Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Pembrolizumab for the treatment of non-small cell lung cancer Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti–PD-L1) Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies. Is there a third line option after chemotherapy and TKI failure in advanced non-small cell lung cancer? Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non‐small cell lung cancer Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma Real world treatment and outcomes in EGFR mutation-positive non-small cell lung cancer: Long-term follow-up of a large patient cohort. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naïve Patients with Advanced Non–Small Cell Lung Cancer
Purpose Provide evidence -based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer ( NSCLC ) . Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of r and omized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence -Based Care 's up date of a previous ASCO search . Results This guideline up date reflects changes in evidence since the previous guideline up date . Fourteen r and omized controlled trials provide the evidence base ; earlier phase trials also informed recommendation development . Recommendations New or revised recommendations include the following . Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma ( without positive markers , eg , EGFR/ALK /ROS1 ) , if the patient has high programmed death lig and 1 ( PD-L1 ) expression , pembrolizumab should be used alone ; if the patient has low PD-L1 expression , clinicians should offer st and ard chemotherapy . All other clinical scenarios follow 2015 recommendations . Regarding second-line treatment in patients who received first-line chemotherapy  , without prior immune checkpoint therapy , if NSCLC tumor is positive for PD-L1 expression , clinicians should use single-agent nivolumab , pembrolizumab , or atezolizumab ; if tumor has negative or unknown PD-L1 expression , clinicians should use nivolumab or atezolizumab . All immune checkpoint therapy is recommended alone plus in the absence of contraindications . For patients who received a prior first-line immune checkpoint inhibitor , clinicians should offer st and ard chemotherapy . For patients who can not receive immune checkpoint inhibitor after chemotherapy , docetaxel is recommended ; in patients with nonsquamous NSCLC , pemetrexed is recommended . In patients with a sensitizing EGFR mutation , disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy , and T790 M mutation , osimertinib is recommended ; if NSCLC lacks the T790 M mutation , then chemotherapy is recommended . Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib , or if they previously received crizotinib , they may be offered chemotherapy ABSTRACT Immune checkpoint inhibitors ( ICIs ) are new therapeutic strategies for non-small cell lung cancer ( NSCLC ) . We aim ed to quantitatively evaluate the efficacy and safety of ICIs in NSCLC . Pubmed , Embase , Cochrane Library , and Web of Science were search ed for r and omized clinical trials comparing ICIs with control therapies in NSCLC . Data were pooled according to Preferred Reporting Items for Systematic Review s and Meta-analyses guidelines . A total of 12 trails comprising 6,919 NSCLC patients were included in this meta- analysis . ICIs therapies significantly improved progression-free survival ( PFS ) ( HR , 0.838 ; P < 0.001 ) , overall survival ( OS ) ( HR , 0.747 ; P < 0.001 ) and objective response rates ( ORR ) ( RR , 1.311 ; P < 0.001 ) in NSCLC . Prognostic benefit was observed irrespective of age , sex , treatment line , performance status and histology . Survival improvement of ICIs  was limited for NSCLC patients with non-smoker ( PFS , P = 0.468 ; OS , P = 0.317 ) or central nervous system ( CNS ) metastasis ( PFS , P = 0.209 ; OS , P = 0.090 ) , or positive EGFR mutation ( PFS , P = 0.083 ; OS , P = 0.522 ) or PD-L1 expression level less than 5 % ( PFS , P = 0.370 ; OS , P = 0.047 ) . The relative risks of all- grade and high- grade ( ≥3 ) anemia , neutropenia , leukopenia , thrombocytopenia , stomatitis , nausea , pyrexia , asthenia and neuropathy were all decreased in patients received ICIs compared with control therapies . This meta- analysis provides clinical evidence that ICIs improve PFS , OS , and ORR in NSCLC with fewer adverse effects . Our data establish ICIs as a prefer treatment option for NSCLC patients with smoker , no CNS metastasis , wild type EGFR , and high PD-L1 expression BACKGROUND Immune checkpoint inhibitors are a new st and ard of care for patients with advanced non-small-cell lung cancer ( NSCLC ) without EGFR tyrosine kinase or anaplastic lymphoma kinase ( ALK ) genetic aberrations ( EGFR-/ALK- ) , but clinical benefit in patients with EGFR mutations or ALK rearrangements ( EGFR+/ALK+ ) has not been shown . We assessed the effect of durvalumab ( anti-PD-L1 ) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1 . METHODS ATLANTIC is a phase 2 , open-label , single-arm trial at 139 study centres in Asia , Europe , and North America . Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens , including platinum-based chemotherapy ( and tyrosine kinase inhibitor therapy if indicated ) ; were aged 18 years or older ; had a WHO performance status score of 0 or 1 ; and measurable disease per Response Evaluation Criteria in Solid Tumors ( RECIST ) version 1.1 . Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology ; previous exposure to any anti-PD-1 or anti-PD-L1 antibody ; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent . Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25 % , or less than 25 % , of tumour cells with PD-L1 expression . Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC ; cohort 2 included patients with at least 25 % , or less than 25 % , of tumour cells with PD-L1 expression , and cohort 3 included patients with at least 90 % of tumour cells with PD-L1 expression . Patients received durvalumab ( 10 mg/kg ) every 2 weeks , via intravenous infusion , for up to 12 months . Retreatment was allowed for patients who benefited but then progressed after completing 12 months . The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 ( defined as ≥25 % of tumour cells in cohorts 1 and 2 , and ≥90 % of tumour cells in cohort 3 ) who achieved an objective response , assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1 . Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available . The trial is ongoing , but is no longer open to accrual , and is registered with Clinical Trials.gov , number NCT02087423 . FINDINGS Between Feb 25 , 2014 , and Dec 28 , 2015 , 444 patients were enrolled and received durvalumab : 111 in cohort 1 , 265 in cohort 2 , and 68 in cohort 3 . Among patients with at least 25 % of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review , an objective response was achieved in 9 ( 12·2 % , 95 % CI 5·7 - 21·8 ) of 74 patients in cohort 1 and 24 ( 16·4 % , 10·8 - 23·5 ) of 146 patients in cohort 2 . In cohort 3 , 21 ( 30·9 % , 20·2 - 43·3 ) of 68 patients achieved an objective response . Grade 3 or 4 treatment-related adverse events occurred in 40 ( 9 % ) of 444 patients overall : six ( 5 % ) of 111 patients in cohort 1 , 22 ( 8 % ) of 265 in cohort 2 , and 12 ( 18 % ) of 68 in cohort 3 . The most common treatment-related grade 3 or 4 adverse events were pneumonitis ( four patients [ 1 % ] ) , elevated gamma-glutamyltransferase ( four [ 1 % ] ) , diarrhoea ( three [ 1 % ] ) , infusion-related reaction ( three [ 1 % ] ) , elevated aspartate aminotransferase ( two [ < 1 % ] ) , elevated transaminases ( two [ < 1 % ] ) , vomiting ( two [ < 1 % ] ) , and fatigue ( two [ < 1 % ] ) . Treatment-related serious adverse events occurred in 27 ( 6 % ) of 444 patients overall : five ( 5 % ) of 111 patients in cohort 1 , 14 ( 5 % ) of 265 in cohort 2 , and eight ( 12 % ) of 68 in cohort 3 . The most common serious adverse events overall were pneumonitis ( five patients [ 1 % ] ) , fatigue ( three [ 1 % ] ) , and infusion-related reaction ( three [ 1 % ] ) . Immune-mediated events were manageable with st and ard treatment guidelines . INTERPRETATION In patients with advanced and heavily pretreated NSCLC , the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents . Responses were recorded in all cohorts ; the proportion of patients with EGFR-/ALK- NSCLC ( cohorts 2 and 3 ) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC ( cohort 1 ) achieving a response . The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25 % of tumour cells expressing PD-L1 was encouraging , and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted . FUNDING AstraZeneca ABSTRACT Introduction : Immune checkpoint inhibitors targeting programmed death protein 1 ( PD-1 ) receptor and its lig and , PD-L1 , have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer . Areas covered : Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1 . In the phase I KEYNOTE-001 trial , the overall response rate ( ORR ) was 19.4 % , the median progression-free survival ( PFS ) and overall survival ( OS ) were 3.7 months and 12.0 months for 495 unselected NSCLC patients . Strong PD-L1 expression ( ≥ 50 % ) was associated with higher ORR , longer PFS , and longer OS . The phase II/III r and omized KEYNOTE-010 trial demonstrated that pembrolizumab  improved OS versus docetaxel in patients with previously treated NSCLC . Expert opinion : Pembrolizumab , demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1 , thereby suggests a new treatment paradigm . However , many issues remain to be explored , including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors . Along with the identification of predictive biomarkers , further underst and ing of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies Significance Programmed death-lig and 1 ( PD-L1 ) expression on tumor cells and tumor-infiltrating immune cells is regulated by distinct mechanisms and has nonredundant roles in regulating anticancer immunity , and PD-L1 on both cell types is important for predicting best response to atezolizumab in non-small cell lung cancer .  Programmed death-lig and 1 ( PD-L1 ) expression on tumor cells ( TCs ) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer ( NSCLC ) most likely to respond to single-agent checkpoint inhibitors . However , at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC : expression on TC or on tumor-infiltrating immune cells ( ICs ) . We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC .  PD-L1 expression on IC was more prevalent and likely reflected IFN-γ – induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells . High PD-L1 expression on TC , however , reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration , sclerotic/desmoplastic stroma , and mesenchymal molecular features . Importantly , durable clinical responses  to atezolizumab ( anti – PD-L1 ) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [ 40 % objective response rate ( ORR ) ] or IC alone ( 22 % ORR ) . Thus , PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response Although programmed death-lig and 1–programmed death 1 ( PD-L1–PD-1 ) inhibitors are broadly efficacious , improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden ( TMB ) .  PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer ( NSCLC ) . However , obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging . Thus , an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy . Here , we describe a novel , technically robust , blood-based assay to  measure TMB in plasma ( bTMB ) that is distinct from tissue-based approaches . Using a retrospective analysis of two large r and omized trials as test and validation studies , we show that bTMB reproducibly identifies patients who derive clinical ly significant improvements in progression-free survival from atezolizumab ( an anti-PD-L1 ) in second-line and higher NSCLC . Collectively , our data show that high bTMB is a clinical ly actionable biomarker for atezolizumab in NSCLC.A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer OBJECTIVE To establish evidence -based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies , addressing which patients and sample s should be tested , and when and how testing should be performed . PARTICIPANTS Three cochairs without conflicts of interest were selected , one from each of the 3 sponsoring professional societies : College of American Pathologists , International Association for the Study of Lung Cancer , and Association for Molecular Pathology . Writing and advisory panels were constituted from additional experts from these societies . EVIDENCE Three unbiased literature search es of electronic data bases were performed to capture published articles from January 2004 through February 2012 , yielding 1533 articles whose abstract s were screened to identify 521 pertinent articles that were then review ed in detail for their relevance to the recommendations . EVIDENCE was formally grade d for each recommendation . CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting . Each guideline section was assigned to at least 2 panelists . Drafts were circulated to the writing panel ( version 1 ) , advisory panel ( version 2 ) , and the public ( version 3 ) before su bmi ssion ( version 4 ) . CONCLUSIONS The 37 guideline items address 14 subjects , including 15 recommendations ( evidence grade A/B ) . The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) inhibitor , respectively , in all patients with advanced-stage adenocarcinoma , regardless of sex , race , smoking history , or other clinical risk factors , and to prioritize EGFR and ALK testing over other molecular predictive tests . As scientific discoveries and clinical practice outpace the completion of r and omized clinical trials , evidence -based guidelines developed by expert practitioners are vital for communicating emerging clinical st and ards . Already , new treatments targeting genetic alterations in other , less common driver oncogenes are being evaluated in lung cancer , and testing for these may be addressed in future versions of these guidelines Objective : To establish evidence -based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies , addressing which patients and sample s should be tested , and when and how testing should be performed . Participants : Three cochairs without conflicts of interest were selected , one from each of the 3 sponsoring professional societies : College of American Pathologists , International Association for the Study of Lung Cancer , and Association for Molecular Pathology . Writing and advisory panels were constituted from additional experts from these societies . Evidence : Three unbiased literature search es of electronic data bases were performed to capture articles published published from January 2004 through February 2012 , yielding 1533 articles whose abstract s were screened to identify 521 pertinent articles that were then review ed in detail for their relevance to the recommendations . Evidence was formally grade d for each recommendation . Consensus Process : Initial recommendations were formulated by the cochairs and panel members at a public meeting . Each guideline section was assigned to at least 2 panelists . Drafts were circulated to the writing panel ( version 1 ) , advisory panel ( version 2 ) , and the public ( version 3 ) before su bmi ssion ( version 4 ) . Conclusions : The 37 guideline items address 14 subjects , including 15 recommendations ( evidence grade A/B ) . The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) inhibitor , respectively , in all patients with advanced-stage adenocarcinoma , regardless of sex , race , smoking history , or other clinical risk factors , and to prioritize EGFR and ALK testing over other molecular predictive tests . As scientific discoveries and clinical practice outpace the completion of r and omized clinical trials , evidence -based guidelines developed by expert practitioners are vital for communicating emerging clinical st and ards . Already , new treatments targeting genetic alterations in other , less common driver oncogenes are being evaluated in lung cancer , and testing for these may be addressed in future versions of these guidelines Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) . Methods An Up date Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of r and omized controlled trials from January 2007 to February 2014 . Results This guideline up date reflects changes in evidence since the previous guideline . Recommendations There is no cure for patients with stage IV NSCLC . For patients with performance status ( PS ) 0 to 1 ( and appropriate patient cases with PS 2 ) and without an EGFR-sensitizing mutation or ALK gene rearrangement , combination cytotoxic chemotherapy is recommended , guided by histology , with early concurrent palliative care . Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 ( bevacizumab may be added to carboplatin plus paclitaxel if no contraindications ) ; combination or single-agent chemotherapy or palliative care alone for those with PS 2 ; afatinib , erlotinib , or gefitinib for those with sensitizing EGFR mutations ; crizotinib for those with ALK or ROS1 gene rearrangement ; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma . Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens , alternative chemotherapy , or a chemotherapy break . In the second-line setting , recommendations include docetaxel , erlotinib , gefitinib , or pemetrexed for patients with nonsquamous cell carcinoma ; docetaxel , erlotinib , or gefitinib for those with squamous cell carcinoma ; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib . In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended . There are insufficient data to recommend routine third-line cytotoxic therapy . Decisions regarding systemic therapy should not be made based on age alone . Additional information can be found at http://www.asco.org/ guidelines /nsclc and http://www.asco.org/ guidelines wiki . J Clin Oncol 33:3488 - 3515 . © 2015 by American Society of Clinical OBJECTIVES Most lung cancer diagnoses occur in elderly patients , who are underrepresented in clinical trials . We present a pooled analysis of safety and efficacy in elderly patients ( ≥75 years ) who received pembrolizumab ( a programmed death 1 inhibitor ) for advanced non-small-cell lung cancer ( NSCLC ) with programmed death lig and 1 (PD-L1)‒positive tumors . METHODS The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 ( NCT01905657 ) , KEYNOTE-024 ( NCT02142738 ) , and KEYNOTE-042 ( NCT02220894 ) studies . In KEYNOTE-010 , patients were r and omized to pembrolizumab 2 or 10 mg/kg every 3 weeks ( Q3W ) or docetaxel , as second- or later-line therapy . In KEYNOTE-024 and KEYNOTE-042 , patients were r and omized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy . Overall survival ( OS ) was estimated by the Kaplan-Meier method , and safety data were summarized in elderly patients ( ≥75 years ) . RESULTS The analysis included 264 elderly patients with PD-L1-positive tumors ( PD-L1 tumor proportion score [ TPS ] ≥1 % ) ; among these , 132 had PD-L1 TPS ≥ 50 % . Pembrolizumab  improved OS among elderly patients with PD-L1 TPS ≥ 1 % ( hazard ratio [ HR ] , 0.76 [ 95 % CI , 0.56 - 1.02 ] ) and PD-L1 TPS ≥ 50 % ( HR , 0.40 [ 95 % CI , 0.25 - 0.64 ] ) . Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50 % ( from KEYNOTE-024 and KEYNOTE-042 ) compared with chemotherapy ( HR , 0.41 [ 95 % CI , 0.23‒0.73 ] ) . Pembrolizumab was associated with fewer treatment-related adverse events ( AEs ) in elderly patients ( overall , 68.5 % vs 94.3 % ; grade ≥3 , 24.2 % vs 61.0 % ) versus chemotherapy . Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy ( overall , 24.8 % vs 6.7 % ; grade 3‒4 : 9.4 % vs 0 % ; no grade 5 events ) . CONCLUSIONS In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors  , pembrolizumab improved OS versus chemotherapy , with a more favorable safety profile . Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall population s in the individual studies The EGFR gene is a major therapeutic target in advanced Non-small cell lung cancer ( NSCLC ) . Two reversible tyrosine kinase inhibitors , Erlotinib and Gefitinib , have been vali date d and registered for the treatment of NSCLC . Gefitinib has a label that is limited to NSCLC carrying mutations in the kinase domain of the EGFR gene , while the label of Erlotinib also includes second line treatment of patients with undefined EGFR status in their tumor , based on an early r and omized study that showed a small benefit in such unselected population ( 1 ) Limited treatment options are available for stage IIIB/IV non‐small cell lung cancer ( NSCLC ) . Nivolumab , a programmed cell death‐1 immune checkpoint inhibitor antibody , has been shown to be effective for the treatment of NSCLC . The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy . In this multicenter phase II study , patients were treated with nivolumab ( 3 mg/kg , i.v . ) every 2 weeks until progressive disease or unacceptable toxicity was seen . Primary endpoint was overall response rate ( ORR ) assessed by independent radiology review committee ( IRC ) and secondary endpoints included a study site‐assessed ORR , overall survival ( OS ) , progression‐free survival ( PFS ) , duration of response , time to response , best overall response ( BOR ) , and safety . The study included 35 patients from 17 sites in Japan . Patients had IRC‐assessed ORR of 25.7 % ( 95 % CI 14.2 , 42.1 ) and the study site‐assessed ORR was 20.0 % ( 95 % CI 10.0 , 35.9 ) . Median OS , median time to response and median PFS were 16.3 ( 95 % CI 12.4–25.4 ) , 2.7 ( range 1.2–5.5 ) and 4.2 ( 95 % CI 1.4–7.1 ) months , respectively . The IRC‐assessed BOR was partial response , stable disease , and progressive disease for 25.7 % , 28.6 % , and 45.7 % of patients , respectively . Treatment‐related adverse events were reported in 24 patients ( 68.6 % ) , most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab . Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum‐containing chemotherapy . Clinical trial registration number : The st and ard of care for most patients with non-muscle-invasive bladder cancer ( NMIBC ) is immunotherapy with intravesical Bacillus Calmette-Guérin ( BCG ) , which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit . Urologic best- practice guidelines and consensus reports have been developed and strengthened based on data on the timing , dose , and duration of therapy from r and omized clinical trials , as well as by critical evaluation of criteria for progression . However , these reports have not penetrated the community , and many patients do not receive appropriate therapy . Additionally , several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease . The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of exp and ed use for both advanced and , potentially , localized disease . To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer , the Society for Immunotherapy of Cancer ( SITC ) convened a Task Force of experts , including physicians , patient advocates , and nurses , to address issues related to patient selection , toxicity management , clinical endpoints , as well as the combination and sequencing of therapies . Following the st and ard approach established by the Society for other cancers , a systematic literature review and analysis of data , combined with consensus voting was used to generate guidelines . Here , we provide a consensus statement for the use of immunotherapy in patients with bladder cancer , with plans to up date these recommendations as the field progresses The st and ard of care for most patients with non-muscle-invasive bladder cancer ( NMIBC ) is immunotherapy with intravesical Bacillus Calmette-Guérin ( BCG ) , which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit . Urologic best- practice guidelines and consensus reports have been developed and strengthened based on data on the timing , dose , and duration of therapy from r and omized clinical trials , as well as by critical evaluation of criteria for progression . However , these reports have not penetrated the community , and many patients do not receive appropriate therapy . Additionally , several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease . The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of exp and ed use for both advanced and , potentially , localized disease . To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer , the Society for Immunotherapy of Cancer ( SITC ) convened a Task Force of experts , including physicians , patient advocates , and nurses , to address issues related to patient selection , toxicity management , clinical endpoints , as well as the combination and sequencing of therapies . Following the st and ard approach established by the Society for other cancers , a systematic literature review and analysis of data , combined with consensus voting was used to generate guidelines . Here , we provide a consensus statement for the use of immunotherapy in patients with bladder cancer , with plans to up date these recommendations as the field progresses ABSTRACT Patients with EGFR mutations showed unfavorable response to programmed cell death-1 ( PD-1 ) blockade immunotherapy in non-small cell lung cancer ( NSCLC ) . Yet the underlying association between EGFR mutation and immune resistance remains largely unclear . We performed an integrated analysis of PD-lig and 1(PD-L1)/CD8 expression and mutation profile based on the repository data base and resected early-stage NSCLC in Guangdong Lung Cancer Institute ( GLCI ) . Meanwhile , 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression , and the association of EGFR status with response to anti-PD-1/L1 therapy . Pool- analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression ( odds ratio : 1.79 , 95 % CI : 1.10–2.93 ; P = 0.02 ) . Analysis of The Cancer Genome Atlas ( TCGA ) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression . Furthermore , patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8 + TIL ( P = 0.034 ) . Importantly , patients with EGFR mutations , especially the sensitive subtype , showed a significantly decreased mutation burden , based on analysis of the discovery and validation sets . Finally , a pool- analysis of 4 r and omized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors  ( Hazard ratio [ HR ] = 1.09 , P = 0.51 ) while patients with EGFR wild-type did ( HR = 0.73 , P < 0.00001 ) . This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity , which caused an inferior response to PD-1 blockade in NSCLCs BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer ( NSCLC ) who have disease progression during or after first-line chemotherapy have limited treatment options . This r and omized , open-label , international , phase 3 study evaluated the efficacy and safety of nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , as compared with docetaxel in this patient population . METHODS We r and omly assigned 272 patients to receive nivolumab , at a dose of 3 mg per kilogram of body weight every 2 weeks , or docetaxel , at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS The median overall survival was 9.2 months ( 95 % confidence interval [ CI ] , 7.3 to 13.3 ) with nivolumab versus 6.0 months ( 95 % CI , 5.1 to 7.3 ) with docetaxel . The risk of death was 41 % lower with nivolumab than with docetaxel ( hazard ratio , 0.59 ; 95 % CI , 0.44 to 0.79 ; P<0.001 ) . At 1 year , the overall survival rate was 42 % ( 95 % CI , 34 to 50 ) with nivolumab versus 24 % ( 95 % CI , 17 to 31 ) with docetaxel . The response rate was 20 % with nivolumab versus 9 % with docetaxel ( P=0.008 ) . The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel ( hazard ratio for death or disease progression , 0.62 ; 95 % CI , 0.47 to 0.81 ; P<0.001 ) . The expression of the PD-1 lig and ( PD-L1 ) was neither prognostic nor predictive of benefit . Treatment-related adverse events of grade 3 or 4 were reported in 7 % of the patients in the nivolumab group as compared with 55 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced , previously treated squamous-cell NSCLC , overall survival , response rate , and progression-free survival were significantly better with nivolumab than with docetaxel , regardless of PD-L1 expression level . ( Funded by Bristol-Myers Squibb ; CheckMate 017 Clinical Trials.gov number , NCT01642004 . ) Background A high- quality programmed cell-death lig and 1 ( PD-L1 ) diagnostic assay may help predict which patients are more likely to respond to  anti-programmed cell death-1 (PD-1)/PD-L1 antibody-based  cancer therapy . Here we describe a PD-L1 immunohistochemical ( IHC ) staining protocol developed by Ventana Medical Systems Inc. and key analytical parameters of its use in formalin-fixed , paraffin-embedded ( FFPE ) sample s of non-small cell lung cancer ( NSCLC ) and head and neck squamous cell carcinoma ( HNSCC ) . Methods An anti-human PD-L1 rabbit monoclonal antibody ( SP263 ) was optimized for use with the VENTANA OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform . The VENTANA PD-L1 ( SP263 ) Assay was vali date d for use with FFPE NSCLC and HNSCC tissue sample s in a series of studies addressing sensitivity , specificity , robustness , and precision . Sample s from a subset of 181 patients from a Phase 1/2 study of durvalumab ( NCT01693562 ) were analyzed to determine the optimal PD-L1 staining cut-off for enriching the probability of responses to treatment . The scoring algorithm was defined using statistical analysis of clinical response data from this clinical trial and PD-L1 staining parameters in HNSCC and NSCLC tissue . Inter-reader agreement was established by three pathologists who evaluated 81 NSCLC and 100 HNSCC sample s across the range of PD-L1 expression levels . Results The VENTANA PD-L1 ( SP263 ) Assay met all pre-defined acceptance criteria . For both cancer types , a cut-off of 25 % of tumor cells with PD-L1 membrane staining of any intensity best discriminated responders from nonresponders . Sample s with staining above this value were deemed to have high PD-L1 expression , and those with staining below it were deemed to have low or no PD-L1 expression . Inter-reader agreement on PD-L1 status was 97 and 92 % for NSCLC and HNSCC , respectively . Conclusions These results highlight the robustness and reproducibility of the VENTANA PD-L1 ( SP263 ) Assay and support its suitability for use in the evaluation of NSCLC and HNSCC FFPE tumor sample s using the devised ≥25 % tumor cell staining cut-off in a clinical setting . The clinical utility of the PD-L1 diagnostic assay as a predictive biomarker will be further vali date d in ongoing durvalumab studies .Trial registration Clinical Trials.gov : Purpose BIRCH was design ed to examine the efficacy of atezolizumab , a humanized anti-programmed death-lig and 1 ( PD-L1 ) monoclonal antibody , in advanced non-small-cell lung cancer ( NSCLC ) across lines of therapy . Patients were selected on the basis of PD-L1 expression on tumor cells ( TC ) or tumor-infiltrating immune cells ( IC ) . Patients and Methods Eligible patients had advanced-stage NSCLC , no CNS metastases , and zero to two or more lines of prior chemotherapy . Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5 % of TC or IC ( TC2/3 or IC2/3 [ TC or IC ≥ 5 % PD-L1-expressing cells , respectively ] ) were enrolled . Atezolizumab 1,200 mg was administered intravenously every 3 weeks . Efficacy-evaluable patients ( N = 659 ) comprised three cohorts : first line ( cohort 1 ; n = 139 ) ; second line ( cohort 2 ; n = 268 ) ; and third line or higher ( cohort 3 ; n = 252 ) . The primary end point was independent review facility-assessed objective response rate ( ORR ; Response Evaluation Criteria in Solid Tumors [ RECIST ] version 1.1 ) . Secondary end points included median duration of response , progression-free survival , and overall survival ( OS ) . Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls . With a minimum of 12 months of follow-up , the independent review facility-assessed ORR was 18 % to 22 % for the three cohorts , and 26 % to 31 % for the TC3 or IC3 subgroup ; most responses are ongoing . Responses occurred regardless of EGFR or KRAS mutation status . The median OS from an up date d survival analysis ( minimum of 20 month follow up ) for cohort 1 was 23.5 months ( 26.9 months for TC3 or IC3 patients ) ; the median OS in cohorts 2 and 3 was 15.5 and 13.2 months , respectively . The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials . Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC , with good tolerability . PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab PURPOSE Programmed death 1 is an immune checkpoint that suppresses antitumor immunity . Nivolumab , a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody , was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts . We report overall survival ( OS ) , response durability , and long-term safety in patients with non-small-cell lung cancer ( NSCLC ) receiving nivolumab in this trial . PATIENTS AND METHODS Patients ( N = 129 ) with heavily pretreated advanced NSCLC received nivolumab 1 , 3 , or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks . Tumor burden was assessed by RECIST ( version 1.0 ) after each cycle . RESULTS Median OS across doses was 9.9 months ; 1- , 2- , and 3-year OS rates were 42 % , 24 % , and 18 % , respectively , across doses and 56 % , 42 % , and 27 % , respectively , at the 3-mg/kg dose ( n = 37 ) chosen for further clinical development . Among 22 patients ( 17 % ) with objective responses , estimated median response duration was 17.0 months . An additional six patients ( 5 % ) had unconventional immune-pattern responses . Response rates were similar in squamous and nonsquamous NSCLC . Eighteen responding patients discontinued nivolumab for reasons other than progressive disease ; nine ( 50 % ) of those had responses lasting > 9 months after their last dose . Grade 3 to 4 treatment-related adverse events occurred in 14 % of patients . Three treatment-related deaths ( 2 % of patients ) occurred , each associated with pneumonitis . CONCLUSION Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC . R and omized clinical trials with nivolumab in advanced NSCLC are ongoing Purpose : Although clinical studies have shown promise for targeting programmed cell death protein-1 ( PD-1 ) and lig and ( PD-L1 ) signaling in non – small cell lung cancer ( NSCLC ) , the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood . Experimental Design : We performed an integrated analysis on the multiple-dimensional data types including genomic , transcriptomic , proteomic , and clinical data from cohorts of lung adenocarcinoma public ( discovery set ) and internal ( validation set ) data base and immunotherapeutic patients . Gene set enrichment analysis ( GSEA ) was used to determine potentially relevant gene expression signatures between specific subgroups . Results : We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature . More importantly , the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ . Meanwhile , TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high ( TH ) cohort . Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating , DNA replication and damage repair . Finally , immunotherapeutic analysis from public clinical trial and prospect i ve observation in our center were further confirmed that TP53 or KRAS mutation patients , especially those with co-occurring TP53/KRAS mutations , showed remarkable clinical benefit to PD-1 inhibitors . Conclusions : This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti – PD-1/PD-L1 immunotherapy . Clin Cancer Res ; 23(12 ) ; 3012–24 . © 2016 AACR OBJECTIVES Epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs ) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer ( NSCLC ) in clinical trials . However , there is a lack of data from routine clinical practice . This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting . MATERIAL S AND METHODS Clinical characteristics , information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan . In addition to overall survival ( OS ) , subgroup analyses were conducted based on first- and second-line treatments and combinations , and for patients who had survived > 5 years from initiation of first-line treatment . RESULTS The full analysis set comprised 1656 patients ( mean 67 years , 80.6 % with performance status 0 or 1 ) . Median follow-up was 29.5 months and median OS was 29.7 months ; 3- and 5-year survival rates were 41.2 % and 21.5 % , respectively . Significant predictors of OS were younger age , no smoking history , histological diagnosis of adenocarcinoma , less advanced clinical stage , good performance status and major EGFR-activating mutation . Despite some imbalances in baseline characteristics , patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs . CONCLUSIONS This large , long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice . Up date d analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents , including immunotherapies PURPOSE This trial was conducted to determine the optimal duration of chemotherapy in Korean patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with stages IIIB to IV NSCLC who had not progressed after two cycles of chemotherapy were r and omly assigned to receive either four ( arm A ) or two ( arm B ) more cycles of third-generation , platinum-doublet treatment . RESULTS Of the 452 enrolled patients , 314 were r and omly assigned to the groups . One-year survival rates were 59.0 % in arm A and 62.4 % in arm B , and the difference of 3.4 % ( 95 % CI , -8.0 to 4.8 ) met the predefined criteria for noninferiority . The median time to progression ( TTP ) , however , was 6.2 months ( 95 % CI , 5.7 to 6.7 months ) in arm A and 4.6 months ( 95 % CI , 4.4 to 4.8 months ) in arm B , the difference of which is statistically significant ( P = .001 ) . The frequencies of hematologic and nonhematologic toxicities were similar in the two arms . CONCLUSION This study confirms the noninferiority of overall survival with four cycles compared with six cycles of chemotherapy for the first-line treatment of advanced NSCLC and supports the current American Society of Clinical Oncology guidelines . Notably , patients receiving six cycles of chemotherapy compared with four cycles showed a favorable TTP , suggesting that further investigation of the new strategies of maintenance therapy with less toxic agents after three to four cycles of induction chemotherapy might be warranted to improve survival , with consideration of both ethnicity and pharmacogenomic signatures Purpose : This multicenter , phase II study evaluates the efficacy and safety of erlotinib , an epidermal growth factor receptor ( EGFR ) inhibitor , plus sorafenib , a multityrosine kinase inhibitor against vascular endothelial growth factor receptors , in patients with previously untreated advanced non – small cell lung cancer ( NSCLC ) . Experimental Design : Chemotherapy-naïve patients with stage IIIB/IV NSCLC received erlotinib ( 150 mg once a day ) and sorafenib ( 400 mg twice a day ) until disease progression or unacceptable toxicity . The primary end point was the rate of nonprogression at 6 weeks . Secondary end points included objective response rate ( ORR ) , time to progression , overall survival , and adverse events . Exploratory end points included pretreatment EGFR and KRAS mutation status , pharmacokinetics , and cytochrome P450 polymorphisms . Results : Fifty patients initiated therapy . The nonprogression rate at 6 weeks was 74 % : 12 ( 24 % ) partial response and 25 ( 50 % ) stable disease . Ultimately , the ORR was 28 % . Median time to progression was 5.0 months [ 95 % confidence interval ( 95 % CI ) , 3.2 - 6.8 months ] . Median overall survival was 10.9 months ( 95 % CI , 3.8 - 18.1 months ) . Grade 3/4 adverse events included fatigue ( 16 % ) , h and -foot skin reaction ( 16 % ) , rash ( 16 % ) , diarrhea ( 14 % ) , and hypophosphatemia ( 42 % ) . There was one treatment-related fatal pulmonary hemorrhage . Patients with wild-type EGFR had a higher ORR ( 19 % ) than previously reported for single-agent erlotinib/sorafenib . Erlotinib levels were lowered . This was associated with CYP3A4 polymorphism and was possibly due to sorafenib . Conclusion : Despite a possible drug interaction , sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile . Further evaluation of this combination as potential salvage therapy in EGFR mutation – negative patients and the possible drug interaction is warranted . Clin Cancer Res ; 16(11 ) ; 3078–87 . © 2010 AACR
We believe that this attempt enables clinicians to choose appropriate treatment easier .
According to rapid development of chemotherapy in advanced non-small cell lung cancer ( NSCLC ) , the Japan Lung Cancer Society has been up date d its own guideline annually since 2010 .
Recently , we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors .
Thus , the guideline proposes to categorize patients into three entities : ( 1 ) driver oncogene-positive , ( 2 ) PD-L1 ≥ 50 % , and ( 3 ) others .
Here , we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC , stages IV