Maintaining clarity:Review of maintenance therapy in nonsmall cell lung cancer

The purpose of this article is to review the role of maintenance therapy in the treatment of advanced nonsmall cell lung cancer(NSCLC). A brief overview about induction chemotherapy and its primary function in NSCLC is provided to address the basis of maintenance therapies foundation. The development of how maintenance therapy is utilized in this population is discussed and current guidelines for maintenance therapy are reviewed. Benefits and potential pitfalls of maintenance therapy are addressed, allowing a comprehensive review of the achieved clinical benefit that maintenance therapy may or may not have on NSCLC patient population. A review of current literature was conducted and a table is provided comparing the results of various maintenance therapy clinical trials. The table includes geographical location of each study, the number of patients enrolled, progression free survival and overall survival statistics, post-treatment regimens and if molecular testing was conducted. The role of molecular testing in relation to therapeutic treatment options foradvanced NSCLC patients is discussed. A treatment algorithm clearly depicts first line and second line treatment for management of NSCLC and includes molecular testing, maintenance therapy and the role clinical trials have in treatment of NSCLC. This treatment algorithm has been specifically tailored and developed to assist clinicians in the management of advanced NSCLC.

Treatment of Esthesioneuroblastoma and Nonsmall Cell Lung Cancer with Phenylbutyrate

Esthesioneuroblastoma is a malignant tumor, arising in the upper nasal cavity, that could spread to the frontal lobe of the brain as well as metastasize to the lymph nodes. Due to the low incidence of this tumor, FDA-approved treatment modalities do not exist and clinical trials have not been performed. We present an interesting case of a 66-year-old female, diagnosed with Kadish stage B esthesioneuroblastoma and stage IIA nonsmall cell carcinoma of the lung, who benefited from our treatment. Both malignancies were diagnosed in 2002 at which time the patient consented to undergo left upper lobectomy for her lung cancer, but she refused the craniofacial resection and radiation therapy recommended for treatment of her esthesioneuroblastoma. From 2003 to 2004 she received treatment at the Burzynski Clinic with oral sodium phenylbutyrate (0.2 g/kg/day). She tolerated the treatment very well without significant adverse events. Gradual reduction in her tumor size was confirmed by repeat MRIs. From treatment start in March 2003 to December 2003 her tumor decreased by 40%. Subsequent MRI from March 2004 revealed increased tumor size, which, however, was still a 13% reduction from the baseline MRI. What is important to mention is that in addition to shrinkage of the esthesioneuroblastoma, the patient obtained the clinical benefit of 3.5-years longer survival than was predicted for her lung cancer—whereas the median survival for a patient with stage IIA adenocarcinoma of the left upper lobe of the lung is approximately two years, our patient survived more than five and a half years. The effect of phenylbutyrate (PB) and its metabolite phenylacetate on neuroblastoma and lung cancer is documented by numerous preclinical studies and is also evident in this case. It is proposed that the activity of these two compounds is mediated through increased expression of the p21 tumor suppressor gene. p21 is a strong inhibitor of cyclin-D and cyclin-dependent kinase 4, which contribute to undifferentiated phenotype in neuroblastoma and are instrumental in cell cycle progression from G1 to S phase. It is hoped that future research and combination of PB with other chemotherapeutic and targeted agents will provide better control of esthesioneuroblastoma and lung cancer.

Evaluation of Three Small Molecular Drugs for Targeted Therapy to Treat Nonsmall Cell Lung Cancer

Objective： To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors （EGFR-TKIs） in clinical practice.This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib,erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications.Data Sources： An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib,icotinib, and erlotinib in the English language from January 2005 to December 2014 was used.Study Selection： The search terms or keywords included but not limited to ＆quot;lung cancer＆quot;, ＆quot;nonsmall cell lung cancer （NSCLC）＆quot;,＆quot;epidemiology＆quot;, ＆quot;EGFR＆quot;, ＆quot;TKIs＆quot;, and ＆quot;optimal selection＆quot;.Results： As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain.The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food.The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage.Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food.Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment.In marked contrast, icotinib is available only in China as the second-or third-line therapeutic approach for treating advanced lung cancer.In addition, it exhibits a similar efficacy but better safety profile than gefitinib.Conclusions： Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with advanced NSCLC.

A Matched Comparison Study of Uniportal Versus Triportal Thoracoscopic Lobectomy and Sublobectomy for Early-stage Nonsmall Cell Lung Cancer

Background： Both uniportal and triportal thoracoscopic lobectomy and sublobectomy are feasible for early-stage non-small cell lung cancer （NSCLC）. The aim of this study was to compare the perioperative outcomes of uniportal and triportal thoracoscopic Iobectomy and sublobectomy for early-stage NSCLC. Methods： A total of 405 patients with lung lesions underwent thoracoscopic lobectomy or sublobectomy through a uniportal or triportal procedure in approximately 7-month period （From November 2014 to May 2015）. A propensity-matched analysis, incorporating preoperative variables, was used to compare the short-term outcomes of patients who received uniportal or triportal thoracoscopic lobectomy and sublobectomy. Results： Fifty-eight patients underwent uniportal and 347 patients underwent triportal pulmonary resection. The conversion rate for uniportal and triportal procedure was 3.4% （2/58） and 2.3% （8/347）, respectively. The complication rate for uniportal and triportal procedure was 10.3% and 9.5%, respectively. There was no perioperative death in either group. Most patients had early-stage NSCLC in both groups （uniportal： 45/47, 96%; triportal： 313/343, 91%）. Propensity score-matching analysis demonstrated no significant differences in operation time, intraoperative blood loss, numbers of dissected lymph nodes, number of stations of lymph node dissected, duration of chest tube, and complication rate between uniportal and triportal group for early-stage NSCLC. However, the duration of postoperative hospitalization was longer in the uniportal group （6.83 ± 4.17 vs. 5.42 ± 1.86 d, P = 0.036） compared with the triportal group. Conclusions： Uniportal thoracoscopic lobectomy and sublobectomy is safe and feasible, with comparable short-term outcomes with triportal thoracoscopic pulmonary resection. Uniportal lobectomy and sublobectomy lead to similar cure rate as triportal Iobectomy and sublobectomy for early NSCLC.

Macrophage Inhibitory Cytokine-1 as a Novel Diagnostic and Prognostic Biomarker in Stage I and II Nonsmall Cell Lung Cancer

Background： Increased level of serum macrophage inhibitory cytokine- 1 （MIC- 1 ）, a member oftransfonning growth thctor-β superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-I can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer （NSCLC）. Methods： A prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease （BPD） and 105 healthy controls were also included in the study. Serum M IC- 1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed. Results： In patients with NSCLC, serum protein levels of M IC-I were significantly increased compared with healthy controls and BPD patients （all P 〈 0.001 ）. A threshold of 1000 pg/ml ofM IC-1 was found in patients with early-stage （Stage 1 and II） NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels ofMIC- ] were associated with age （P = 0.001 ）, gender （P = 0.030）, and T stage （P = 0.022）. Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 （〉I 465 pg/ml） was lower than that of NSCLC patients with low serum MIC-1 levels （77.6% vs. 94.8%）. Multivariate Cox regression survival analysis showed that a high serum level ofMIC- 1 was an independent risk factor lbr reduced overall survival （hazard ratio - 3.37, 95% confidential interval： 1.09-10.42, P = 0.035）. Conclusion： The present study suggested that serum M1C-I may be a potential diagnostic and prognostic biomarker ~cbr patients with early-stage NSCLC.

Assessment on the Efficacy and Safety of Aidi Injection Combined with Vinorelbine and Cisplatin for Treatment of Advanced Nonsmall Cell Lung Cancer

Background： The aim of this study was to assess the efficacy and safety of vinorelbine and cisplatin （NP chemotherapy） alone or in combination with Aidi injection for the treatment of advanced nonsmall cell lung cancer （NSCLC）. Methods： Pertinent publications were identified in PubMed, EMBASE, Cochrane Library, CNKI, CQVIR and Wanfang databases, up to December 8, 2015. After quality assessment of all included randomized controlled trials evaluating Aidi injection combined with NP chemotherapy for the treatment of advanced NSCLC, a meta-analysis was performed by Review Manager 5.2 and STATA 12.0 for statistical analyses. Results： Twelve studies including 509 and 503 cases in the experimental and control groups, respectively, were finally analyzed. The meta-analysis revealed that when cisplatin dose ranging from 20 to 40 mg/m2, combination of Aidi injection and NP chemotherapy was statistically different compared with NP chemotherapy alone in enhancing efficiency （relative risk [RR] = 1.24, 95% confidence interval [C/] [ 1.05-1.47], P = 0.010） and reducing the incidence of Grade II or above nausea and vomiting （RR = 0.49, 95% CI [0.30-0.80], P = 0.005）. Meanwhile, with cisplatin ranging from 80 to 120 mg/m2, no significant differences in efficiency （RR = 1.11, 95% CI [0.87- 1.42], P = 0.390） and Grade II or above nausea and vomiting （RR = 0.88, 95% CI [0.71-1.10], P = 0.260） were obtained. In addition, Aidi injection combined with NP chemotherapy was superior to NP chemotherapy alone in improving the quality of life, alleviating Grade II or above leukopenia and thrombocytopenia. Conclusions： Aidi injection combined with NP chemotherapy can enhance efficiency, improve the quality of life, and decrease adverse effects in patients with advanced NSCLC.

A Model Predicting Lymph Node Status for Patients with Clinical Stage TlaNO-2MO Nonsmall Cell Lung Cancer

Background： Lymph node status of patients with early-stage nonsmall cell lung cancer has an influence on the choice of surgery. To assess the lymph node status more correspondingly and accurately, we evaluated the relationship between the preoperative clinical variables and lymph node status and developed one model for predicting lymph node involvement. Methods： We collected clinical and dissected lymph node information of 474 patients with clinical stage TlaN0-2M0 nonsmall cell lung cancer （NSCLC）. Logistic regression analysis of clinical characteristics was used to estimate independent predictors of lymph node metastasis. The prediction model was validated by another group. Results： Eighty-two patients were diagnosed with positive lymph nodes （17.3%）, and four independent predictors of lymph node disease were identified： larger consolidation size （odds ratio [OR] = 2.356, 95% confidence interval [CI]： 1.517-3.658, P 〈 0.001）, central tumor location （OR = 2.810, 95% CI： 1.545-5.109, P = 0.001 ）, abnormal status of tumor marker （OR = 3.190, 95% CI： 1.797-5.661, P 〈 0.001 ）, and clinical N1-N2 stage （OR = 6.518, 95% CI： 3.242-11.697, P 〈 0.001）. The model showed good calibration （Hosmer-Lemeshow goodness-of-fit, P 〈 0.766） with an area under the receiver operating characteristics curve （AUC） of 0.842 （95% [CI]： 0.797-0.886）. For the validation group, the AUC was 0.810 （95% CI： 0.731-0.889）. Conclusions： The model can assess the lymph node status of patients with clinical stage TlaN0-2M0 NSCLC, enable surgeons perform an individualized prediction preoperatively, and assist the clinical decision-making procedure.

Inhibition of Nonsmall Cell Lung Cancer Cell Migration by Protein Arginine Methyltransferase 1-small Hairpin RNA Through Inhibiting Epithelial-mesenchymal Transition,Extracellular Matrix Degradation, and Src Phosphorylation In Vitro

Background：Protein arginine methyltransferases 1 （PRMT1） is over-expressed in a variety of cancers,including lung cancer,and is correlated with a poor prognosis of tumor development.This study aimed to investigate the role of PRMT1 in nonsmall cell lung cancer （NSCLC） migration in vitro.Methods：In this study,PRMT1 expression in the NSCLC cell line A549 was silenced using lentiviral vector-mediated short hairpin RNAs.Cell migration was measured using both scratch wound healing and transwell cell migration assays.The mRNA expression levels of matrix metalloproteinase 2 （MMP-2） and tissue inhibitor ofmetalloproteinase 1,2 （TIMP l,2） were measured using quantitative real-time reverse transcription-polymerase chain reaction.The expression levels of protein markers for epithelial-mesenchymal transition （EMT） （E-cadherin,N-cadherin）,focal adhesion kinase （FAK）,Src,AKT,and their corresponding phosphorylated states were detected by Western blot.Results：Cell migration was significantly inhibited in the PRMT1 silenced group compared to the control group.The mRNA expression of MMP-2 decreased while TIMP 1 and TIMP2 increased significantly.E-cadherin mRNA expression also increased while N-cadherin decreased.Only phosphorylated Src levels decreased in the silenced group while FAK or AKT remained unchanged.Conclusions：PRMT1-small hairpin RNA inhibits the migration abilities of NSCLC A549 cells by inhibiting EMT,extracellular matrix degradation,and Src phosphorylation in vitro.

Gemcitabine and cisplatin treatment over a 3-week versus a 4-week dosing schedule： a randomized trial coducted in Chinese patients with nonsmall cell lung cancer

Background Gemcitabine plus cisplatin is a standard treatment for stages IIIB and IV nonsmall cell lung cancer （NSCLC）. This randomized phase Ⅱ study evaluated a 3-week versus a 4-week schedule of gemcitabine-cisplatin as first line treatment for Chinese patients with advanced NSCLC. Methods Patients were randomized to receive cisplatin 75 mg/m^2 on day 1 plus either gemcitabine 1250 mg/m^2 on days 1 and 8 of a 21-day cycle （3-week group） or gemcitabine 1000 mg/m2 on days 1,8 and 15 of a 28-day cycle （4-week group）. Results One hundred patients were enrolled in this study. The response rate was 24% （12/51 patients） in the 3-week group and 27% （13/49 patients） in the 4-week group. There were no statistically significant differences between the two treatment groups in survival （hazard ratio： 1.19; 95% CI： 0.68-2.09） with a median survival of 12.1 months and 13.8 months in the 3-week group and the 4-week group respectively. The rate of grade 3/4 toxicity in the 3-week group was 55% compared with 86% in the 4-week group （P=0.001）. The difference in the incidence of grade 3/4 haematological toxicities did not reach statistical significance （3-week： 37%, 4-week： 57%）, however grade 3/4 drug related neutropenia （3-week： 27%, 4-week： 51%） and thrombocytopenia （3-week： 8%, 4-week： 31%） were significantly lower in the 3-week group. Grade 3/4 nonhaematological toxicities were less in the 3-week group （33% cf 63%; P=0.005）. Conclusions The differences in the efficacy endpoints were all in favour of the 4-week schedule of gemcitabine plus cisplatin, however these differences did not reach statistical significance. Fewer grade 3/4 toxicities were observed in the 3-week group compared with the 4-week group.

贝伐珠单抗联合埃克替尼克服一例非小细胞肺癌患者奥希替尼耐药（英文）

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor(EGFR)19 del mutation positive.Treatment with icotinib was given,but her disease progressed after 6 months remission.CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis,and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction(ARMS-PCR)confirmed EGFR T790M mutation.Treatment with osimertinib was initiated.After 2 months remission,the disease progressed.Re-biopsy was performed for the tumor in the inferior lobe of left lung,and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del.Icotinib was re-challenged,but disease progressed continuously.Bevacizumab was added,and partial response was achieved after 2-cycle of combination therapy.The non-small cell lung cancer(NSCLC)in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment.This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.

Defining lung cancer stem cells exosomal payload of miRNAs in clinical perspective

Since the first publication regarding the existence of stem cells in cancer[cancer stem cells(CSCs)]in 1994,many studies have been published providing in-depth information about their biology and function.This research has paved the way in terms of appreciating the role of CSCs in tumour aggressiveness,progression,recurrence and resistance to cancer therapy.Targeting CSCs for cancer therapy has still not progressed to a sufficient degree,particularly in terms of exploring the mechanism of dynamic interconversion between CSCs and non-CSCs.Besides the CSC scenario,the problem of cancer dissemination has been analyzed indepth with the identification and isolation of microRNAs(miRs),which are now considered to be compelling molecular markers in the diagnosis and prognosis of tumours in general and specifically in patients with non-small cell lung cancer.Paracrine release of miRs via“exosomes”(small membrane vesicles(30-100 nm),the derivation of which lies in the luminal membranes of multi-vesicular bodies)released by fusion with the cell membrane is gaining popularity.Whether exosomes play a significant role in maintaining a dynamic equilibrium state between CSCs and non-CSCs and their mechanism of activity is as yet unknown.Future studies on CSC-related exosomes will provide new perspectives for precision-targeted treatment strategies.

Non-small-cell lung cancer with epidermal growth factor receptor L861Q-L833F compound mutation benefits from both afatinib and osimertinib: A case report

BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.

Lung adenocarcinoma harboring rare epidermal growth factor receptor L858R and V834L mutations treated with icotinib:A case report

BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations.However,patients with rare,even compound EGFR mutations have different responses to EGFR-tyrosine-kinase inhibitors,which bring uncertainty to clinical treatment.CASE SUMMARY A 45-year-old female patient presented with a 3-mo history of cough and white sputum without chest pain.Chest computed tomography revealed lung spaceoccupying lesions and multiple lymphadenectasis.Bronchoscopy and pathology suggested lung adenocarcinoma.Compound variation of EGFR gene(exon 21 L858 R/V834 L)was detected in both tissue and circulating tumor deoxyribonucleic acid samples.As a result of next-generation sequencing and her family’s wishes,the patient was given oral treatment with icotinib hydrochloride(125 mg/d,tid)from March 21,2019 and has achieved stable disease for the last 1 year.CONCLUSION Non-small cell lung adenocarcinoma with EGFR L858 R/V834 L was treated successfully with icotinib,and it may be a new medication treatment option.

Recent advances in immunotherapy for lung cancer

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.

Thermal Ablation in the Management of Adrenal Metastasis Originating from Non-small Cell Lung Cancer： A 5-year Single-center Experience

Background：Treatment of adrenal metastasis from lung carcinoma may prolong survival in the selected patients.However,not all patients can undergo surgery;thus,minimally invasive ablation procedures such as radiofrequency ablation （RFA） and microwave ablation （MWA） have gained acceptance as alternative treatment methods.This study summarized a 5-year single-center experience regarding the evaluation of safety and efficacy of computed tomography （CT）-guided thermal ablation in the management of adrenal metastasis originating from non-small cell lung cancer （NSCLC）.Methods：The data of NSCLC patients ablated for adrenal metastasis at the Department of Diagnostic Imaging and Interventional Radiology,General Hospital Sotiria,were retrospectively analyzed.Patients were divided into two groups：RFA group and MWA group according to the therapeutic approaches.Preprocedural blood tests included measurement of international normalized ratio,partial thromboplastin time,and platelet enumeration.A dual-phase contrast-enhanced spiral CT was performed immediately after the procedure to assess the immediate response after ablation and to screen for related complications.Follow-up was performed with CT or magnetic resonance imaging at 1,3,6 months and 1 year after ablation and every 6 months thereafter.Results：A total of 99 ablation sessions in 71 patients with adrenal metastasis originating from NSCLC were included in the final analysis.Self-limited,postablation syndrome occurred in 16/99 （16.1%） of ablation sessions.All procedures were technically successful.Immediate postablation imaging showed no contrast enhancement of the ablated tumor in all patients.Follow-up imaging at 3 months revealed local tumor progression in 8 （22.8%） patients of the RFA group and 7 （19.4%） patients of MWA group,all of them underwent a second session successfully.The 1-year assessment revealed local recurrence of the ablated tumor in six patients （17.1%） of RFA group and seven patients （19.4%） of MWA group.Among these 71 patients,those with tumor size 〉3.5 cm had a higher local recurrence rate （65.2%,15/23） than those with tumors 〈3.5 cm （16.7%,8/48;P =0.012）.There was no significant difference in the median survival time between RFA （14.0 months） and MWA （14.6 months） groups （P 〉 0.05）.Conclusions：RFA and MWA showed comparable efficacy and safety in adrenal metastasis treatment.

Spatial metabolomics for evaluating response to neoadjuvant therapy in non-small cell lung cancer patients

Background:The response to neoadjuvant chemotherapy(NAC)differs substantially among individual patients with non-small cell lung cancer(NSCLC).Major pathological response(MPR)is a histomorphological read-out used to assess treatment response and prognosis in patientsNSCLC afterNAC.Although spatial metabolomics is a promising tool for evaluating metabolic phenotypes,it has not yet been utilized to assess therapy responses in patients with NSCLC.We evaluated the potential application of spatial metabolomics in cancer tissues to assess the response to NAC,using a metabolic classifier that utilizes mass spectrometry imaging combined with machine learning.Methods:Resected NSCLC tissue specimens obtained after NAC(n=88)were subjected to high-resolution mass spectrometry,and these data were used to develop an approach for assessing the response to NAC in patients with NSCLC.The specificities of the generated tumor cell and stroma classifiers were validated by applying this approach to a cohort of biologically matched chemotherapy-naive patients with NSCLC(n=85).Results:The developed tumor cell metabolic classifier stratified patients into different prognostic groups with 81.6%accuracy,whereas the stroma metabolic classifier displayed 78.4%accuracy.By contrast,the accuracies of MPR and TNM staging for stratification were 62.5%and 54.1%,respectively.The combination of metabolic and MPR classifiers showed slightly lower accuracy than either individual metabolic classifier.In multivariate analysis,metabolic classifiers were the only independent prognostic factors identified(tumor:P=0.001,hazards ratio[HR]=3.823,95%confidence interval[CI]=1.716-8.514;stroma:P=0.049,HR=2.180,95%CI=1.004-4.737),whereasMPR(P=0.804;HR=0.913;95%CI=0.445-1.874)and TNM staging(P=0.078;HR=1.223;95%CI=0.977-1.550)were not independent prognostic factors.Using Kaplan-Meier survival analyses,both tumor and stroma metabolic classifiers were able to further stratify patients as NAC responders(P<0.001)and non-responders(P<0.001).Conclusions:Our findings indicate that the metabolic constitutions of both tumor cells and the stroma are valuable additions to the classical histomorphology-based assessment of tumor response.

Bevacizumab biosimilar LY01008 compared with bevacizumab(Avastin)as first-line treatment for Chinese patients with unresectable,metastatic,or recurrent non-squamous non-small-cell lung cancer:A multicenter,randomized,double-blinded,phase Ⅲ trial

Background:Previous studies have demonstrated the preclinical pharmacological and toxicological consistency,and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab(Avastin).This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer(NSCLC).Methods:StageⅢB-ⅣNSCLC patients with evaluable lesions,good physical status,and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin(combined treatment)for 4-6 cycles,followed by maintenance monotherapy with LY01008 until disease progression,intolerable toxicity,or death.The primary endpoint was objective response rate(ORR)in accordance with Response Evaluation Criteria in Solid Tumors(RECIST)version 1.1 confirmed by independent radiological review committees(IRRC).Secondary endpoints included disease control rate(DCR),duration of response(DoR),progression-free survival(PFS),overall survival(OS),and safety.This study was registered in Clinical Trials.gov(NCT03533127).Results:Between December 15^(th),2017,and May 15^(th),2019,a total of 649 patients were randomized to the LY01008(n=324)or Avastin(n=325)group.As of September 25th,2019 for primary endpoint analysis,589 patients received ORR evaluation,with a median number of combined treatment cycles of 5(range 1-6)andmedian duration of treatment of 3.0(range 0.0-5.1)months.ORRof responseevaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%,respectively.The stratified ORR ratio was 0.91(90%CI 0.80-1.04,within the prespecified equivalence margin of 0.75-1.33).Up to May 15^(th),2020,with a median follow-up of 13.6(range 0.8-28.4)months,no notable differences in DCR,median DoR,median PFS,median OS,and 1-year OS rate were observed between the LY01008 and Avastin groups.There were no clinically meaningful differences in safety and immunogenicity across treatment groups.Conclusions:LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC.LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable,metastatic,LY01008 and Avastin groups.There were no clinically meaningful differences in safety and immunogenicity across treatment groups.Conclusions:LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC.LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable,metastatic,or recurrent non-squamous NSCLC patients in the first-line setting.