Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LEC...Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.展开更多
Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and...Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.展开更多
Objective： To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer （NSCLC）. Methods： A total of 89 patients with stage IIIB or IV NSCLC received icotinib ...Objective： To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer （NSCLC）. Methods： A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. Results： A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate （RR） was 36.0% （32/89）, and the disease control rate （DCR） was 69.7% （62/89）. RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma （P〈0.05）. The symptom improvement rate was 57.3% （51/89）, and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 （33.7%）] and diarrhea [15/89 （16.9%）]. The level of toxicity was typically low. Conclusions： The use of icofinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.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
Early detection of lung cancer (LC) is vital for reducing LC-related mortality. However, noninvasive diagnostic tools remain a great challenge. We aim to identify blood-based biomarkers for the early detection of LC. ...Early detection of lung cancer (LC) is vital for reducing LC-related mortality. However, noninvasive diagnostic tools remain a great challenge. We aim to identify blood-based biomarkers for the early detection of LC. Here, LC-associated hypomethylation in alpha-1,3-fucosyltransferase VII (FUT7) is identified via the Illumina 850K array in a discovery study and validated by mass spectrometry in two independent casecontrol studies with blood samples from 1720 LC patients (86.8% LC at stage I, blood is collected before surgery and treatment) and 3143 healthy controls. Compared to the controls, blood-based FUT7 hypomethylation is identified in LC patients at stage I, and even in LC patients with malignant nodules ≤1 cm and in patients with adenocarcinoma in situ. Gender plays a role in the LC-associated FUT7 hypomethylation in blood, which is more significant in males than in females. We also reveal that FUT7 hypomethylation in LC could be enhanced by the advanced stage of cancer, involvement of lymph nodes, and larger tumor size. Based on a large sample size and semi-quantitative methods, our study reveals a strong association between blood-based FUT7 hypomethylation and LC, suggesting that methylation signatures in blood may be a group of potential biomarkers for detection of early-stage LC.展开更多
Objective: Anti-vascular endothelial growth factor(VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer(NSCLC). Here, we aim to update the equivalent efficacy assessment between QL...Objective: Anti-vascular endothelial growth factor(VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer(NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data.Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate(ORR);equivalence was confirmed if the two-sided 90% confidence interval(90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival(PFS) and overall survival(OS).Results: The two-year updated data showed similar ORR(QL1101 vs. bevacizumab: 53.1% vs. 54.3%;relative risk=0.977;90% CI: 0.838-1.144), PFS(235 d vs. 254 d, log-rank P=0.311), and OS(577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group(22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group(n=157) and the bevacizumab group(n=148)(PFS: 253 d vs. 272 d, log-rank P=0.387;OS: 673 d vs. 790 d, log-rank P=0.101;mean tumor shrinkage rate: 26.6% vs. 27.5%).Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.展开更多
With the advances in surgery, chemotherapy, and radiotherapy over the last decades, the treatment strategies of lung cancer has been largely changed. In this review, we summarize recent advances in lung cancer and tre...With the advances in surgery, chemotherapy, and radiotherapy over the last decades, the treatment strategies of lung cancer has been largely changed. In this review, we summarize recent advances in lung cancer and treatment research. We discuss current clinical management, highlight stage-specific therapy approaches, chemotherapy options for advanced-stage of non-small-cell lung cancer (NSCLC) patients, along with new agents such as epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. We also give an outlook into NSCLC disease biology, focuse on the importance of EGFR activating mutations and the role of the tumor-microenvironment. Finally we summarize the new recommendations in treating small-cell-lung cancer (SCLC).展开更多
Objective： To investigate the expressions and the clinical significance of P53, C-erbB-2 and vascular endothelial growth factor （VEGF） in non-small cell lung cancer （NSCLC）. Methods： 121 specimens of NSCLC were ...Objective： To investigate the expressions and the clinical significance of P53, C-erbB-2 and vascular endothelial growth factor （VEGF） in non-small cell lung cancer （NSCLC）. Methods： 121 specimens of NSCLC were examined for P53, C-erbB-2 and VEGF by immunohistochemical staining. Results： The positive rates of P53, C-erbB-2 and VEGF in the carcinomatous tissue were 43%, 39% and 31% respectively. P53 gene protein expression in lung cancer was significantly related to histological type and P-TNM staging of lung cancer patients （P 〈 0.05）, and was not associated with the sex, age, the size of primary cancer, lymph node metastasis and cell differentiation （P 〉 0.05）. C-erbB-2 gene protein expression in lung cancer was closely related to histological type and cell differentiation （P 〈 0.05）, and was not associated with the sex, age, the size of primary cancer, lymph node metastasis and P-TNM staging of lung cancer patients （P 〉 0.05）. VEGF in lung cancer was only closely related to cell differentiation （P 〈 0.05）, and was not associated with the sex, age, the size of pdmary cancer, lymph node metastasis, histological type and P-TNM staging of lung cancer patients （P 〉 0.05）. Conclusion： It is possible for P53, C-erbB-2 and VEGF to play an important role in the oncogenesis and development of non-small cell lung cancer.展开更多
Background:The prognosis for non-small cell lung cancer(NSCLC)patients treatedwith standard platinum-based chemotherapywas suboptimal,with safety concerns.Following encouraging results from a preliminary phase I study...Background:The prognosis for non-small cell lung cancer(NSCLC)patients treatedwith standard platinum-based chemotherapywas suboptimal,with safety concerns.Following encouraging results from a preliminary phase I study,this phase II trial investigated the efficacy and safety of first-line sintilimab and anlotinib in metastatic NSCLC.Methods:In this open-label,randomized controlled trial(NCT04124731),metastatic NSCLC without epithelial growth factor receptor(EGFR),anaplastic lymphoma kinase(ALK),or proto-oncogene tyrosine-protein kinase ROS(ROS1)mutations,and previous treatments for metastatic disease were enrolled.Participants were randomly assigned in a 1:1 ratio to either sintilimab(200 mg every 3 weeks)plus anlotinib(12 mg D1-14 every 3 weeks)or a standard platinum-based chemotherapy regimen.Patients in the chemotherapy group were permitted to switch to sintilimab after disease progression.The primary endpoint was the objective response rate(ORR).Results:From November 2019 to March 2023,99 patients were randomized into the sintilimab plus anlotinib group(n=49)and the chemotherapy group(n=50).The ORR was significantly higher in the sintilimab plus anlotinib group(44.9%;95%confidence interval[CI]=30.7%-59.8%)compared to the chemotherapy group(18.0%;95%CI=8.6%-31.4%,P=0.003).Progression-free survival(PFS)was also notably longer(median:14.4 vs.5.6 months;hazard ratio[HR]=0.39;95%CI=0.23-0.67;P<0.001).The 24-month overall survival rate was 58.4%(95%CI=40.4%-72.6%)and 43.2%(95%CI=26.0%-59.2%),respectively.The rate of grade 3 or higher treatment-related adverse events was lower in the sintilimab plus anlotinib group(28.0%)than in the chemotherapy group(49.0%),especially for the hematological toxicities.Conclusion:First-line sintilimab plus anlotinib showed improved ORR and PFS,alongside a superior safety profile,compared to the standard platinumbased chemotherapy for metastatic NSCLC patients.展开更多
Silent mutations within the RAS gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies.Kirsten-RAS(KRAS)mutations,predominantly oncogenic,are pivotal drivers in v...Silent mutations within the RAS gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies.Kirsten-RAS(KRAS)mutations,predominantly oncogenic,are pivotal drivers in various cancers.While extensive research has elucidated the molecular mechanisms and biological consequences of active KRAS mutations,the functional significance of silent mutations remains relatively understudied.This review synthesizes current knowledge on KRAS silent mutations,highlighting their impact on cancer development.Silent mutations,which do not alter protein sequences but can affect RNA stability and translational efficiency,pose intriguing questions regarding their contribution to tumor biology.Understanding these mutations is crucial for comprehensively unraveling KRAS-driven oncogenesis and exploring novel therapeutic avenues.Moreover,investigations into the clinical implications of silent mutations in KRAS-mutant tumors suggest potential diagnostic and therapeutic strategies.Despite being in early stages,research on KRAS silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments.In conclusion,this review underscores the evolving landscape of KRAS silent mutations,advocating for further exploration to bridge fundamental biology with clinical applications in oncology.展开更多
Oncogenic KRAS mutations are frequently detected in NSCLC.It remains a major challenge to target all KRAS mutants.MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC;however,their easy adaptive res...Oncogenic KRAS mutations are frequently detected in NSCLC.It remains a major challenge to target all KRAS mutants.MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC;however,their easy adaptive resistance precludes further application.Here,we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases(RTKs)and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC.Furthermore,we evaluated this strategy in a clinical study(NCT04967079)involving 33 advanced non-G12C KRAS-mutant NSCLC patients.The phase Ia containing 13 patients showed that the recommended phase 2 dose(RP2D)is trametinib(2 mg)plus anlotinib(8 mg),the objective response rate(ORR)is 69.2%(95%CI:38.6-90.9),the median progression-free survival(PFS)is 6.9 months(95%CI:3.9 to could not be evaluated),disease control rate(DCR)is 92%(95%CI:64.0–99.8)and the rate of adverse events(AEs)≥grade 3 is 23%.The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D,with the ORR at 65%(95%CI:40.8–84.6),the median PFS is 11.5 months(95%CI:8.3–15.5),the median overall survival(OS)is 15.5 months(95%CI:15.5 to could not be evaluated),the DCR at 100%(95%CI:83.2–100.0),the median duration of overall response(DoR)is 9.3 months(95%CI:2.5–12.1),and the rate of AEs≥grade 3 at 35%.Overall,this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.展开更多
Clinical Question How to choose the drugs of adjuvant therapy for nonsmall-cell lung cancer(NSCLC)patients harboring driver gene mutation?Recommendations Recommendation 1:We suggest osimertinib(80 mg)adjuvant therapy ...Clinical Question How to choose the drugs of adjuvant therapy for nonsmall-cell lung cancer(NSCLC)patients harboring driver gene mutation?Recommendations Recommendation 1:We suggest osimertinib(80 mg)adjuvant therapy in stage Ib–IIIa EGFR-positive(Ex19del or L858R)NSCLC patients after surgery.According to the results of the ADAURA study,the benefit of osimertinib administration increases with advancing tumor stage.(Strong recommendation,high certainty of evidence)展开更多
To the Editor:Lung cancer,specifically lung adenocarcinoma(LUAD),is one of the primary cause of cancer-related mortality globally.[1,2]Nevertheless,only a small subset of individuals with LUAD have derived clinical be...To the Editor:Lung cancer,specifically lung adenocarcinoma(LUAD),is one of the primary cause of cancer-related mortality globally.[1,2]Nevertheless,only a small subset of individuals with LUAD have derived clinical benefits from chemoimmunotherapy in either first-line or subsequent treatment settings.Both programmed death-ligand 1(PDL1)expression and tumor mutational burden(TMB)have proven inadequate in accurately predicting treatment outcomes in these scenarios.[3]Consequently,there exists a pressing necessity to identify a reliable biomarker to inform treatment decisions.展开更多
A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC...A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC)patients without pretreatment.This study presents the prespecifiedfinal analysis of overall survival(OS)and biomarkers utilizing circulating tumor DNA(ctDNA)and tissuebased sequencing.Additionally,the analysis revealed a higher median overall survival(OS,23.8 months)in the toripalimab group than that in the control group(17.0 months).(HR=0.69,95%CI:0.57-0.93,nominal P=0.01).This survival benefit was particularly notable in the nonsquamous subgroup.As thefirst phase 3 study to perform both baseline tissue whole-exome sequencing(WES)and peripheral blood ctDNA testing,we investigated efficacy predictive biomarkers based on both tissue and ctDNA,Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden,as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment.Furthermore,a ctDNA response observed on cycle 3 day 1,was associated with improved clinical outcomes for patients treated with the combination therapy.In conclusion,Toripalimab plus chemotherapy yields significant improvements in OS as afirst-line treatment.The study highlights the utility of ctDNA as a proxy for tumor tissue,providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.展开更多
Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ...Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.展开更多
文摘Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.
文摘Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.
文摘Objective： To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer （NSCLC）. Methods： A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. Results： A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate （RR） was 36.0% （32/89）, and the disease control rate （DCR） was 69.7% （62/89）. RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma （P〈0.05）. The symptom improvement rate was 57.3% （51/89）, and the main symptoms improved were cough, pain, chest distress, dyspnea, and Eastern Cooperative Oncology Group performance status. The main toxic effects were rash [30/89 （33.7%）] and diarrhea [15/89 （16.9%）]. The level of toxicity was typically low. Conclusions： The use of icofinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.
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.
基金supported by the Nanjing Social Supporting Department and Social Supporting Ministry of Jiangsu Province granted from 2018 to 2020,and the Nanjing TANTICA Co.Ltd(grant no.2018LC01.1).
文摘Early detection of lung cancer (LC) is vital for reducing LC-related mortality. However, noninvasive diagnostic tools remain a great challenge. We aim to identify blood-based biomarkers for the early detection of LC. Here, LC-associated hypomethylation in alpha-1,3-fucosyltransferase VII (FUT7) is identified via the Illumina 850K array in a discovery study and validated by mass spectrometry in two independent casecontrol studies with blood samples from 1720 LC patients (86.8% LC at stage I, blood is collected before surgery and treatment) and 3143 healthy controls. Compared to the controls, blood-based FUT7 hypomethylation is identified in LC patients at stage I, and even in LC patients with malignant nodules ≤1 cm and in patients with adenocarcinoma in situ. Gender plays a role in the LC-associated FUT7 hypomethylation in blood, which is more significant in males than in females. We also reveal that FUT7 hypomethylation in LC could be enhanced by the advanced stage of cancer, involvement of lymph nodes, and larger tumor size. Based on a large sample size and semi-quantitative methods, our study reveals a strong association between blood-based FUT7 hypomethylation and LC, suggesting that methylation signatures in blood may be a group of potential biomarkers for detection of early-stage LC.
基金supported by Shanghai Xuhui District municipal health commission [grant number XHLHGG201806]Shanghai Shenkang three-year project [grant number SHDC2020CR4017]。
基金supported by the foundation of Chinese Society of Clinical Oncology (No. Y-2019AZZD-0355 & Y-QL2019-0125)the foundation of Shanghai Chest Hospital (No. 2019YNJCM11)the program of system biomedicine innovation center from Shanghai Jiao Tong University (No. YG2021QN121)
文摘Objective: Anti-vascular endothelial growth factor(VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer(NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data.Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate(ORR);equivalence was confirmed if the two-sided 90% confidence interval(90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival(PFS) and overall survival(OS).Results: The two-year updated data showed similar ORR(QL1101 vs. bevacizumab: 53.1% vs. 54.3%;relative risk=0.977;90% CI: 0.838-1.144), PFS(235 d vs. 254 d, log-rank P=0.311), and OS(577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group(22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group(n=157) and the bevacizumab group(n=148)(PFS: 253 d vs. 272 d, log-rank P=0.387;OS: 673 d vs. 790 d, log-rank P=0.101;mean tumor shrinkage rate: 26.6% vs. 27.5%).Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.
文摘With the advances in surgery, chemotherapy, and radiotherapy over the last decades, the treatment strategies of lung cancer has been largely changed. In this review, we summarize recent advances in lung cancer and treatment research. We discuss current clinical management, highlight stage-specific therapy approaches, chemotherapy options for advanced-stage of non-small-cell lung cancer (NSCLC) patients, along with new agents such as epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. We also give an outlook into NSCLC disease biology, focuse on the importance of EGFR activating mutations and the role of the tumor-microenvironment. Finally we summarize the new recommendations in treating small-cell-lung cancer (SCLC).
文摘Objective： To investigate the expressions and the clinical significance of P53, C-erbB-2 and vascular endothelial growth factor （VEGF） in non-small cell lung cancer （NSCLC）. Methods： 121 specimens of NSCLC were examined for P53, C-erbB-2 and VEGF by immunohistochemical staining. Results： The positive rates of P53, C-erbB-2 and VEGF in the carcinomatous tissue were 43%, 39% and 31% respectively. P53 gene protein expression in lung cancer was significantly related to histological type and P-TNM staging of lung cancer patients （P 〈 0.05）, and was not associated with the sex, age, the size of primary cancer, lymph node metastasis and cell differentiation （P 〉 0.05）. C-erbB-2 gene protein expression in lung cancer was closely related to histological type and cell differentiation （P 〈 0.05）, and was not associated with the sex, age, the size of primary cancer, lymph node metastasis and P-TNM staging of lung cancer patients （P 〉 0.05）. VEGF in lung cancer was only closely related to cell differentiation （P 〈 0.05）, and was not associated with the sex, age, the size of pdmary cancer, lymph node metastasis, histological type and P-TNM staging of lung cancer patients （P 〉 0.05）. Conclusion： It is possible for P53, C-erbB-2 and VEGF to play an important role in the oncogenesis and development of non-small cell lung cancer.
基金Science and Technology Innovation Action PlanMedical Innovation Research Special Project of Shanghai,Grant/Award Number:21Y11913500Medical and Health Technology Development Research Center of the National Health Commission,Grant/Award Number:WKZX2023CX030003。
文摘Background:The prognosis for non-small cell lung cancer(NSCLC)patients treatedwith standard platinum-based chemotherapywas suboptimal,with safety concerns.Following encouraging results from a preliminary phase I study,this phase II trial investigated the efficacy and safety of first-line sintilimab and anlotinib in metastatic NSCLC.Methods:In this open-label,randomized controlled trial(NCT04124731),metastatic NSCLC without epithelial growth factor receptor(EGFR),anaplastic lymphoma kinase(ALK),or proto-oncogene tyrosine-protein kinase ROS(ROS1)mutations,and previous treatments for metastatic disease were enrolled.Participants were randomly assigned in a 1:1 ratio to either sintilimab(200 mg every 3 weeks)plus anlotinib(12 mg D1-14 every 3 weeks)or a standard platinum-based chemotherapy regimen.Patients in the chemotherapy group were permitted to switch to sintilimab after disease progression.The primary endpoint was the objective response rate(ORR).Results:From November 2019 to March 2023,99 patients were randomized into the sintilimab plus anlotinib group(n=49)and the chemotherapy group(n=50).The ORR was significantly higher in the sintilimab plus anlotinib group(44.9%;95%confidence interval[CI]=30.7%-59.8%)compared to the chemotherapy group(18.0%;95%CI=8.6%-31.4%,P=0.003).Progression-free survival(PFS)was also notably longer(median:14.4 vs.5.6 months;hazard ratio[HR]=0.39;95%CI=0.23-0.67;P<0.001).The 24-month overall survival rate was 58.4%(95%CI=40.4%-72.6%)and 43.2%(95%CI=26.0%-59.2%),respectively.The rate of grade 3 or higher treatment-related adverse events was lower in the sintilimab plus anlotinib group(28.0%)than in the chemotherapy group(49.0%),especially for the hematological toxicities.Conclusion:First-line sintilimab plus anlotinib showed improved ORR and PFS,alongside a superior safety profile,compared to the standard platinumbased chemotherapy for metastatic NSCLC patients.
基金National Natural Science Foundation of China(Nos.82473102,82272913,82301980,and 82072573)National Multi-disciplinary Treatment Project for Major Disease(No.2020NMDTP)+1 种基金Chinese Society of Clinical Oncology(Nos.Y-2019AZZD-0355 and Y-QL2019-012)Shanghai Jiao Tong University(No.YG2021QN12)
文摘Silent mutations within the RAS gene have garnered increasing attention for their potential roles in tumorigenesis and therapeutic strategies.Kirsten-RAS(KRAS)mutations,predominantly oncogenic,are pivotal drivers in various cancers.While extensive research has elucidated the molecular mechanisms and biological consequences of active KRAS mutations,the functional significance of silent mutations remains relatively understudied.This review synthesizes current knowledge on KRAS silent mutations,highlighting their impact on cancer development.Silent mutations,which do not alter protein sequences but can affect RNA stability and translational efficiency,pose intriguing questions regarding their contribution to tumor biology.Understanding these mutations is crucial for comprehensively unraveling KRAS-driven oncogenesis and exploring novel therapeutic avenues.Moreover,investigations into the clinical implications of silent mutations in KRAS-mutant tumors suggest potential diagnostic and therapeutic strategies.Despite being in early stages,research on KRAS silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments.In conclusion,this review underscores the evolving landscape of KRAS silent mutations,advocating for further exploration to bridge fundamental biology with clinical applications in oncology.
基金supported by the foundation of National Natural Science Foundation of China grants(Project No.82473102 to J.L.,82272913 to B.H.,82301980 to B.Z.,82341002 to H.J.,32293192 to H.J.,82030083 to H.J.)National Multidisciplinary Treatment Project for Major Disease(Project No.2020NMDTP to B.H.)+4 种基金the Chinese Society of Clinical Oncology(Project No.Y-2019AZZD-0355 to B.H.&Y-QL2019-0125 to J.L.)Shanghai Jiao Tong University(Project No.YG2021QN121 to J.L.).the National Key R&D Program of China(grants 2022YFA1103900 to H.J.2020YFA0803300 to H.J.)the Basic Frontier Scientific Research Program of the Chinese Academy of Science(ZDBS-LYSM006 to H.J.)the Innovative Research Team of High-level Local University in Shanghai(SSMU-ZLCX20180500 to H.J.).
文摘Oncogenic KRAS mutations are frequently detected in NSCLC.It remains a major challenge to target all KRAS mutants.MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC;however,their easy adaptive resistance precludes further application.Here,we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases(RTKs)and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC.Furthermore,we evaluated this strategy in a clinical study(NCT04967079)involving 33 advanced non-G12C KRAS-mutant NSCLC patients.The phase Ia containing 13 patients showed that the recommended phase 2 dose(RP2D)is trametinib(2 mg)plus anlotinib(8 mg),the objective response rate(ORR)is 69.2%(95%CI:38.6-90.9),the median progression-free survival(PFS)is 6.9 months(95%CI:3.9 to could not be evaluated),disease control rate(DCR)is 92%(95%CI:64.0–99.8)and the rate of adverse events(AEs)≥grade 3 is 23%.The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D,with the ORR at 65%(95%CI:40.8–84.6),the median PFS is 11.5 months(95%CI:8.3–15.5),the median overall survival(OS)is 15.5 months(95%CI:15.5 to could not be evaluated),the DCR at 100%(95%CI:83.2–100.0),the median duration of overall response(DoR)is 9.3 months(95%CI:2.5–12.1),and the rate of AEs≥grade 3 at 35%.Overall,this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.
文摘Clinical Question How to choose the drugs of adjuvant therapy for nonsmall-cell lung cancer(NSCLC)patients harboring driver gene mutation?Recommendations Recommendation 1:We suggest osimertinib(80 mg)adjuvant therapy in stage Ib–IIIa EGFR-positive(Ex19del or L858R)NSCLC patients after surgery.According to the results of the ADAURA study,the benefit of osimertinib administration increases with advancing tumor stage.(Strong recommendation,high certainty of evidence)
基金National Natural Science Foundation of China(Nos.82373425 and 82372722)Medical Innovation Research Special Project of the Science and Technology Commission of Shanghai Municipality(No.23Y11904200)+3 种基金Shanghai Innovative Medical Device Application Demonstration Project 2023(No.23SHS02600)"Science and Technology Innovation Action Plan"Medical Innovation Research Special Project of Shanghai(No.21Y11913500)key project of the Medical and Health Technology Development Research Center of the National Health Commission(No.WKZX2023CX030003)Shanghai Key Laboratory Open Project(No.STCSM 22DZ2229005)
文摘To the Editor:Lung cancer,specifically lung adenocarcinoma(LUAD),is one of the primary cause of cancer-related mortality globally.[1,2]Nevertheless,only a small subset of individuals with LUAD have derived clinical benefits from chemoimmunotherapy in either first-line or subsequent treatment settings.Both programmed death-ligand 1(PDL1)expression and tumor mutational burden(TMB)have proven inadequate in accurately predicting treatment outcomes in these scenarios.[3]Consequently,there exists a pressing necessity to identify a reliable biomarker to inform treatment decisions.
基金supported by National key R&D program of China(2022YFC2505000)to J.WNSFC general program(82272796)NSFC special program(82241229)to J.W+1 种基金CAMS Innovation Fund for Medical Sciences(CIFMS 20adjuvant-I2M-1-009)to J.W,CAMS Key Laboratory of Translational Research on Lung Cancer(2018PT31035)to J.WAiyou foundation(KY201701)to J.W,CAMS Innovation Fund for Medical Sciences(2021-1-I2M-012)to Z.W.Beijing Natural Science Foundation(7222144)to J.Z,NSFC program(82303969)to J.Z.
文摘A randomized double-blind phase 3 trial(CHOICE-01,NCT03856411)demonstrated that combining toripalimab with chemotherapy substantially improves progression-free survival(PFS)in advanced non-small cell lung cancer(NSCLC)patients without pretreatment.This study presents the prespecifiedfinal analysis of overall survival(OS)and biomarkers utilizing circulating tumor DNA(ctDNA)and tissuebased sequencing.Additionally,the analysis revealed a higher median overall survival(OS,23.8 months)in the toripalimab group than that in the control group(17.0 months).(HR=0.69,95%CI:0.57-0.93,nominal P=0.01).This survival benefit was particularly notable in the nonsquamous subgroup.As thefirst phase 3 study to perform both baseline tissue whole-exome sequencing(WES)and peripheral blood ctDNA testing,we investigated efficacy predictive biomarkers based on both tissue and ctDNA,Genomic sequencing of ctDNA showed high concordance with tumor tissue independently confirmed that individuals exhibiting a high tumor mutational burden,as well as mutations in the FA-PI3K-Akt and IL-7 signaling pathways benefited more from the toripalimab treatment.Furthermore,a ctDNA response observed on cycle 3 day 1,was associated with improved clinical outcomes for patients treated with the combination therapy.In conclusion,Toripalimab plus chemotherapy yields significant improvements in OS as afirst-line treatment.The study highlights the utility of ctDNA as a proxy for tumor tissue,providing novel prospects for predicting efficacy of immuno-chemotherapy through continuous ctDNA monitoring.
基金This work was supported by the Key Program of the National Natural Science Foundation of China(31830021)Major International Joint Research Program of China(31420103901)+12 种基金“111 project”(B16021)Scientific and Technological Plan of Guangdong Province(201704KW010)(Z.Y.)Fundamental Research Funds for the Central Universities,Natural Science Foundation of Guangdong Province,China(2020A1515010132)(Y.W.)General Research Fund,Research Grants Council of Hong Kong(17122519,17121214,17115015,and 17126317)(W.T.)Hong Kong SAR,ChinaThis work was also partially supported by the National Natural Science Foundation of China(31570898)the Natural Science Foundation of Guangdong Province,China(2016A030313112)(Z.X.)grant Ka 502/19-1 from the German Research Council(Deutsche Forschungsgemeinschaft)the Cluster of Excellence ExC 306“Inflammation-at-Interfaces”(Deutsche Forschungsgemeinschaft)(D.K.)Y.H.was supported by the China Postdoctoral Science Foundation(2017M622898)Y.X.was supported by the Postdoctoral Fund of the First Affiliated Hospital of Jinan University(809008)L.K.was supported by a long-term fellowship from the German Academic Exchange Service(DAAD)C.P.is the recipient of a grant from the Erich und Gertrud Roggenbruck Foundation.
文摘Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy.Due to their HLA-independent mode of action,allogeneic Vγ9Vδ2 T cells can be considered for clinical application.To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy,the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized,and clinical safety and efficacy also need to be proven.Therefore,we developed a novel formula to improve the expansion of peripheralγδT cells from healthy donors.Then,we used a humanized mouse model to validate the therapeutic efficacy of expandedγδT cells in vivo;furthermore,the expandedγδT cells were adoptively transferred into late-stage liver and lung cancer patients.We found that the expanded cells possessed significantly improved immune effector functions,including proliferation,differentiation,and cancer cell killing,both in vitro and in the humanized mouse model.Furthermore,a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells.Among these 132 patients,8 liver cancer patients and 10 lung cancer patients who received≥5 cell infusions showed greatly prolonged survival,which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy.Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy,which will inspire further clinical investigations and eventually benefit cancer patients.
