Non-small Cell Lung Cancer Histology Research Articles

MicroRNA-based biomarkers for diagnosis of non-small cell lung cancer (NSCLC).

BackgroundThe development of biomarkers for the early detection of non‐small cell lung cancer (NSCLC) is clinically important. We have developed miRNA biomarkers in sputum and plasma, respectively, for NSCLC. Herein, we evaluate whether integrated analysis of the miRNAs across the different types of specimens could improve the early detection of NSCLC.MethodsUsing reverse transcription PCR, we determined expressions of two miRNAs (miRs‐31‐5p and 210‐3p) in sputum and three miRNAs (miRs‐21‐5p, 210‐3p, and 486‐5p) in plasma of a training cohort of 76 NSCLC patients and 72 cancer‐free smokers. The results were validated in a testing cohort of 56 NSCLC patients and 55 cancer‐free smokers.ResultsThe panels of two sputum miRNAs and three plasma miRNAs had 65.8–75.0% sensitivities and 83.3–87.5% specificities for diagnosis of NSCLC in the training cohort. The individual sputum or plasma miRNA panel had a higher sensitivity for squamous cell carcinoma or adenocarcinoma of the lung, respectively. From the miRNAs, we optimized an integrated panel of biomarkers consisting of two sputum miRNAs (miRs‐31‐5p and 210‐3p) and one plasma miRNA (miR‐21‐5p) that had higher sensitivity (85.5%) and specificity (91.7%) for diagnosis of NSCLC compared with the individual panels alone. Furthermore, the performance of the integrated panel of biomarkers was independent of histology and stage of NSCLC, and patients' age, sex, and ethnicity. The performance of the integrated panel of biomarkers was confirmed in the testing cohort.ConclusionsIntegrating biomarkers across different body fluids would synergistically improve the early detection of NSCLC.Key points Lung cancer is a heterogeneous disease and develops from complex aberrations.Integrating sputum and plasma miRNAs has higher accuracy than when they are used alone

Adequate tumour cellularity is essential for accurate PD-L1 immunohistochemistry assessment on cytology cell-block specimens.

PD-L1 immunohistochemistry (IHC) is an essential predictive biomarker for patients with non-small cell lung cancer (NSCLC), required to inform treatment decisions regarding anti-PD-1 immune checkpoint inhibitor therapy. This study aims to investigate the concordance between PD-L1 IHC assessed on NSCLC cytology and histology specimens and to determine the impactce of tumour cellularity. Matched cytology and histology NSCLC specimens were retrieved from the archives of the Royal Melbourne Hospital and the Royal Prince Alfred Hospital. PD-L1 IHC was performed concurrently on both specimens at the Peter MacCallum Cancer Centre using the SP263 assay kit on the Ventana Benchmark Ultra staining platform and scored by two experienced pathologists. Overall agreement between matched cytology and histology specimens was good (intraclass correlation coefficient =0.653, n=58); however, markedly increased when the analysis was limited to cell-blocks with >100 tumour cells (intraclass correlation coefficient =0.957, n=29). Specificity at both 1% and 50% cut-offs was high regardless of cellularity; however, sensitivity decreased in samples with <100 tumour cells. PD-L1 IHC on cytology cell-block specimens in NSCLC is an acceptable alternative to histological specimens, provided adequate tumour cells are present. Clinicians and pathologists should be mindful of the risk of false negative PD-L1 IHC in samples with low tumour cellularity, to avoid excluding patients from potentially beneficial treatment.

The impact of histology in the outcomes of patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) and adjuvant chemotherapy

IntroductionStereotactic body radiation therapy (SBRT) is the standard of care treatment for nonsurgical patients with early-stage non-small cell lung cancer (NSCLC). A recent report has indicated an improvement in overall survival (OS) with adjuvant chemotherapy in patients with tumors ≥ 4 cm treated with SBRT. We present a retrospective study evaluating the impact of histology in patients treated with SBRT and adjuvant chemotherapy. Materials and MethodsPatients (≥18 years) diagnosed with clinical stages I-II NSCLC from 2004 to 2013 were identified using the National Cancer Database (n = 12,055). The Kaplan-Meier method was used to estimate overall survival (OS) distributions and the log-rank test was used to compare distributions by treatment strategy. Clinical stages I and II were subdivided according to the TNM staging and log-rank tests was used to compare survival distributions by treatment strategy within each subgroup. We performed subgroup analysis for the three main NSCLC histologies (i.e., adenocarcinoma, squamous cell carcinoma (SCC), and large cell). ResultsIn patients with adenocarcinoma, SCC and, large cell carcinoma; adjuvant chemotherapy was associated with worse OS in tumors < 4 cm (P<.0001, P<.0099, and P=.0082, respectively). In patients with adenocarcinoma and tumor ≥ 4 cm, adjuvant chemotherapy was not associated with improved OS (P=.262); however, in patients with SCC and large cell, adjuvant chemotherapy improved OS (P<.0001, and P=.0129, respectively). ConclusionIn patients with NSCLC ≥ 4 cm treated with SBRT, adjuvant chemotherapy was associated with improved OS in patients with SCC and large cell histologies.

Efficacy of Docetaxel Plus Ramucirumab as Palliative Third-Line Therapy Following Second-Line Immune-Checkpoint-Inhibitor Treatment in Patients With Non-Small-Cell Lung Cancer Stage IV.

Background:Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects with chemotherapy. Effects might be even stronger after immune-checkpoint-inhibitor (ICI) therapy. The purpose of this analysis was to evaluate the efficacy of ramucirumab plus docetaxel (R + D) as third-line treatment after failure of a first-line platinum-based chemotherapy and a second-line ICI treatment in patients with non-small-cell lung cancer (NSCLC) stage IV.Methods:Retrospective data were collected from 9 German thoracic oncology centers. Only patients who had received at least 1 cycle of third-line R + D were included. The numbers of cycles, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated.Results:Sixty-seven patients met the criteria for inclusion. Third-line treatment with R + D achieved an ORR of 36% and a disease control rate (DCR) of 69%. Median PFS for third-line therapy was 6.8 months with a duration of response (DOR) of 10.2 months. A median OS of 29 months was observed from the start of first-line therapy with a median OS of 11.0 months from the start of third-line treatment. No unexpected toxicities occurred.Conclusion:R + D is a highly effective and safe third-line treatment after failure of second-line programmed cell death protein 1/programmed cell death-ligand 1 (PD1/PD-L1)-derived ICI therapy irrespective of NSCLC histology. As there may be synergistic effects of second- and third-line treatments, this sequence is a very suitable option for patients not treated with first-line ICI. In addition, R + D should continue to be investigated as a second-line treatment option after failure of chemotherapy plus ICI in the palliative first–line treatment.

1513P - Atezolizumab in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs)

BackgroundAtezolizumab, an ani-PD-L1 monoclonal antibody, has been used in the treatment of a wide variety of cancers. Recently, atezolizumab has shown significant antitumor activity against non-small cell lung cancer (NSCLC), the majority of lung cancer which is the leading cause of cancer-related mortality in both sexes. The purpose of our study is to consolidate the efficacy of atezolizumab in combination with chemotherapy for first-line treatment of advanced NSCLC. MethodsWe systematically conducted a comprehensive literature search using PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019. RCTs utilizing first-line atezolizumab chemoimmunotherapy in patients with advanced NSCLC were incorporated. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q -statistic. Random effects model was applied. ResultsA total of 2725 patients with advanced NSCLC from four phase III RCTs (IMpower – 130, 131, 132 and 150) were eligible. The study arm used standard chemotherapy regimens in combination with atezolizumab while control arm used only standard chemotherapy regimens. The randomization ratio was 2:1 in IMpower130 study and 1:1 in other studies. IMpower131 study included patients with squamous histology and other studies were employed in patients with non-squamous NSCLC. The pooled HR for PFS was statistically significant at 0.64 (95% CI: 0.59-0.70; P<0.00001) and the pooled HR for OS was 0.83 (95% CI: 0.75- 0.93; P=0.0008). In non-squamous NSCLC histology group, the pooled HR for PFS was noted at 0.62 (95% CI: 0.56-0.69; P<0.00001) and the pooled HR for OS was 0.79 (95% CI: 0.70- 0.90; P=0.0002). ConclusionsOur meta-analysis demonstrated that first-line atezolizumab in combination with chemotherapy significantly improved PFS and OS compared to standard chemotherapy in patients with advanced NSCLC, regardless of the histology. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Effect of sevoflurane-based or propofol-based anaesthesia on the incidence of postoperative acute kidney injury: A retrospective propensity score-matched analysis.

Propofol may help to protect against ischaemic acute kidney injury (AKI); however, research on this topic is sparse. The current study aimed to investigate whether there were differences in the incidence of postoperative AKI after lung resection surgery between patients who received propofol-based total intravenous anaesthesia (TIVA) and those who received sevoflurane-based inhalational anaesthesia. A retrospective observational study. A single tertiary care hospital. Medical records of patients aged 19 years or older who underwent curative lung resection surgery for nonsmall cell lung cancer between January 2005 and February 2018 were examined. After propensity score matching, the incidence of AKI in the first 3 postoperative days was compared between patients who received propofol and those who received sevoflurane. Logistic regression analyses were also used to investigate whether propofol-based TIVA lowered the risk of postoperative AKI. The analysis included 2872 patients (1477 in the sevoflurane group and 1395 in the propofol group). After propensity score matching, 661 patients were included in each group; 24 (3.6%) of the 661 patients in the sevoflurane group developed AKI compared with 23 (3.5%) of the 661 patients in the propofol group (95% confidence intervals of difference in incidence -0.019 to 0.022, P = 0.882). The logistic regression analyses revealed that the incidence of AKI was not different in the two groups (odds ratio 0.96, 95% confidence interval 0.53 to 1.71, P = 0.882). In this retrospective study, no significant difference was found in the incidence of postoperative AKI after lung resection surgery between patients who received propofol-based TIVA and those who received sevoflurane-based inhalational anaesthesia. Considering the methodological limitation of this retrospective study, further studies are required to confirm these results.

Early clinical experience with the pan-FGFR inhibitor rogaratinib in patients with non-small cell lung cancer selected based on FGFR mRNA expression levels.

e20661 Background: FGFR1 gene amplifications are observed in squamous (sq) non-small cell lung cancer (NSCLC) and may suggest tractable oncogenic dependency. However, their value in predicting clinical activity of FGFR inhibitors is unclear. We explored tumor FGFR1-3 mRNA expression levels to select patients (pts) for treatment with rogaratinib, an oral, potent, small-molecule inhibitor of FGFR1-4. The first-in-human study of rogaratinib included pts with all NSCLC histologies. Methods: Pts with refractory advanced NSCLC were screened for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples, and FGFR1-3 overexpression was defined by pre-specified cut-offs. Pts received rogaratinib 800 mg BID on a continuous 21-day cycle. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.1 after cycles 2, 5, and 8. Results: 260 NSCLC biopsies were screened for FGFR1-3 tumor mRNA expression; 244 (93.8%) were evaluable. FGFR1-3 mRNA overexpression was found in 47% of sq NSCLC, and only 14% of non-sq NSCLC, with FGFR3 being the most commonly overexpressed subtype. 40 FGFR mRNA-positive pts were enrolled and treated. Rogaratinib was well tolerated; hyperphosphatemia (75%), diarrhea (53%), and decreased appetite (35%) were the most frequent treatment-emergent adverse events. Events were mostly mild or moderate. 36 treated pts were evaluable for response. The overall response rate was 5.6% (2 partial responses, 1 lasting for &gt; 16 months). Disease control rate was 64%. Disease stabilization was seen in pts with mRNA overexpression across all FGFR subtypes and also in pts who failed prior lines of therapy, including anti-PD-L1. Molecular studies are ongoing to identify additional predictors of response to improve pt selection. Conclusions: Rogaratinib has a favorable safety and tolerability profile and clinical activity in pts with refractory FGFR1-3 tumor mRNA-positive NSCLC. It has potential for further exploration in combination with other agents. A clinical trial is currently enrolling FGFR mRNA-overexpressing pts with advanced and pre-treated sq NSCLC. Clinical trial information: NCT03762122.

Multi-subtype classification model for non-small cell lung cancer based on radiomics: SLS model.

Histological subtypes of non-small cell lung cancer (NSCLC) are crucial for systematic treatment decisions. However, the current studies which used noninvasive radiomic methods to classify NSCLC histology subtypes mainly focused on two main subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC), while multi-subtype classifications that included the other two subtypes of NSCLC: large cell carcinoma (LCC) and not otherwise specified (NOS), were very few in the previous studies. The aim of this work was to establish a multi-subtype classification model for the four main subtypes of NSCLC and improve the classification performance and generalization ability compared with previous studies. In this work, we extracted 1029 features from regions of interest in computed tomography (CT) images of 349 patients from two different datasets using radiomic methods. Based on "three-in-one" concept, we proposed a model called SLS wrapping three algorithms, synthetic minority oversampling technique, ℓ2,1-norm minimization, and support vector machines, into one hybrid technique to classify the four main subtypes of NSCLC: SCC, ADC, LCC, and NOS, which could cover the whole range of NSCLC. We analyzed the 247 features obtained by dimension reduction, and found that the extracted features from three methods: first order statistics, gray level co-occurrence matrix, and gray level size zone matrix, were more conducive to the classification of NSCLC subtypes. The proposed SLS model achieved an average classification accuracy of 0.89 on the training set (95% confidence interval [CI]: 0.846 to 0.912) and a classification accuracy of 0.86 on the test set (95% CI: 0.779 to 0.941). The experiment results showed that the subtypes of NSCLC could be well classified by radiomic method. Our SLS model can accurately classify and diagnose the four subtypes of NSCLC based on CT images, and thus it has the potential to be used in the clinical practice to provide valuable information for lung cancer treatment and further promote the personalized medicine.

A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer

Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11–199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

Standardization of imaging features for radiomics analysis

Radiomics has the potential to provide tumor characteristics with noninvasive and repeatable way. The purpose of this paper is to evaluate the standardization effect of imaging features for radiomics analysis. For this purpose, we prepared two CT databases ; one includes 40 non-small cell lung cancer (NSCLC) patients for whom tumor biopsies was performed before stereotactic body radiation therapy in The University of Tokyo Hospital, and the other includes 29 early-stage NSCLC datasets from the Cancer Imaging Archive. The former was used as the training data, whereas the later was used as the test data in the evaluation of the prediction model. In total, 476 imaging features were extracted from each data. Then, both training and test data were standardized as the min-max normalization, the z-score normalization, and the whitening from the principle component analysis. All of standardization strategies improved the accuracy for the histology prediction. The area under the receiver observed characteristics curve was 0.725, 0.789, and 0.785 in above standardizations, respectively. Radiomics analysis has shown that robust features have a high prognostic power in predicting early-stage NSCLC histology subtypes. The performance was able to be improved by standardizing the data in the feature space. J. Med. Invest. 66 : 35-37, February, 2019.

The present and future burden of previously treated advanced non-small cell lung cancer (NSCLC) by histology and line of therapy in France, Germany, Italy, and Spain: model-based predictions

BackgroundThe burden of advanced non-small cell lung cancer (NSCLC) is not well understood, and the number of patients likely to receive treatment in Europe has not been quantified. The aim of this study was to forecast the annual number of patients with squamous and non-squamous advanced NSCLC likely to receive second and third lines of therapy (LOT) from 2016 to 2020 in France, Germany, Italy, and Spain.MethodsA patient count model (PCM) was developed in Microsoft Excel to estimate the number of patients with refractory advanced NSCLC eligible to receive systemic treatment. Using historical population-based cancer registry data, segmented linear regression (“Joinpoint”) was used to forecast age- and sex-stratified lung cancer incidence rates in each country through 2020. Yearly incident case count totals by country were apportioned according to NSCLC histology and stage at diagnosis. Country-specific treatment rates came from a recent medical chart review study, and early- to advanced-stage disease progression rates were estimated over a 10-year interval. A probabilistic sensitivity analysis (PSA) was performed to estimate variability in the patient counts.ResultsThe combined number of squamous and non-squamous advanced NSCLC patients estimated to receive second and third LOT, respectively, in 2016 were France = 11,600 and 3500; Germany = 15,100 and 4900; Italy = 13,500 and 2500; Spain = 9400 and 2100. The forecasted numbers of patients receiving second and third LOT, respectively, in 2020 were France = 13,900 and 4200; Germany = 16,200 and 5200; Italy = 15,100 and 2600; Spain = 11,000 and 2500.ConclusionsDriven by growth in the incidence of NSCLC among women, the model forecasts an overall increase in the number of patients with advanced-stage squamous and non-squamous NSCLC likely to receive systemic treatment in the year 2020. The results highlight the significant burden of refractory advanced NSCLC and the need for more robust surveillance data to accurately quantify the burden of disease.

Evolving National Practice Patterns of Hypofractionated Stereotactic Radiation Therapy Versus Single-Fraction Radiosurgery for Brain Metastases

Single-fraction stereotactic radiosurgery (SF-SRS) has been increasingly utilized in the treatment of patients with brain metastases, but the national uptake of hypofractionated stereotactic radiotherapy (HF-SRT) is unknown. We sought to characterize the evolution of practice patterns of HF-SRT in relation to SF-SRS in the United States over the past decade. The National Cancer Database was used to identify patients with breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, and prostate cancer diagnosed in 2004-2014 who underwent either SF-SRS or HF-SRT to the brain. SF-SRS was defined as radiotherapy dose ≥15 Gy in 1 fraction, while HF-SRT was defined as radiotherapy dose ≥21 Gy in 3 fractions, ≥24 Gy in 4 fractions, or ≥25 Gy in 5 fractions. Chi-square analyses and multivariable logistic regression were used to investigate temporal, sociodemographic, and clinicopathologic predictors of HF-SRT receipt. Our cohort included 7,068 patients, among whom 5,243 (74%) received SF-SRS and 1,825 (26%) received HF-SRT. Median age was 63 years, and 51% of patients were female. The most common histology was NSCLC (87.2%). The proportion of patients receiving HF-SRT increased steadily from 20.3% in 2004 to 30.3% in 2014 (P<.001). Patients who received surgery at a distant site from the primary were more likely to undergo HF-SRT (35.3% versus 22.5%, P<.001). On multivariable analysis, predictors of increased utilization of HF-SRT included treatment year 2010-2014 versus 2004-2009 (odds ratio [OR] 1.14), colorectal versus NSCLC histology (OR 2.13), breast versus NSCLC histology (OR 1.72), surgery versus no surgery at distant site (OR 1.93), omission versus receipt of upfront chemotherapy (OR 1.49), and non-Northeast versus Northeast location (OR 1.39) (P<.05 for each). This analysis demonstrates steadily rising utilization of HF-SRT in the treatment of brain metastases nationally over the past decade. Adoption of HF-SRT also varied widely by histology, receipt of surgery or chemotherapy, and geographic location. Given the increased utilization of HF-SRT, further study is needed to investigate the underlying explanations for these differences and their impact on local control, distant intracranial control, and toxicity outcomes.

19P Single sample predictor of non-small cell lung cancer histology based on gene expression analysis of archival tissue

19P Single sample predictor of non-small cell lung cancer histology based on gene expression analysis of archival tissue

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study

Immune checkpoint inhibitors are a new standard 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. 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 ClinicalTrials.gov, number NCT02087423. 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 standard treatment guidelines. 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. AstraZeneca.

Classification of early stage non-small cell lung cancers on computed tomographic images into histological types using radiomic features: interobserver delineation variability analysis.

Radiomics, which involves the extraction of large numbers of quantitative features from medical images, has attracted attention in cancer research. In radiomics analysis, tumor segmentation is a crucial step. In this study, we evaluated the potential application of radiomics for predicting the histology of early stage non-small cell lung cancer (NSCLC) by analyzing interobserver variability in tumor delineation. Forty patient datasets were included in this study, 21 involving adenocarcinomas and 19 involving squamous cell carcinomas. All patients underwent stereotactic body radiotherapy treatment. In total, 476 features were extracted from each dataset, representing treatment planning, computed tomography images, and gross tumor volume (GTV). The definition of GTV can significantly affect the histology prediction. Therefore, in the present study, the effect of interobserver tumor delineation variability on radiomic features was evaluated by preparing 4 volumes of interest (VOIs) for each patient, as follows: the original GTV (which was delineated at treatment planning); two GTVs delineated retrospectively by radiation oncologists; and a semi-automatic GTV contoured by a medical physicist. Radiomic features extracted from each VOI were then analyzed using a naïve Bayesian model. Area-under-the-curve (AUC) analysis showed that interobserver variability in delineation is a significant factor in radiomics performance. Nevertheless, with 8 selected features, AUC values averaged over the VOIs were high (0.725±0.070). The present study indicated that radiomics has potential for predicting early stage NSCLC histology despite variability in delineation. The high prediction accuracy implies that noninvasive histology evaluation by radiomics is a promising clinical application.

Complete resection of the primary lesion improves survival of certain patients with stage IV non-small cell lung cancer.

The standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) is systemic chemotherapy. However, certain patients, such as those with oligometastasis or M1a disease undergo resection of the primary lesion. We conducted a retrospective review of the records of 1,471 consecutive patients with NSCLC who underwent resection of the primary lesion for between June 2005 and May 2016. The present study included 38 patients with stage IV NSCLC who underwent complete resection of the primary lesion as first-line treatment. The median follow-up duration for the 38 patients (27 men) was 17.7 months (range, 1-82.3 months). The T factors were T1/T2/T3/T4 in 4/16/12/6 patients, respectively. The N factors were N0/N1/N2/N3 in 16/8/12/2 patients, respectively. The M factors were M1a/M1b/M1c in 19/13/6 patients, respectively. Of the 19 M1a patients, 11 were classified as cM0. We introduced the novel classification M-better/M-worse. M-better includes cM0 patients and M1b and M1c patients in whom all lesions have been locally controlled. M-worse includes cM1a patients and M1b and M1c patients in whom lesions cannot be locally controlled. The new M-better/M-worse statuses were 24/14 patients, respectively. The histology of NSCLC was adenocarcinoma/squamous cell carcinoma/others in 30/5/3 patients, respectively. The 5-year overall survival rate was 29%, and the median survival time was 725 days. Squamous cell carcinoma and M-worse were significant factors predicting poor outcomes (P=0.0017, P=0.0007, respectively). Even for stage IV NSCLC patients, resection of the primary lesion may be beneficial, especially for those with M-better status and those not diagnosed with squamous-cell carcinoma (SCC).

A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non–small cell lung cancer

AimThe phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non–small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC. Patients and methodsA 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1–14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination. ResultsAll 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a ‘14 days on, 7 days off’ schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients. ConclusionCombining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.

Incidence of Non-Small-Cell Lung Cancer And Burden of Egfr Mutations: A 10-Year Global Forecast

To estimate the incidence of Non-Small Cell Lung Cancer (NSCLC) globally between 2016 and 2026 and the estimated prevalence of EGFR mutations in this population. Oncogenic mutations have attracted more attention as carriers are eligible for targetted treatments and disease outcome can be modified based on the presence of specific mutations. To estimate the incidence of NSCLC we analyzed country-specific cancer registries for lung cancer (C34) and NSCLC histology data (IARC, 2013). We reviewed the peer-reviewed literature for population-based studies estimating the prevalence of EGFR mutations in patients diagnosed with NSCLC. The ten-year forecast for incidence incorporated risk factors such as economic development, smoking, screening and demographic changes related to aging and population growth. When country-specific data were unavailable, a risk-factor and GDP-based model was used to extrapolate data from a proxy country. The prevalence of EGFR mutation was assumed to be constant over the forecast period. In 2016, the incidence of NSCLC varied widely, ranging from 3 to 57 per 100,000 in Africa and North America respectively, with approximately 2 million cases diagnosed globally. Over the next ten years, we expect approximately 25% increase in incident NSCLC cases worldwide. Africa and low-income Asia Pacific countries are expected to grow around 40% due to demographic change and other risk factors. The prevalence of EGFR mutation ranged from 19-41%, with approximately 668 thousand NSCLC patients with EGFR mutations worldwide, in 2016. The incidence of NSCLC will continue to increase over the next ten years due to an increase in risk factors, population growth, and aging. Further analyses estimating the increase in NSCLC incidence that is attributable to modifiable risk factors and assessing the prevalence of other oncogenic mutations with targeted-therapy potential is indicated.

Real-world practice patterns for patients with advanced non-small cell lung cancer: multicenter retrospective cohort study in Japan.

BackgroundRecommended therapies for advanced/metastatic non-small cell lung cancer (NSCLC) have changed with the advent of targeted therapies. The objectives of this retrospective chart review study were to describe treatment patterns, biomarker testing practices, and health care resource use for advanced NSCLC at 5 sites in Japan.Patients and methodsWe studied anonymized medical record data of patients aged ≥18 years who initiated systemic therapy for newly diagnosed stage IIIB or IV NSCLC from January 2011 through June 2013. Data were analyzed descriptively by histology and mutation status. Overall survival was estimated using the Kaplan–Meier method.ResultsWe studied 175 patients, including 43 (25%), 129 (74%), and 3 (2%) with squamous, nonsquamous, and unknown NSCLC histology, respectively; 83% had stage IV NSCLC. Overall, 123 patients (70%) were male; the median age was 70 years (range, 47–86); and 33 (19%) were never-smokers. In the nonsquamous cohort, 105 (81%) and 25 (19%) of patients were tested for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, respectively; 44 (42%) had EGFR-positive NSCLC and 2 (8%) had ALK-positive NSCLC, including 26/46 (57%) women and 21/46 (46%) never-smokers. In the squamous cohort, 17 (40%) and 4 (9%), respectively, were tested; 1 EGFR-positive tumor was detected. After first-line therapy, 105 (60%) patients received second-line, and 54/105 (51%; or 31% overall) received third-line therapy. EGFR tyrosine kinase inhibitors were most commonly prescribed for EGFR-positive NSCLC across all lines. In the nonsquamous EGFR/ALK-negative/unknown cohort, most received first-line platinum combinations, particularly younger patients (78% ≥75 years vs 93% <75 years old). The average hospitalization was 21 days/admission. The median (95% CI) overall survival from start of first-line therapy was 9.9 months (7.6–11.7) for all patients and 17.9 months (9.9–24.4) for patients with EGFR/ALK-positive status.ConclusionBiomarker testing is common for nonsquamous NSCLC at the 5 Japanese study sites. Treatment is personalized by mutation status and age, per guideline recommendations.

Angiogenesis Inhibitors in NSCLC.

Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL) that demonstrated an improvement of about two months in progression-free survival (PFS) in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS) also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib) produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857, p = 0.0235). In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019), and improved OS (12.6 versus 10.3 months) in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.