCLC from September 2009 to July 2013 at our hospital. Logistic regression model was used in the univariate and multivariate analyses. Results: In total, 104 patients were analyzed. Grades 3 to 5 hematologic toxicities were frequent and included neutropenia (42%), febrile neutropenia (7%), anemia (18%), thrombocytopenia (17%), and disseminated intravascular coagulation (2%). On multivariate analyses, the predictors were poor performance status (PS) [odds ratio (OR): 4.89, 95% confidence interval (CI): 1.22 - 19.4] and low body mass index (OR: 1.44, 95% CI: 1.05 - 1.98) for febrile neutropenia;concomitant chronic infectious disease (OR: 6.63, 95% CI: 1.59 - 27.5) and bevacizumab use (OR: 3.57, 95% CI: 1.36 - 9.32) for neutropenia;poor PS (OR: 3.02, 95% CI: 1.33 - 6.85) for thrombocytopenia;and low serum albumin level (OR: 0.22, 95% CI: 0.08 - 0.63) for non-hematologic toxicities. Conclusions: In addition to the previously reported predictors of PEM toxicities, the presence of concomitant chronic infectious disease was associated with hematologic toxicities. Patient groups who are not sufficiently evaluated in clinical trials should be carefully monitored for the development of more toxicities than expected.
文摘Objective:To explore effect of Pemetrexed combined with cis-platinum chemotherapy on matrix metalloproteinase (MMPs), vascular esandothelial growth factor (VEGF), NK cells and immune function in patients with non-squamous non-small cell lung cancer.Method:A total of86 cases of non-squamous non-small cell lung cancer patients were divided into control group (n=44) and observation group (n=42), control group was given docetaxel combined cis-platinum chemotherapy, pemetrexed combined cis-platinum chemotherapy, was applied for observation group. Compared MMP-2, MMP-9, VEGF, NK cells and immune function level before and after treatment in both groups.Results: MMP-2, MMP-9, VEGF, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups before treatment was no significant difference. After treatment, MMP-2, MMP-9, VEGF, CD8+level in both groups was significant lower than before treatment intra-group, and observation was lower than control group, there was significant difference. After treatment, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+ level in both groups was increased dramatically than before treatment of intra-group, moreover, NK cells, CD3+, CD4+, CD8+, CD4+/CD8+level in observation group after treatment was obvious higher than in control group after treatment, there was significant difference.Conclusion:Pemetrexed combined with cis-platinum chemotherapy for non-squamous non-small cell lung cancer could effectively decrease serum MMPs, VEGF level and increase NK cell level, regulate immune function, with definite clinical significance.
基金Startup Fund for Scientific Research,Fujian Medical University(Grant No.2018QH1091)。
文摘Lung cancer is the most widespread type of cancer and the primary cause of cancer-related death in the world.In this study,we aimed to analyze the cost-effectiveness of second-line chemotherapy strategies based on gemcitabine,pemetrexed,and docetaxel for advanced non-squamous non-small cell lung cancer patients in China.A Markov model based on three states,progression-free survival,progressed survival and death,was constructed to simulate the progression of the disease in a 6-year horizon.Sensitivity analysis was performed to evaluate the robustness of the model.The primary outcome of the model was the incremental cost-effectiveness ratio at a willingness-to-pay threshold of 3×per capita GDP of China in 2018($29383).The baseline model results showed that the quality-adjusted life years over the course of the disease associated with second-line chemotherapy strategies were 0.233,0.417 and 0.272 for gemcitabine,pemetrexed and docetaxel,respectively,and the corresponding total costs were$5321.02,$12143.94,and$9479.42.Gemcitabine,pemetrexed and docetaxel resulted in the incremental cost-effectiveness ratios of$37081.09 and$106625.64 per quality-adjusted life year gained.The incremental cost-effectiveness ratio of pemetrexed and docetaxel compared with gemcitabine exceeded the willingness-to-pay threshold.One-way sensitivity analysis showed that the utility value of gemcitabine in the progressed survival state was the most influential parameter.
文摘Lung carcinoma is associated with a high mortality worldwide,being the leading cause of cancer death.It is mainly classified into squamous non-small cell lung cancer(NSCLC),non-squamous NSCLC,and small cell lung cancer.However,such malignancy has been increasingly subdivided into histological and molecular subtypes to guide treatment.Therapies can be used in adjuvant and palliative settings.Regarding immunotherapy,it has been widely tested in both first or subsequent palliative lines.In this sense,drugs such as pembrolizumab,nivolumab,atezolizumab,ipilimumab,avelumab,and durvalumab have been assessed in large studies.Some of these trials have also studied these medicines in adjuvant and in maintenance therapy.In recent years,advances in immunotherapy have raised the hope that the unfavorable prognosis observed in several affected individuals can be changed.Immunotherapy has increased the overall survival in squamous NSCLC,non-squamous NSCLC,and small cell lung cancer.However,it has added to the oncology practice some side effects that are unusual in standard chemotherapy and require special clinical support.In order to show how immunotherapy is being applied in the treatment of lung carcinoma,we reviewed the main studies in adjuvant and palliative scenarios.What is the better scheme?What is the better combination?What is the better dose?When should we use immunotherapy?Does programmed cell death ligand 1 expression significantly interfere in immunotherapy efficiency?Some of these questions have already been answered,while others require more investigations.
基金supported by Clinical Research Plan of SHDC(No.SHDC2020CR4001)Shanghai Nature Science Foundation(20ZR1447100)。
文摘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.
基金supported by the Medical Science and Technology Research Fund of Guangdong Province(Grant No.C2018062).
文摘Aim:Our study aimed to explore the prognostic predictive potential of a novel RNA-based signature called ImmuneScore in advanced non-squamous NSCLC patients receiving combined immune checkpoint inhibitor(ICI)treatment and chemotherapy.Methods:RNA-sequencing data of 113 patients screened out from ORIENT-11 trial were retrospectively analyzed.ImmuneScore was calculated by the ESTIMATE algorithm.The association of ImmuneScore with early tumor progression,progression-free survival(PFS),and overall survival(OS)was analyzed using chi-square test,Cox regression test,and log-rank test.Receiver operating characteristic(ROC)curves were generated,with higher values of area under the ROC curves(AUCs)indicating better prediction ability.Results:ImmuneScore was negatively correlated with early tumor progression rate(4.3%vs.18.6%,P=0.013)while positively correlated with PFS(HR=0.29,95%CI:0.16-0.53,P<0.001)and OS(HR=0.32,95%CI:0.18-0.58,P<0.001),demonstrating higher AUCs than that of Programmed death-ligand 1(PD-L1)tumor proportion score(TPS)(early tumor progression:0.64 vs.0.68;PFS:0.67 vs.0.58;OS:0.73 vs.0.63).Nomograms integrating ImmuneScore and other significant variables(age and T-stage for PFS,gender and T-stage for OS)yielded good performance in PFS and OS prediction.Conclusion:ImmuneScore serves as a novel RNA-based prognostic signature superior to PD-L1 in advanced non-squamous NSCLC patients receiving chemotherapy combined with ICI therapy.Higher ImmuneScore indicates lower early tumor progression rate,longer PFS,and longer OS.
基金supported by the National Natural Science Foundation of China (82170108, 81700092, 81871889, 82072586, 81630071)the Clinical Research Projects in Health industry of Shanghai Municipal Health Commission (202340017)+6 种基金the Foundation of the Center for Medical and Engineering Interdisciplinary Innovation, University of Shanghai for Science and Technology (2023GD-XK08Z)the National Youth Talent (to Z. Wang)Basic Research Foundation of Shanghai Chest Hospital (2020YNJCM05)the National Key Research and Development Project of China (2022YFC2505004, 2022YFC2505000)CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012)CAMS Key lab of translational research on lung cancer (2018PT31035)Beijing Natural Science Foundation (7212084)
文摘In non-small cell lung cancers,the non-squamous and squamous subtypes(nsqNSCLC and sqNSCLC)exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor(ICI)-based treatments.In our inhouse training cohort(n=85),the presence of the LRP1B deleterious mutation(LRP1B-del)was associated with longer and shorter progression-free survival(PFS)on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteraction<0.001).Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs(P=0.040)and sqNSCLCs(P=0.014),respectively.In the POPLAR/OAK cohort,nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel(hazard ratio(HR)=0.70,P=0.046),whereas this benefit was negligible in those without LRP1B-del(HR=1.05,P=0.64).Conversely,sqNSCLCs without LRP1Bdel benefited more from atezolizumab(HR=0.60,P=0.002)than those with LRP1B-del(HR=1.30,P=0.31).Consistent results were observed in the in-house CHOICE-01 cohort,in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone(Pinteraction=0.008).This multi-cohort study delineates the antithetical impacts of LRP1Bdel in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy alone.Our findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs,emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.
