Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critica...Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critical role in EGFR-driven lung tumors.This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer(NSCLC).The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Methods:In total,73 patients with surgically resected NSCLC and EGFR mutations were identified.PD-L1 expression and CD8+tumor-infiltrating lymphocyte(TIL)density were assessed by immunohistochemistry.A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen(26.0%)patients were positive for PD-L1 expression,which was significantly associated with concomitant KRAS mutation(P=0.020)and marginally associated with higher CD8+TILs density(P=0.056).Positive PD-L1 expression was associated with markedly inferior overall survival(OS)in multivariate analysis(P=0.032).The combination of PD-L1 and CD8+TILs expression could be used to stratify the population into three groups with distinct prognoses.A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS[hazard ratio(HR)=0.90;95%confidence interval(CI),0.42–1.38]or progression-free survival(HR=1.03;95 CI,0.73–1.33)in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs.Conclusions:PD-L1 expression tended to correlate with CD8+TIL expression,concomitant KRAS mutation,and poor survival in surgically resected EGFR-mutant NSCLC.PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.展开更多
Objective: Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insuf...Objective: Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insufficient. This study aimed to investigate the effect of first-line EGFR-TKIs or platinum-based chemotherapy in NSCLC patients with uncommon EGFR mutations. Methods: We retrospectively enrolled 504 patients with EGFR-mutant NSCLC. The clinical characteristics and treatment outcomes were collected and compared between patients with common and uncommon EGFR-mutant NSCLC. Results: Seventy patients (13.9%) harboring uncommon EGFR mutations were included. Thirty of these patients received EGFR-TKIs and 40 received platinum-based chemotherapy as first-line therapy. The objective response rate (ORR) and median progression-free survival (mPFS) of patients treated with TKIs in the uncommon mutation group was significantly inferior to that in the common mutation group (ORR: 23.3% vs. 51.8%, P=0.003; mPFS: 7.1 vs. 10.9 months, P〈0.001). In the uncommon group, mPFS was similar between first-line EGFR-TKIs treatment and platinum-based chemotherapy (7.1 vs. 6.1 months, P=0.893). In patients with EGFR G719X or L861Q mutations, the mPFS was longer in the first-line EGFR-TKIs treatment group than in the chemotherapy group, but the difference was not statistically significant (G719X: 8.2 vs. 5.8 months, P=0.061; L861Q: 7.6 vs. 4.1 months, P=0.872). Multivariate analyses identified adenocarcinoma (P=0.003) as the independent predictive factor for PFS in patients with uncommon EGFR mutations who were treated with first-line EGFR-TKIs. Conclusions: The current study demonstrated that the effect of first-line EGFR-TKIs was similar to that of platinum-based chemotherapy in patients with uncommon EGFR-mutant NSCLC. Adenocarcinoma was the independent predictive factor for PFS in uncommon EGFR-mutant NSCLC patients treated with first-line EGFR- TKIs.展开更多
Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harbo...Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.展开更多
Objective: To identify the differences between cavitating squamous cell lung carcinoma (cSLC) and non-cavitating squamous cell lung carcinoma (ncSLC). Methods: Fifty-one patients with cSLC and 281 with ncSLC confirmed...Objective: To identify the differences between cavitating squamous cell lung carcinoma (cSLC) and non-cavitating squamous cell lung carcinoma (ncSLC). Methods: Fifty-one patients with cSLC and 281 with ncSLC confirmed by surgery in our hospital between 1999 to 2000 were collected and their clinical, histological and survival features were retrospectively analyzed. Results: Patients with cSLC had more frequent manifestation of infection and weight loss. They usually experienced longer duration of pre-diagnosis and showed bigger tumor mass, larger primary tumor invasion with worse differentiated than ncSLC patients. There was no significant difference in age, sex, smoking history, family tumor history, personal tuberculosis history, disease location, TNM stage, lymph node invasion, and metastasis between the two groups. Median survival time was 29 months for cSLC and 35 months for ncSLC. One- and 3- year survival rates were 86.3% and 43.1% for cSLC vs. 91.1% and 47.0% for ncSLC respectively (P>0.05). Conclusion: Patients with cSLC presented with a bigger mass, a larger extent of primary tumor invasion, worse differentiated, more obstructed pneumonia that might result in longer duration of pre-diagnosis and more weight loss. As lack of differences in disease stages, lymph node invasion, metastasis and especially survival time with ncSLC, cSLC couldn’t be classified as a special type of squamous cell carcinoma by present evidences.展开更多
To the Editor:In recent years,impressive outcomes have been achieved in patients harboring human epidermal growth factor receptor 2(HER2)mutations,which accounts for 1%to 4%of cases in non-small cell lung cancer(NSCLC).
Lung cancer is the malignant tumor with the highest morbidity andmortality in China, and nonsmall cell lung cancer is a common form oflung cancer. After undergoing chemotherapy and molecular targetedtherapy, the treat...Lung cancer is the malignant tumor with the highest morbidity andmortality in China, and nonsmall cell lung cancer is a common form oflung cancer. After undergoing chemotherapy and molecular targetedtherapy, the treatment of lung cancer has now fully entered the era ofimmunotherapy. Immunotherapy‐based treatment has become one of thestandard treatments for lung cancer. Immunotherapy has also graduallymoved from the back line to the front line, from advanced to earlypatients. This article focuses on the latest developments in perioperativeand advanced lung cancer immunotherapy, discusses the problems andchallenges at the current stage, and explores new directions for futuredevelopment.展开更多
In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-...In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-stage non-small cell lung cancer(NSCLC)patients miss the optimal timing for treatment due to the lack of clinical presentations.Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China.The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC,thus prolonging survival in patients with positive drivers.In the exploration of immune escape mechanisms,programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China.In the Chinese Society of Clinical Oncology’s guidelines for NSCLC,maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy.Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC.In this review,we summarized recent advances in NSCLC in China in terms of epidemiology,biology,molecular pathology,pathogenesis,screening,diagnosis,targeted therapy,and immunotherapy。展开更多
Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression ...Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.展开更多
Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established a...Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer.An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy.Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection,both of these biomarkers are imperfect.Due to the complex cancer-immune interactions among tumor cells,the tumor microenvironment and host immunity,collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy.Furthermore,as a result of the wide use of ICIs,managing acquired resistance to ICI treatment remains an inevitable challenge.A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles.In this review,we describe the cutting-edge progress made in patients with lung cancer,the optimal duration of ICI treatment,ICIs in some special populations,the unique response patterns during ICI treatment,the emerging predictive biomarkers,and our understanding of primary and acquired resistance mechanisms to ICI treatment.展开更多
Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to ...Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.Methods:ORIENT-3 was an open-label,multicenter,randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy.Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m^(2) of docetaxel intravenously every 3 weeks,stratified by the Eastern Cooperative Oncology Group performance status.The primary endpoint was overall survival(OS)in the full analysis set(FAS).Secondary endpoints included progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),duration of response(DoR)and safety.Results:Between August 25,2017,and November 7,2018,290 patients were randomized.For FAS,10 patients fromthe docetaxel armwere excluded.Themedian OS was 11.79(n=145;95%confidence interval[CI],10.28-15.57)months with sintilimab versus 8.25(n=135;95%CI,6.47-9.82)months with docetaxel(hazard ratio[HR]:0.74;95%CI,0.56-0.96;P=0.025).Sintilimab treatment significantly prolonged PFS(median 4.30 vs.2.79 months;HR:0.52;95%CI,0.39-0.68;P<0.001)and showed higher ORR(25.50%vs.2.20%,P<0.001)and DCR(65.50%vs.37.80%,P<0.001)than the docetaxel arm.The median DoRwas 12.45(95%CI,4.86-25.33)months in the sintilimab arm and 4.14(95%CI,1.41-7.23)months in the docetaxel arm(P=0.045).Treatment-related adverse events of grade≥3were reported in 26(18.1%)patients in the sintilimab arm and 47(36.2%)patients in the docetaxel arm.Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors,including OVOL2(HR:0.35;P<0.001)and CTCF(HR:3.50;P<0.001),for sintilimab treatment.Conclusions:Compared with docetaxel,sintilimab significantly improved the OS,PFS,and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.展开更多
This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who fai...This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled.Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles,followed by the maintenance of toripalimab and pemetrexed.The primary endpoint was objective-response rate(ORR).Integrated biomarker analysis of PD-L1 expression,tumor mutational burden(TMB),CD8+tumor-infiltrating lymphocyte(TIL)density,whole-exome,and transcriptome sequencing on tumor biopsies were also conducted.Forty patients were enrolled with an overall ORR of 50.0%and disease-control rate(DCR)of 87.5%.The median progression free survival(PFS)and overall survival were 7.0 and 23.5 months,respectively.The most common treatment-related adverse effects were leukopenia,neutropenia,anemia,ALT/AST elevation,and nausea.Biomarker analysis showed that none of PD-L1 expression,TMB level,and CD8+TIL density could serve as a predictive biomarker.Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type.Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC.DSPP mutation might serve as a potential biomarker for this combination.A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing(NCT03924050).展开更多
Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative a...Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative advanced non-small-cell lung cancer(NSCLC),the predictive biomarkers remain undetermined.Here,we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy.Methods:Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone.Tumor immune microenvironmental markers,including PD-1 ligand(PDL1),CD8,CD68,CD4 and forkhead box P3,were assessed using multiplex immunofluorescence(mIF)assays.Kaplan-Meier curveswere used to determine treatment outcome differences according to their expression status.Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations.Results:Responders had significantly higher CD8/PD-L1(P=0.015)or CD68/PD-L1 co-expression levels(P=0.021)than non-responders in the camrelizumab plus chemotherapy group,while no difference was observed in the chemotherapy group.Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS(P=0.002,P=0.024;respectively)and OS(P=0.006,P=0.026;respectively)than those with low co-expression in camrelizumab plus chemotherapy group.When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification,significantly better PFS(P=0.003)and OS(P=0.032)were observed in high co-expression subgroups.The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features.Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression,the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups(both 13.0%vs.0.0%,P=0.023).Notably,enriched PI3K(P=0.012)and cell cycle pathway(P=0.021)were found in the CD8/PD-L1 co-expression group.Conclusion:Tumor immune microenvironmental marker expression,especially CD8/PD-L1 or CD68/PD-L1 co-expression,was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.展开更多
Background:Lipusu is the first commercialized liposomal formulation of pacli-taxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma(LSCC)in a small-scale study.Here,we cond...Background:Lipusu is the first commercialized liposomal formulation of pacli-taxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma(LSCC)in a small-scale study.Here,we conducted a multicenter,randomized,phase 3 study to compare the efficacy and safety of cis-platin plus Lipusu(LP)versus cisplatin plus gemcitabine(GP)as first-line treat-ment in locally advanced or metastatic LSCC.Methods:Patients enrolled were aged between 18 to 75 years,had locally advanced(clinical stage IIIB,ineligible for concurrent chemoradiation or surgery)or metastatic(Stage IV)LSCC,had no previous systemic chemother-apy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors(version 1.1)before administration of the trial drug.The primary endpoint was progression-free survival(PFS).The secondary endpoints included objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety profiles.To explore the possible predictive value of plasma cytokines for LP treatment,plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology.The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.Results:The median duration of follow-up was 15.4 months.237 patients in the LP group and 253 patients in the GP group were included in the per protocol set(PPS).In the PPS,the median PFS was 5.2 months versus 5.5 months in the LP and GP group(hazard rtio[HR]:1.03,P=0.742)respectively.The median OS was 14.6 months versus 12.5 months in the LP and GP group(HR:0.83,P=0.215).The ORR(41.8%versus 45.9%,P=0.412)and DCR(90.3%versus 88.1%,P=0.443)were also similar between the LP and GP group.A significantly lower proportion of patients in the LP group experienced adverse events(AEs)leading to treatment interruptions(10.9%versus 26.4%,P<0.001)or treatment termination(14.3%versus 23.1%,P=0.011).The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR,and 15 cytokines were associated with improved PFS,with 14 cytokines,including TNF-a,IFN-y,IL-6,and IL-8,demonstrating an overlapping trend.Conclusion:The LP regimen demonstrated similar PFS,OS,ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles.The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.展开更多
In a recent study published in Science,Lennon et al.1 investigated the feasibility and safety of multi-cancer peripheral blood testing in combination with positron emission tomography-computed tomography(PET-CT)imagin...In a recent study published in Science,Lennon et al.1 investigated the feasibility and safety of multi-cancer peripheral blood testing in combination with positron emission tomography-computed tomography(PET-CT)imaging to detect cancer in 10,006 women not previously known to have cancer.Their findings reveal that multi-cancer blood testing coupled with diagnostic PET-CT can be safely incorporated into routine clinical care to screen for cancer without discouraging patients from engaging in other forms of standard-of-care(SOC)screening;moreover,it is possible to intervene on the basis of blood testing results,in some cases leading to surgery with intent to cure(Fig.1).展开更多
基金supported in part by grants from the National Natural Science Foundation of China(Grant No.81672286,81772467 and 81874036)“Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(Grant No.16SG18)the Chronic Diseases Program of Shanghai Shen Kang Pharmaceutical Development Co.Ltd(Grant No.SHDC 12015314)
文摘Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critical role in EGFR-driven lung tumors.This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer(NSCLC).The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Methods:In total,73 patients with surgically resected NSCLC and EGFR mutations were identified.PD-L1 expression and CD8+tumor-infiltrating lymphocyte(TIL)density were assessed by immunohistochemistry.A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen(26.0%)patients were positive for PD-L1 expression,which was significantly associated with concomitant KRAS mutation(P=0.020)and marginally associated with higher CD8+TILs density(P=0.056).Positive PD-L1 expression was associated with markedly inferior overall survival(OS)in multivariate analysis(P=0.032).The combination of PD-L1 and CD8+TILs expression could be used to stratify the population into three groups with distinct prognoses.A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS[hazard ratio(HR)=0.90;95%confidence interval(CI),0.42–1.38]or progression-free survival(HR=1.03;95 CI,0.73–1.33)in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs.Conclusions:PD-L1 expression tended to correlate with CD8+TIL expression,concomitant KRAS mutation,and poor survival in surgically resected EGFR-mutant NSCLC.PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.
基金supported in part by grants from the National Natural Science Foundation of China(No.81372392 and 81402486)
文摘Objective: Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insufficient. This study aimed to investigate the effect of first-line EGFR-TKIs or platinum-based chemotherapy in NSCLC patients with uncommon EGFR mutations. Methods: We retrospectively enrolled 504 patients with EGFR-mutant NSCLC. The clinical characteristics and treatment outcomes were collected and compared between patients with common and uncommon EGFR-mutant NSCLC. Results: Seventy patients (13.9%) harboring uncommon EGFR mutations were included. Thirty of these patients received EGFR-TKIs and 40 received platinum-based chemotherapy as first-line therapy. The objective response rate (ORR) and median progression-free survival (mPFS) of patients treated with TKIs in the uncommon mutation group was significantly inferior to that in the common mutation group (ORR: 23.3% vs. 51.8%, P=0.003; mPFS: 7.1 vs. 10.9 months, P〈0.001). In the uncommon group, mPFS was similar between first-line EGFR-TKIs treatment and platinum-based chemotherapy (7.1 vs. 6.1 months, P=0.893). In patients with EGFR G719X or L861Q mutations, the mPFS was longer in the first-line EGFR-TKIs treatment group than in the chemotherapy group, but the difference was not statistically significant (G719X: 8.2 vs. 5.8 months, P=0.061; L861Q: 7.6 vs. 4.1 months, P=0.872). Multivariate analyses identified adenocarcinoma (P=0.003) as the independent predictive factor for PFS in patients with uncommon EGFR mutations who were treated with first-line EGFR-TKIs. Conclusions: The current study demonstrated that the effect of first-line EGFR-TKIs was similar to that of platinum-based chemotherapy in patients with uncommon EGFR-mutant NSCLC. Adenocarcinoma was the independent predictive factor for PFS in uncommon EGFR-mutant NSCLC patients treated with first-line EGFR- TKIs.
文摘Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.
文摘Objective: To identify the differences between cavitating squamous cell lung carcinoma (cSLC) and non-cavitating squamous cell lung carcinoma (ncSLC). Methods: Fifty-one patients with cSLC and 281 with ncSLC confirmed by surgery in our hospital between 1999 to 2000 were collected and their clinical, histological and survival features were retrospectively analyzed. Results: Patients with cSLC had more frequent manifestation of infection and weight loss. They usually experienced longer duration of pre-diagnosis and showed bigger tumor mass, larger primary tumor invasion with worse differentiated than ncSLC patients. There was no significant difference in age, sex, smoking history, family tumor history, personal tuberculosis history, disease location, TNM stage, lymph node invasion, and metastasis between the two groups. Median survival time was 29 months for cSLC and 35 months for ncSLC. One- and 3- year survival rates were 86.3% and 43.1% for cSLC vs. 91.1% and 47.0% for ncSLC respectively (P>0.05). Conclusion: Patients with cSLC presented with a bigger mass, a larger extent of primary tumor invasion, worse differentiated, more obstructed pneumonia that might result in longer duration of pre-diagnosis and more weight loss. As lack of differences in disease stages, lymph node invasion, metastasis and especially survival time with ncSLC, cSLC couldn’t be classified as a special type of squamous cell carcinoma by present evidences.
基金National Natural Science Foundation of China(Nos.81972167,82172869 and 82002419)Shanghai Shenkang Hospital Development Center(No.SHDC12019133)+1 种基金Clinical Research Foundation of Shanghai Pulmonary Hospital(No.FKLY20008)Shanghai Innovative Collaboration Project(No.2020CXJQ02)
文摘To the Editor:In recent years,impressive outcomes have been achieved in patients harboring human epidermal growth factor receptor 2(HER2)mutations,which accounts for 1%to 4%of cases in non-small cell lung cancer(NSCLC).
文摘Lung cancer is the malignant tumor with the highest morbidity andmortality in China, and nonsmall cell lung cancer is a common form oflung cancer. After undergoing chemotherapy and molecular targetedtherapy, the treatment of lung cancer has now fully entered the era ofimmunotherapy. Immunotherapy‐based treatment has become one of thestandard treatments for lung cancer. Immunotherapy has also graduallymoved from the back line to the front line, from advanced to earlypatients. This article focuses on the latest developments in perioperativeand advanced lung cancer immunotherapy, discusses the problems andchallenges at the current stage, and explores new directions for futuredevelopment.
基金National Natural Science Foundation of China,Grant/Award Number:81871865Collaborative Innovation Program of Shanghai Municipal Health Commission,Grant/Award Number:2020CXJQ02Science and Technology Innovation Action Plan Project of Shanghai Municipal Science and Technology Commission,Grant/Award Numbers:19411950300,19411950301。
文摘In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-stage non-small cell lung cancer(NSCLC)patients miss the optimal timing for treatment due to the lack of clinical presentations.Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China.The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC,thus prolonging survival in patients with positive drivers.In the exploration of immune escape mechanisms,programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China.In the Chinese Society of Clinical Oncology’s guidelines for NSCLC,maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy.Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC.In this review,we summarized recent advances in NSCLC in China in terms of epidemiology,biology,molecular pathology,pathogenesis,screening,diagnosis,targeted therapy,and immunotherapy。
基金supported in part by a grant from National Natural Science Foundation of China(81802255)Shanghai Pujiang Program(17PJD036,China)+6 种基金a grant from Shanghai Municipal Commission of Health and Family Planning Program(20174Y0131,China)National Key Research&Development Project(2016YFC0902300,China)major disease clinical skills enhancement program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitalsShanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC(16CR1001A,China)“Dream Tutor”Outstanding Young Talents Program(fkyq1901,China)key disciplines of Shanghai Pulmonary Hospital(2017ZZ02012,China)grant of Shanghai Science and Technology Commission(16JC1405900,China)。
文摘Genomic instability remains an enabling feature of cancer and promotes malignant transformation.Alterations of DNA damage response(DDR)pathways allow genomic instability,generate neoantigens,upregulate the expression of programmed death ligand 1(PD-L1)and interact with signaling such as cyclic GMPe AMP synthase-stimulator of interferon genes(cGASe STING)signaling.Here,we review the basic knowledge of DDR pathways,mechanisms of genomic instability induced by DDR alterations,impacts of DDR alterations on immune system,and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.
基金This work was partly supported by grants from the National Natural Science Foundation of China(No.81703020,81871865,81972169)National R&D projects(2016YFC0902300)Shanghai Science and Technology Medical Guidance Project(16411964400).
文摘Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer.An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy.Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection,both of these biomarkers are imperfect.Due to the complex cancer-immune interactions among tumor cells,the tumor microenvironment and host immunity,collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy.Furthermore,as a result of the wide use of ICIs,managing acquired resistance to ICI treatment remains an inevitable challenge.A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles.In this review,we describe the cutting-edge progress made in patients with lung cancer,the optimal duration of ICI treatment,ICIs in some special populations,the unique response patterns during ICI treatment,the emerging predictive biomarkers,and our understanding of primary and acquired resistance mechanisms to ICI treatment.
基金funded by Innovent biologics,Inc.Eli Lilly and Companypartly supported by China National Major Project for New Drug Innovation(2017ZX09304015).
文摘Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.Methods:ORIENT-3 was an open-label,multicenter,randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy.Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m^(2) of docetaxel intravenously every 3 weeks,stratified by the Eastern Cooperative Oncology Group performance status.The primary endpoint was overall survival(OS)in the full analysis set(FAS).Secondary endpoints included progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),duration of response(DoR)and safety.Results:Between August 25,2017,and November 7,2018,290 patients were randomized.For FAS,10 patients fromthe docetaxel armwere excluded.Themedian OS was 11.79(n=145;95%confidence interval[CI],10.28-15.57)months with sintilimab versus 8.25(n=135;95%CI,6.47-9.82)months with docetaxel(hazard ratio[HR]:0.74;95%CI,0.56-0.96;P=0.025).Sintilimab treatment significantly prolonged PFS(median 4.30 vs.2.79 months;HR:0.52;95%CI,0.39-0.68;P<0.001)and showed higher ORR(25.50%vs.2.20%,P<0.001)and DCR(65.50%vs.37.80%,P<0.001)than the docetaxel arm.The median DoRwas 12.45(95%CI,4.86-25.33)months in the sintilimab arm and 4.14(95%CI,1.41-7.23)months in the docetaxel arm(P=0.045).Treatment-related adverse events of grade≥3were reported in 26(18.1%)patients in the sintilimab arm and 47(36.2%)patients in the docetaxel arm.Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors,including OVOL2(HR:0.35;P<0.001)and CTCF(HR:3.50;P<0.001),for sintilimab treatment.Conclusions:Compared with docetaxel,sintilimab significantly improved the OS,PFS,and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.
基金This study was also supported in part by grants from the National Natural Science Foundation of China(No.81871865,81874036,81972167,82102859,31930022,31771476,and 12026608)National Science and Technology Major Project(No.2017YFA0505500)+5 种基金the Strategic Priority Project of Chinese Academy of Sciences(No.XDB38040400,XDB38020000)the Backbone Program of Shanghai Pulmonary Hospital(No.FKGG1802)Shanghai Pujiang Talent Plan(No.2019PJD048)Shanghai Science and Technology Committee Foundation(NO.19411950300)Shanghai Key disciplines of Respiratory(No.2017ZZ02012)the Shanghai Sailing Program(No.20YF1407500).
文摘This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled.Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles,followed by the maintenance of toripalimab and pemetrexed.The primary endpoint was objective-response rate(ORR).Integrated biomarker analysis of PD-L1 expression,tumor mutational burden(TMB),CD8+tumor-infiltrating lymphocyte(TIL)density,whole-exome,and transcriptome sequencing on tumor biopsies were also conducted.Forty patients were enrolled with an overall ORR of 50.0%and disease-control rate(DCR)of 87.5%.The median progression free survival(PFS)and overall survival were 7.0 and 23.5 months,respectively.The most common treatment-related adverse effects were leukopenia,neutropenia,anemia,ALT/AST elevation,and nausea.Biomarker analysis showed that none of PD-L1 expression,TMB level,and CD8+TIL density could serve as a predictive biomarker.Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type.Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC.DSPP mutation might serve as a potential biomarker for this combination.A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing(NCT03924050).
基金supported in part by grants from the National Natural Science Foundation of China(No.81871865,81874036,81972167 and 82102859)the Backbone Program of Shanghai Pulmonary Hospital(No.FKGG1802)+4 种基金Shanghai Pujiang Talent Plan(No.2019PJD048)Shanghai Science and Technology Committee Foundation(NO.19411950300)Shanghai Key disciplines of Respiratory(No.2017ZZ02012)Oncology development incentive program of Shanghai Pulmonary Hospital,Shanghai Multidisciplinary Cooperative Project for Diagnosis and Treatment of Major DiseasesKey Clinical Project Development Program of Shanghai.
文摘Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative advanced non-small-cell lung cancer(NSCLC),the predictive biomarkers remain undetermined.Here,we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy.Methods:Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone.Tumor immune microenvironmental markers,including PD-1 ligand(PDL1),CD8,CD68,CD4 and forkhead box P3,were assessed using multiplex immunofluorescence(mIF)assays.Kaplan-Meier curveswere used to determine treatment outcome differences according to their expression status.Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations.Results:Responders had significantly higher CD8/PD-L1(P=0.015)or CD68/PD-L1 co-expression levels(P=0.021)than non-responders in the camrelizumab plus chemotherapy group,while no difference was observed in the chemotherapy group.Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS(P=0.002,P=0.024;respectively)and OS(P=0.006,P=0.026;respectively)than those with low co-expression in camrelizumab plus chemotherapy group.When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification,significantly better PFS(P=0.003)and OS(P=0.032)were observed in high co-expression subgroups.The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features.Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression,the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups(both 13.0%vs.0.0%,P=0.023).Notably,enriched PI3K(P=0.012)and cell cycle pathway(P=0.021)were found in the CD8/PD-L1 co-expression group.Conclusion:Tumor immune microenvironmental marker expression,especially CD8/PD-L1 or CD68/PD-L1 co-expression,was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.
基金Nanjing Luye Pharmaceutical Co.Ltd,Nanjing,China,Grant/Award Number:2017ZZ02012sponsored by Nanjing Luye Pharmaceu-tical Co.Ltd,Nanjing,China,and supported in part by grants from Shanghai Key disciplines of Respiratory(No.2017ZZ02012)and Shanghai Major Diseases Multidisci-plinary Cooperation Diagnosis and Treatment Construc-tion Project.
文摘Background:Lipusu is the first commercialized liposomal formulation of pacli-taxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma(LSCC)in a small-scale study.Here,we conducted a multicenter,randomized,phase 3 study to compare the efficacy and safety of cis-platin plus Lipusu(LP)versus cisplatin plus gemcitabine(GP)as first-line treat-ment in locally advanced or metastatic LSCC.Methods:Patients enrolled were aged between 18 to 75 years,had locally advanced(clinical stage IIIB,ineligible for concurrent chemoradiation or surgery)or metastatic(Stage IV)LSCC,had no previous systemic chemother-apy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors(version 1.1)before administration of the trial drug.The primary endpoint was progression-free survival(PFS).The secondary endpoints included objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety profiles.To explore the possible predictive value of plasma cytokines for LP treatment,plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology.The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.Results:The median duration of follow-up was 15.4 months.237 patients in the LP group and 253 patients in the GP group were included in the per protocol set(PPS).In the PPS,the median PFS was 5.2 months versus 5.5 months in the LP and GP group(hazard rtio[HR]:1.03,P=0.742)respectively.The median OS was 14.6 months versus 12.5 months in the LP and GP group(HR:0.83,P=0.215).The ORR(41.8%versus 45.9%,P=0.412)and DCR(90.3%versus 88.1%,P=0.443)were also similar between the LP and GP group.A significantly lower proportion of patients in the LP group experienced adverse events(AEs)leading to treatment interruptions(10.9%versus 26.4%,P<0.001)or treatment termination(14.3%versus 23.1%,P=0.011).The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR,and 15 cytokines were associated with improved PFS,with 14 cytokines,including TNF-a,IFN-y,IL-6,and IL-8,demonstrating an overlapping trend.Conclusion:The LP regimen demonstrated similar PFS,OS,ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles.The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.
基金supported in part by grants from the National Natural Science Foundation of China(No.81871865,81874036,and 81972167).
文摘In a recent study published in Science,Lennon et al.1 investigated the feasibility and safety of multi-cancer peripheral blood testing in combination with positron emission tomography-computed tomography(PET-CT)imaging to detect cancer in 10,006 women not previously known to have cancer.Their findings reveal that multi-cancer blood testing coupled with diagnostic PET-CT can be safely incorporated into routine clinical care to screen for cancer without discouraging patients from engaging in other forms of standard-of-care(SOC)screening;moreover,it is possible to intervene on the basis of blood testing results,in some cases leading to surgery with intent to cure(Fig.1).