Non-squamous Non-small Cell Lung Carcinoma Research Articles

Phase 3 study of platinum-based chemotherapy with or without pembrolizumab for first-line metastatic, nonsquamous non-small cell lung carcinoma (NSCLC): KEYNOTE-189.

TPS9104Background: Platinum-based chemotherapy is the standard of care for treatment-naive NSCLC patients without an activating EGFR mutation or ALK gene rearrangement. Preliminary data from the phase 1/2 KEYNOTE-021 (NCT02039674) study suggest manageable toxicity and encouraging efficacy of platinum-doublet chemotherapy plus pembrolizumab, an anti–PD-1 monoclonal antibody, in treatment-naive NSCLC. KEYNOTE-189 (NCT02578680) is a randomized, double-blind, phase 3 study to compare the efficacy and safety of platinum-doublet chemotherapy with/without pembrolizumab as first-line treatment in nonsquamous NSCLC. Methods: Patients ≥ 18 years with advanced nonsquamous NSCLC in whom EGFR- or ALK-directed therapy is not indicated, ECOG PS 0-1, and no prior systemic chemotherapy are eligible. Approximately 570 patients will be randomly assigned (2:1) to pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5 Q3W for 4 cycles followed by pembrolizumab 200 mg plus pemetrexed 500 mg/...

EGFR mutation status in Middle Eastern patients with non-squamous non-small cell lung carcinoma: A single institution experience

BackgroundEpidermal growth factor receptor (EGFR) represents an important molecular target in the treatment of lung adenocarcinomas; many anti-EGFR therapies are approved as first line and second-line treatment in patients having metastatic lung adenocarcinomas. The occurrence of this mutation varies in terms of race; it is around 10% in Caucasians and can reach 30% in Asians. Its prevalence in our Middle Eastern region is not well known. MethodsPatients diagnosed with non-squamous non-small cell lung carcinomas between March 2013 and March 2015 were included. This study was conducted at Hôtel-Dieu de France University Hospital, a tertiary medical center in Lebanon. EFGR mutations were analyzed using real time PCR technique on the Rotor-Gene Q using Scorpions and ARMS technologies. The following data was collected: the patients’ characteristics (age, gender, smoking status, stage), the samples’ characteristics (histology subtype, TTF-1 and Napsin A immunostainings, the site and the adequacy and the type of the sample), and the mutational EGFR status (presence and type of mutation). These variables were analyzed using SPSS 20. Results201 patients were included. The mean age was 65.2 years [31–87]; 40.2% were females. 78.1% of the included patients were smokers or ex-smokers. 12.9% of patients had a localized disease, 17.4% a locally advanced disease and 69.7% a metastatic disease. Adenocarcinoma was the main histologic subtype found in 90.5% of patients, followed by large cell carcinoma (3.5%), adenosquamous carcinoma (3.0%) and non-small cell carcinoma not otherwise specified (3.0%). 11.9% of patients had an EGFR mutation: 48% of them presented a deletion on exon 19, 40.0% a L858R mutation on exon 21, 4.0% a G719X mutation in exon 18, 4.0% an insertion in exon 20, and 4% a T790M mutation in exon 20. The presence of an EGFR mutation was significantly associated with the female gender (two-third) (p<0.05) and the non-smoking status (two-third) (p<0.05). ConclusionsThe prevalence of EGFR mutation (11.9%) detected in our Lebanese population is similar to that observed in the Caucasian population. This mutation is also significantly more frequent in females and non-smokers.

Reliability and validity of the Cancer Therapy Satisfaction Questionnaire in lung cancer.

PurposeTo test the reliability and validity of the Cancer Treatment Satisfaction Questionnaire (CTSQ), to assess its relation with quality of life (QoL), and to assess the interpretability of the domain scores in lung cancer patients receiving intravenous chemotherapy.MethodsPatients with stage IIIB and IV non-squamous non-small cell lung carcinoma treated with pemetrexed were enrolled in our study. They completed the 16-item CTSQ and two other (health-related) QoL questionnaires. Information about sociodemographic characteristics, cancer stage, and the experience of adverse events was collected. Internal consistency, construct validity, and clinical interpretability were calculated.ResultsFifty-five patients completed the CTSQ. Correlations of the CTSQ items with its domain were all above 0.40. A high correlation between item 8 and the expectations of therapy and satisfaction with therapy domain was observed (0.50 and 0.48, respectively). The CTSQ domains demonstrated good internal consistency and low to moderate correlations of the CTSQ with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and World Health Organization Quality of Life-BREF. No significant differences in mean domain scores were observed in relation to the number and severity of different adverse events and chemotherapy-related adverse events.ConclusionsThe Dutch version of the CTSQ was found to be a reliable and valid instrument to assess satisfaction and expectations of treatment in lung cancer patients receiving intravenous chemotherapy. Furthermore, the CTSQ proved to be of additional informative value as not all of its domains correlated with the various domains of the existing HRQoL instruments.

Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption.

GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC.

Molecular testing in lung cancer in the era of precision medicine.

The clinical expectations how pathologists should submit lung cancer diagnosis have changed dramatically. Until mid 90-ties a clear separation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) was mostly sufficient. With the invention of antiangiogenic treatment a differentiation between squamous and non-squamous NSCLC was requested. When epidermal growth factor receptor (EGFR) mutation was detected in patients with pulmonary adenocarcinomas and subsequent specific treatment with tyrosine kinase inhibitors (TKIs) was invented, sub-classification of NSCLC and molecular analysis of the tumor tissue for mutations was asked for. Pathologists no longer submit just a diagnosis, but instead are involved in a multidisciplinary team for lung cancer patient management. After EGFR several other driver genes such as echinoderm microtubule associated protein like 4-AL-Kinase 1 (EML4-ALK1), c-ros oncogene 1, receptor tyrosine kinase (ROS1), discoidin domain receptor tyrosine kinase 2 (DDR2), fibroblast growth factor receptor 1 (FGFR1) were discovered, and more to come. Due to new developments in bronchology (EUS, EBUS) the amount of tissue submitted for diagnosis and molecular analysis is decreasing, however, the genes to be analyzed are increasing. Many of these driver gene aberrations are inversions or translocations and thus require FISH analysis. Each of these analyses requires a certain amount of tumor cells or one to two tissue sections from an already limited amount of tissues or cells. In this respect new genetic test systems have been introduced such as next generation sequencing, which enables not only to detect multiple mutations in different genes, but also amplifications and fusion genes. As soon as these methods have been validated for routine molecular analysis this will enable the analysis of multiple genetic changes simultaneously. In this review we will focus on genetic aberrations in NSCLC, resistance to new target therapies, and also to methodological requirements for a meaningful evaluation of lung cancer tissue and cells.

EGFR mutational genotyping of liquid based cytology samples obtained via fine needle aspiration (FNA) at endobronchial ultrasound of non-small cell lung cancer (NSCLC)

ObjectivesEpidermal growth factor receptor (EGFR) gene mutation status should be determined in all patients with advanced, non-squamous non-small cell lung carcinoma (NSCLC) to guide targeted therapy with EGFR tyrosine kinase inhibitors. EGFR mutations are commonly tested by Sanger sequencing or allele specific polymerase chain reaction (ASPCR) on formalin-fixed paraffin-embedded (FFPE) samples including cell blocks (CB) that may fail due to absence of tumor cells. The cell pellet from cytology specimens obtained at the time of endobronchial guided ultrasound fine needle aspiration (EBUS FNA) (EBUS-TBNA, transbronchial needle aspiration) represents an alternative resource for additional tissue. Here we demonstrate the utility of using the FNA cell pellet versus for the detection of EGFR mutations in NSCLC. Materials and methodsFor internal validation, 39 cytology samples from patients with NSCLC referred for EGFR testing were analyzed using the EGFR rotor-gene Q (RGQ) PCR assay (Qiagen).Thereafter, a consecutive series of 228 EBUS FNA samples were tested. ResultsThe ASPCR assay demonstrated acceptable intra-assay, inter-assay and inter-lot reproducibility, sensitivity, and specificity. For the consecutive series, only 6/228 (2.6%) failed analysis (5 due to insufficient DNA yield). Of 228 EBUS FNA cell pellets tested 32 (14.0%) demonstrated clinically relevant mutations. Results and conclusionASPCR can reliably detect EGFR gene mutations in FNA preparations from patients with NSCLC obtained at EBUS.

Quantification of circulating endothelial cells as a predictor of response to chemotherapy with platinum and pemetrexed in patients with advanced non-squamous non-small cell lung carcinoma.

Circulating endothelial cells (CEC) play an important role in tumor neovascularization and may have prognostic value in cancer patients. This study was designed to investigate the role of CEC as a marker for predicting platinum plus pemetrexed first-line chemotherapy efficacy in advanced non-squamous non-small cell lung cancer (NSCLC). A prospective study was performed whose main objective was to study whether the numbers of CEC at baseline and prior to the second and third cycle of chemotherapy were response predictors. Sixty-nine patients received cisplatin plus pemetrexed, and peripheral blood samples were performed at baseline and after second and third cycle. Separation and CEC count were performed using inmunomagnetic separation (CellSearch). The CEC count in 4 mL of peripheral blood was obtained prior to the first, second, and third cycle of treatment. Baseline levels and evolution of CEC were correlated with response to treatment according to RECIST criteria after three cycles of treatment. Sixty-nine patients were included: 43 (64.2 %) received cisplatin/pemetrexed and 24 (35.8 %) carboplatin/pemetrexed. Range of baseline CEC: 8-965 (mean of 153 cel/4 mL). The results after 3 cycles were: 25 partial responses (36.2 %), 17 cases of stabilization of disease (24.6 %), 16 of progressive disease (23.2 %) and 11 non-evaluables (16 %). No significant relationship between the baseline CEC count and response was found (p value = 0.831). Increase >50 % between the first and second cycle was correlated significantly with progression disease (p = 0.008). Patients who had a baseline CEC count greater than the mean (>153 cells/4 mL) showed longer progression-free survival and global survival without statistical significance. In this homogeneous group of patients with NSCLC, there is no correlation between response to treatment and CEC baseline levels. The increase in CEC numbers after the first cycle could be a negative predictive factor.

Effect of reflex testing by pathologists on molecular testing rates in lung cancer patients: Experience from a community-based academic center.

8098 Background: IASLC/CAP and NCCN guidelines recommend molecular testing for non-squamous non-small cell lung carcinoma (NSCLC) patients. Testing is usually performed upon request by medical onco...

1327 - A Phase II Trial of Cisplatin-Docetaxel-Bevacizmab Induction Chemotherapy Followed by Bevacizmab and Pemetrexed Maintenance Therapy in Patients with Nonsquamous Cell Lung Carcinoma: Okayama Lung Cancer Study Group Trial 0903

ABSTRACT Background Addition of bevacizmab (BEV) to platinum-based doublet yields a significant but only modest survival advantage. Recently, in the PARAMOUNT trial pemetrexed (PEM) maintenance therapy produced a high magnitude of PFS improvement. The OLCSG 0903 phase 2 trial investigated efficacy and safety of cisplatin (CDDP)-docetaxel (DOC)-BEV induction therapy followed by BEV-PEM maintenance therapy in patients with advanced nonsquamous non-small cell lung carcinoma. Methods In this trial, 40 patients with good PS (0 or 1) participated in the induction phase, specified as four cycles of induction CDDP (80 mg/m2), DOC (60 mg/m2) and BEV (15 mg/kg) on day 1 of a 21-day cycle. Patients who had not progressed during CDDP-DOC-BEV induction received maintenance BEV (15 mg/kg) and PEM (500 mg/m2) on day 1 of a 21-day cycle until disease progression. The primary endpoint was PFS, and the secondary endpoints included toxicity, OS and response rate. Results Patient characteristics were as follows: median age: 62 years; 78% male; 100% Japanese; 30% PS 0; 73% stage IV; and 70% adenocarcinoma. At the time of this analysis, 23pts (58%) discontinued the treatment, and the proportion of discontinuations to AEs was 35% (8/23). The principal toxicity was myelosuppression (grade 4 hematological: 20 patients [50%]), and grade 3/4 febrile neutropenia was observed in 10 (25%) despite no treatment-related deaths. The objective response rate and disease control rate (% patients with CR/PR/SD) was 82.5% and 97.5%, respectively. The median PFS time was 10.2 months, and the 6-month PFS rate was 63.2% (95% confidence interval: 44.9-76.9 %). Conclusions CDDP-DOC-BEV followed by BEV-PEM maintenance seems an effective and moderately tolerated treatment for patients with advanced nonsquamous non-small cell lung carcinoma. Disclosure K. Hotta: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd Nippon Kayaku. N. Takigawa: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd. K. Kiura: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd Nippon Kayaku. All other authors have declared no conflicts of interest.

Quantification of circulating endothelilial cells (CECs) as a predictor of response to chemotherapy with platinum and pemetrexed in patients with nonsquamous non-small cell lung carcinoma.

e18053 Background: CECs play an important role in tumor neovascularisation and may have prognostic value in cancer patients (pts). The objective of this study is to assess the quantification of CECs as a predictor of response to chemotherapy (CT) in non-squamous NSCLC. Methods: 10ml of blood was obtained prior to the first, second and third cycle of CT in pts treated with platinum plus Pemetrexed. The quantification of CECs was undertaken using CellSearch technology in a central laboratory. The basal levels and the evolution of CECs was correlated with response to treatment according to RECIST criteria after 3 cycles of CT using analysis of variance (ANOVA). Results: Between July 2010 and June 2011 67 pts were included: 43 pts (64.2%) received CDDP/PEM and 24 (35.8%) received CBDCA/PEM. Median age: 60 years (range 40-82), 46 male (68,7%). Nine (13,4%) PS 0; 46 (68,7%) PS 1; 11 (16,4%) PS 2; 1 (1,5%) PS 3. Range of basal CECs: 8 - 1171 cel (median of 85 cel). CECs prior to cycle 2: median of 100 cel (range: 10-1388). CECs prior to ciclo 3: median of 94,5 cel (range: 5-1857). Response after 3 cycles was: 25 PR (36%), 17 SD (25%) and 16 PD (23%) and 11 NE (16%). In the analysis of variance, no significant relationship between the basal CEC count and response was found (p-value=0,831). Decrease &gt;50% between the 1st and 2nd cycle is correlated significantly with progression disease (p=0.026). Conclusions: In this homogeneous group of patients with NSCLC there is no correlation between response to treatment and basal levels of CECs. The decrease in CEC numbers after the first cycle could be a negative predictive factor. The correlation between the variations of CECs with PFS and OS will be presented during the conference.

Whole-genome gene expression in nonsquamous non-small cell lung carcinoma

Whole-genome gene expression in nonsquamous non-small cell lung carcinoma

Population-based pan-Canadian EGFR-mutation testing program.

e18017 Background: Gefitinib was licensed in Canada for the first line treatment of advanced non-small cell lung carcinoma (NSCLC) patients with EGFR tyrosine kinase mutation. Methods: A Pan-Canadian EGFR mutation testing program was established to enable the routine testing of patients who might be eligible for first line gefitinib therapy. Five regional clinical diagnostic centres across Canada were selected for this pilot testing network. Initial efforts included the standardization of testing protocols, selection of assay platforms and evaluation/confirmation of individual laboratory’s assay performance. Testing requests were initiated by the treating oncologists for patients with non-squamous NSCLC histology. In a majority of cases, archival samples resided in the primary care hospitals and required submission to their designated regional test centres. Only Exon-19 deletions and the exon-21 L858R mutation were evaluated, and tests were conducted on archival paraffin embedded tumor samples, which could include cytology cell blocks. Results: From March 18 to November 30, 2010, a total of 1869 requests for mutation testing were made. A total of 1716 samples were received by the test centres. Following pre-test histological evaluation of the submitted samples, mutation testing was conducted on 1588 (92.5%) samples. Altogether 279 (17.6%) were found positive for EGFR exon-19 deletion or exon 21 L858R mutation. The median time for the receipt of samples by the test centres was 7 days, and for test centres to complete and report the result was 11 days. Information on the characteristics of test samples in relation to test outcomes will be presented. Conclusions: Canadian population wide EGFR mutation testing in advanced NSCLC patients is feasible and identified 17.6% patients with EGFR sensitizing mutation-positive tumors. The EGFR mutation testing program is supported by AstraZeneca Canada.

MicroRNA-based assay for differential diagnosis of squamous from non-squamous non-small cell lung carcinoma

11069 Background: Recent advances in biologically directed therapies for non-small cell lung carcinoma (NSCLC) emphasize the need for more accurate sub-classification of NSCLC, as treatment may be dictated by histologic subtype. In particular, squamous histology can be a counter-indication for treatment by VEGF inhibitors. MicroRNAs are highly tissue-specific biomarkers with potential clinical applicability for defining cancer type and origin. MicroRNAs are well preserved in formalin fixed tissue, making them ideal candidates for molecular markers for use in routinely processed material. Here we report on the development and performance of a microRNA-based assay for the differential diagnosis of squamous from non-squamous NSCLC. Methods: We developed protocols for extraction of high-quality RNA that retain the microRNA fraction from FFPE archival tissue samples. MicroRNA microarrays were used to profile more than a hundred NSCLC samples. Specific microRNA qRT-PCR was used to validate results, and to develop a diagnostic assay. Results: We identified a microRNA biomarker that is strongly overexpressed in squamous cell NSCLC. A diagnostic assay (miRview squamous) was developed, that utilizes qRT-PCR measurement of this microRNA, normalized by an additional microRNA and a small nuclear RNA. This assay was validated on a blinded test set of 64 tumor samples, and had sensitivity of 97% and specificity of 91%. More than ¾ of the samples were classified with high confidence, and these classifications were accurate in 96% of the cases. Conclusions: MicroRNAs are becoming an important tool for classification of cancers. A diagnostic assay based on the specificity of a single microRNA accurately identifies squamous from non-squamous NSCLC. This assay provides an important new tool for the classification of NSCLC. [Table: see text]

Risk factors for brain metastases after definitive chemoradiation for locally advanced non-small cell lung cancer

As therapy for locally advanced nonsmall cell lung carcinoma (NSCLC) improves, brain metastases (BM) still remain a great problem. The aim of the study was to analyze risk factors for BM in patients with locally advanced NSCLC after chemoradiation therapy. Records for 150 patients with non-resectable stage IIIA/IIIB NSCLC treated with combined chemoradiation therapy were analyzed. All of them had negative brain metastases imaging result before the treatment. Incidence of BM was examined in relation to age, sex, histological type, stage, performance status scale of wellbeing of cancer patients, weight loss, chemotherapy regimen and chemotherapy timing. One- and 2-year incidence rates of BM were 19 and 31%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (p < 0.004) vs. stage IIIA. Histologically, the patients with nonsquamous tumors had an exceptionally high 2-year BM risk rate of 32% (p < 0.02). Examining treatment-related parameters, 1-year and 2-year actuarial risk of BM were 27 and 39%, respectively, in the patients receiving chemotherapy before radiotherapy and 15 and 20%, respectively, when radiotherapy was not delayed (p < 0.03). On multivariate analysis, timing of chemotherapy (p < 0.05) and stage IIIA vs. IIIB (p < 0.01) remained statistically significant. Patients with IIIB stage, nonsquamous NSCLC, particularly those receiving sequential chemotherapy, had significantly high BM rates.

Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma.

As therapy for locally advanced non-small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site. Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing. Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P <.04) versus stage II/IIIA. Histology alone was not significant (P <.12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P <.01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P <.05). On multivariate analysis, timing of chemotherapy (P <.01) and stage IIIA versus IIIB (P <.01) remained significant. Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.