bluuebunny/crossref_metadata_2025 huggingface dataset:
Vorinostat (V) intratumoral levels and biomarker response in a window of opportunity trial in patients with resectable aerodigestive tract cancer.
Authors: Dragnev Konstantin H. , Beumer Jan Hendrik , Anyang Bean , Ma Tian , Galimberti Fabrizio , Erkmen Cherie Parungo , Nugent William , Rigas James R. , Abraham Kathryn , Johnstone David , Memoli Vincent , Dmitrovsky Ethan
Published: March 2020

7022

Background: Aerodigestive tract cancer (ADT) is the leading cause of cancer-related death in the US. New effective treatments are needed. Among a panel of drugs causing growth inhibition of lung cancer cells and repression of cyclin D1, the histone deacetylase inhibitor V was found most potent. To translate studies into the clinic, a window of opportunity trial of V was conducted. Methods: Pts with resectable ADT received 400 mg V once daily orally for 7 days prior to surgical resection. Serum samples were obtained before the last V dose and at the time of biopsy. Tumor tissue was immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay. Post- versus pre-treatment tumor biopsies were scored for necrosis, acute and chronic inflammation, and immunohistochemical changes in Ki-67, cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results: 15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent resection and had adequate pretreatment samples. Median age 66, 4 women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8 adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and tumor (7pts) concentrations above the detection limits. There was considerable interindividual variation in plasma V concentrations (7.3-192.4 ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50% had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation in the post-treatment biopsies. Most cases with KRAS mutations had biomarker responses. Changes in multiple biomarkers were observed across the range of intratumoral V levels. Conclusions: This is the first report of V concentrations in human tumors. Preoperative treatment with V achieved intratumoral concentrations comparable to serum with evidence of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses in resected ADT. The results demonstrate the value of window of opportunity trials in the investigation of novel cancer therapeutics.
The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients.
Authors: Krasnik MARK , Lüchtenborg Margreet , Jakobsen Erik , Linklater Karen , Mellemgaard Anders , Møller Henrik
Published: March 2020

7026

Background: TNM classification has been the traditional cornerstone of decision-making in treatment choices of lung cancer. In addition to TNM stage and lung function, there is no other objective information to support this decision. Severe comorbidity affects overall survival, and may be an independent prognostic factor. In this study we quantified the effect of comorbidity on stage-specific survival in resected non-small cell lung cancer (NSCLC) patients in a large population-based setting. Methods: Among 3,152 NSCLC patients from the Danish Lung Cancer Registry who underwent surgical resection between 1 January 2005 and 31 December 2010, mortality hazard ratios were calculated during three consecutive time periods following surgery (0-1 month, 1 month - 1 year and >1 year) according to Charlson comorbidity score (CCS 0, 1-2, 3+), ECOG performance status, lung function, age, sex, pathological T and N stage according to the revised 7th edition TNM lung cancer staging system, using Cox proportional hazard modelling. The Kaplan-Meier method was used to describe stage-specific survival according to the Charlson comorbidity score. Results: Increasing severity of comorbidity was independently associated with significantly higher death rates throughout the three periods of follow-up [HR1.18 for CCS 1-2 and 2.06 for CCS 3+ in 0-1 month, 1.13 for CCS 1-2 and 1.57 for CCS 3+ during 1 month - 1 year and 1.14 for CCS 1-2 and 1.84 for CCS 3+ after 1 year]. Stage-specific five-year survival in patients with severe comorbidity (CCS 3+) was significantly lower than in patients without comorbid disease [e.g., 38% (95% CI 23-53%) for pT1 and CCS 3+ vs. 69% (62-75%) for pT1 and CCS 0]. Conclusions: This study shows that severe comorbidity affects survival of NSCLC patients undergoing surgical resection by as much as a single stage increment. As the survival of NSCLC patients after different treatment regiments is mainly based on the TNM classification, further research is necessary to fully identify which patients are most likely to benefit from surgery, but also to provide a basis for developing a better prediction instrument for the survival after combination treatment involving radiotherapy and chemotherapy.
Amatuximab, a chimeric monoclonal antibody to mesothelin, in combination with pemetrexed and cisplatin in patients with unresectable pleural mesothelioma: Results of a multicenter phase II clinical trial.
Authors: Hassan Raffit , Jahan Thierry Marie , Kindler Hedy Lee , Bazhenova Lyudmila , Reck Martin , Pastan Ira , Ellis Alison , Fatato Penny Marie , Heyburn John , Schweizer Charles , Parno Jeff , Wallin Bruce
Published: March 2020

7030

Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in many cancers including malignant mesothelioma (MM). Based on safety of amatuximab in phase I clinical trial and pre-clinical studies showing synergy in combination with chemotherapy, a single arm phase II study of amatuximab plus pemetrexed (P) and cisplatin (C) was initiated in pts. with MM. Methods: Eligibility criteria included pts. with unresectable epithelial or biphasic pleural MM, no prior chemotherapy and KPS > 70%. Pts. received amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m2 and C 75 mg/m2 (PC) given on day 1, of each 21 day cycle for 6 cycles. Pts. with objective response or stable disease received amatuximab monotherapy until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), objective response rate and safety of amatuximab with PC. Results: From 2/2009 to 10/2010, 89 pts. were enrolled at 26 sites. Pt. characteristics: median age 67 yrs. (range 46-80), 78% male, 70% with KPS >90%, 89% epithelial MM, 11% biphasic MM and 88% had stage III/IV disease. Median number of PC plus amatuximab cycles was 5 (range 1-6) and 56 (63%) pts. received single agent amatuximab. In addition to the expected toxicity from PC, hypersensitivity reactions (12.4%; Grade 3/4=4.5%) from amatuximab were noted. By independent radiological review 30 (39%) pts. had partial response and 39 (51%) had stable disease. PFS at 6 months was 52% (95% CI: 39.5-63.5) with a median PFS of 6.1 months (95% CI: 5.4-6.5). As of 1/10/12 the median OS was 14.5 months (95% CI: 12.4-18.5) with 31 pts. still alive and 7 pts. receiving maintenance amatuximab. Conclusions: Amatuximab in combination with PC was generally well-tolerated in this study with 90% of pts. having an objective tumor response or stable disease by independent radiological review. Although PFS is not significantly different from historical results of PC alone, the median OS is 14.5 months with 35% of pts. still alive. Updated OS and biomarker data will be presented at the meeting.
Next-generation sequencing of thymic malignancies.
Authors: Radovich Milan , Porter Ryan Frederick , Conces Madison , Suleiman Yaman , Badve Sunil S. , Kesler Kenneth , Schneider Bryan P. , Loehrer Patrick J.
Published: March 2020

7032

Background: Thymic malignancies are rare with ~500 cases in the US per year. Apart from standard chemotherapy, treatment options are limited. Further, the challenge of histologic subtyping of these tumors along with an inadequate understanding of the transcriptional biology is a hindrance to the development of targeted therapies. Methods: Thymic malignancies and normal tissues were obtained from the Indiana University Simon Cancer Center. The WHO subtypes of our samples include: (4) type A, (2) A/B, (1) B2, (5) B3, (1) C, and (3) normal tissues. RNA was sequenced on a Life Technologies SOLiD sequencer. For gene expression, reads were mapped to the genome using BioScope and outputs imported into Partek GS. In Partek, statistical comparison of gene expression as well as PCA & clustering analyses were performed. Results: Unsupervised hierarchical clustering of gene expression values revealed 100% concordance between gene expression clusters and WHO subtype. A subsequent unsupervised clustering of 705 pre-miRNAs also showed substantial concordance between clusters and subtype. By analyzing the dendrograms, A & A/B tumors were significantly different from B type tumors, as well as C and normal. A substantial differentiator was a large cluster of overexpression in A&A/B tumors that was nearly absent in the others on chr19q13.42 corresponding to the miR-515 cluster (43 miRNAs). When comparing A & A/B tumors vs. B type tumors, 1334 genes are differentially expressed (258 downregulated) (FDR<5%). 95/258 genes are predicted to be downregulated by the miR-515 cluster including several transcription factors and tumor suppressors. When looking at mutations, we detected no recurrent gene fusions, though we are detecting several point mutations and small insertion deletions. These are being followed up by exome sequencing. Conclusions: Analyses reveal that RNA-seq can be used to accurately subtype Thymic Malignancies and the development of an expression based diagnostic is feasible. Further, these data support that the main differentiator of thymomas may lie in the expression of a single miRNA cluster. In addition, several mutations in key pathways are implicated. Ongoing analyses include: alternative splicing, noncoding RNAs, viral analysis and exome sequencing.
A prospective phase II study of induction erlotinib therapy in stage IIIA-N2 non-small cell lung cancer.
Authors: Zhong Wenzhao , Yang Xuening , Liao Riqiang , Nie Qiang , Su Jian , Chen Zhihong , Zhang Xuchao , An Shejuan , Zhou Qing , Yang Jinji , Wu Yi Long
Published: March 2020

7039

Background: Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or induction gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587) . Study Design: Phase II, factorial Assignment, Safety/Efficacy; Primary outcome measures: Response to Induction Therapy; Estimated enrollment: 5 cases with partial response in the erlotinib arm. Results: From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30-42 days), while 12 cases harboring wild-type EGFR received the GC regimen (3 cycles). The primary end point of the response rates were 58% (7/12) for the erlotinib arm and 33% (4/12) for the GC arm (P=0.49). The pathological N2 complete response rates were 17% for the erlotinib arm and 25% for the GC arm (P=0.64). In the erlotinib arm, the most common failure model after initial therapy was distant metastases (9/10), especially brain metastases (3/9). The median progression free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P=0.27). The median overall survival was 27 months for the erlotinib arm and 23 months for the GC arm (P=0.52). In addition, four cases in the erlotinib arm got partial response to the 2nd EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoracotomy. Conclusions: Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib vs GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR mutations (NCT01407822) is currently recruiting participants.
Matched-pair comparison of outcome of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery.
Authors: Shelkey Julia , Fakiris Achilles , DeCamp Malcolm M. , Medford-Davis Laura Nyshel , Flickinger John Charles , Recht Abram , Liss Adam , Belani Chandra Prakash , Deluca Jill , Maheshwari Neelabh , Varlotto John M.
Published: March 2020

7040

Background: Stereotactic body radiotherapy (SBRT) is an alternative to surgery alone for certain patients with clinical stage I non-small cell lung cancer (NSCLC), but comparing their effectiveness is difficult because of differences in patient selection and staging. Methods: Two databases were combined which contained 132 patients treated by lobectomy (LR) and 48 by sublobar resection (SLR) and 137 patients managed with SBRT after negative staging between 1999-2009. We compared rates of overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) between patients treated with surgery and SBRT to each other and in relation to possible prognostic factors. We then performed a matched-pair analysis comparing surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. Results: On univariate analysis, OS was significantly correlated with histology, the Charlson Comorbidity Index, tumor size, aspirin use, and use of SBRT; DFS was correlated only with histology; and no variable was significantly correlated with LRC. Multivariate analysis found improved OS in patients with adenocarcinoma and those undergoing surgical resection. The NSCLC “not otherwise specified” histology was associated with poorer DFS. Overall survival was significantly poorer for SBRT patients in the matched-pair analysis than for patients treated with surgery, but DFS and LRC were not significantly different between these groups. Conclusions: Our retrospective study has demonstrated similar LRC and DFS in patients treated with SBRT or surgery, but worse OS in the former group, when patients were matched for prognostic factors. Our investigation suggests that randomized trials are needed to eliminate selection bias in treatment assignment in order to accurately compare outcomes between these approaches.
Comparative effectiveness of five treatment strategies for early-stage non-small cell lung cancer in the elderly.
Authors: Shirvani Shervin Mohajer , Jiang Jing , Chang Joe Y. , Gomez Daniel Richard , Welsh James , Swisher Stephen , Buchholz Thomas A. , Smith Benjamin D.
Published: March 2020

7062

Background: Early-stage lung cancer incidence among older adults is expected to increase due to demographic trends and CT-based screening, yet optimal treatment in the elderly remains controversial. Using the SEER-Medicare cohort spanning 2001-2007, we determined survival outcomes associated with five strategies used in contemporary practice. Methods: Treatment strategy and covariates were determined in 10,923 patients age≥66 with stage IA-IB non-small cell lung cancer. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for lobectomy, sublobar resection, conventional radiation, stereotactic body radiotherapy (SBRT) and observation. In a second analysis, propensity-score matching was used for pairwise comparison of SBRT with other strategies. Results: Median age was 75 years and 29% had substantial comorbidity. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SBRT (1.1%). In unmatched Cox regression with median follow up of 3.2 years, SBRT was associated with the lowest risk of death within six months of diagnosis (HR 0.47; 95%CI 0.37-0.61; referent is lobectomy). After six months, sublobar resection and SBRT were associated with similar overall survival (P=0.51) and were both modestly worse than lobectomy. With propensity-score matching, survival after SBRT was similar to lobectomy (HR 0.90; 95%CI 0.64-1.27). Conventional radiation and observation were associated with poor outcomes in all analyses. Disease-specific survival outcomes followed similar trends. Conclusions: This population-based experience provides strong support of SBRT as an alternative to surgery or conventional radiation for select patient populations. Evaluation of this new therapy in randomized trials is urgently needed.
Prospective study of tumor suppressor gene (TSG) methylation as a prognostic biomarker in surgically resected non-small cell lung cancer (NSCLC).
Authors: Azzoli Christopher G. , Drilon Alexander Edward Dela Cruz , Sugita Hirofumi , Sima Camelia S. , Huang Eric , Danenberg Peter V. , Kris Mark G. , Rusch Valerie W.
Published: March 2020

7066

Background: In the New England Journal of Medicine, Brock et al. (2008) published a nested case-control study which tested the association between early recurrence of NSCLC after surgical resection, and TSG promoter methylation in tumor and lymph nodes detected by methylation-specific PCR (MSP). They reported that promoter methylation of the TSGs p16, CDH13, RASSF1A, and APC was significantly associated with early recurrence in 51 patients with stage I NSCLC compared to matched patients without early recurrence. We attempted to confirm these findings. Methods: In a prospective study, fresh frozen tumor tissue was acquired after surgical resection in 107 patients with stage I-IIIA NSCLC between 2003-2008. The promoter methylation status of the same 4 genes examined by Brock, et al (p16, CDH13, RASSF1A, APC), as well as 6 additional TSGs (MGMT, WIF-1, METH-2, GSTP1, SOCS3, DAPK) were assessed in the tumor tissue using quantitative MSP (MethyLight assay), with any amount of methylation scored as positive. Methylation status was correlated with clinical features, pathologic stage, disease-free survival (DFS), and overall survival (OS). Results: No significant associations were observed between promoter methylation of individual TSGs and DFS. No significant associations were observed between the number of methylated TSGs and DFS, or OS. Increased RASSF1A methylation was observed in poorly-differentiated and undifferentiated tumors compared to tumors that were well- or moderately-differentiated (p=0.031). Increased WIF-1 methylation and GSTP1 methylation were associated with increasing T (p=0.01) and N stage (p=0.028), respectively. Squamous cell carcinomas (SQCCs) were characterized by increased p16 methylation (p=0.0314) and decreased APC methylation (p=0.0146) compared to tumors of non-SQCC histologies. Conclusions: In this prospective study, we did not confirm that the promoter methylation of p16, CDH13, RASSF1A, and APC, or 6 other TSGs, was prognostic for early recurrence in surgically resected NSCLC.
Expression pattern and biologic relevance of Bcl-2 and Mcl-1 in pulmonary neuroendocrine tumors.
Authors: Chowdry Rajasree Pia , Sica Gabriel , Chen Zhengjia , Goodman Aaron , Kim Sungjin , Deng Xingming , Curran Walter John , Gal Anthony A , Khuri Fadlo Raja , Ramalingam Suresh S , Owonikoko Taofeek Kunle
Published: March 2020

7097

Background: Bcl-2 protein overexpression is frequently described in small cell lung cancer (SCLC) but the biological relevance remains unclear. To better elucidate the role of Bcl2 dysfunction in SCLC, we assessed the total and the biologically relevant phosphorylated forms of the anti-apoptotic Bcl2 family members (Bcl2, pBcl-2, Mcl-1, pMcl-1) in pulmonary neuroendocrine (NE) tumors. Methods: We analyzed archival samples of pulmonary carcinoid, SCLC and large-cell NE carcinoma (LCNEC) by immunohistochemistry (IHC) using specific antibodies. Protein expression was assessed by light microscopy using standard scoring of intensity (0, 1, 2 and 3) and percent cell staining and correlated with age, gender, smoking status, tumor type, stage and survival. Significant differences in expression pattern and correlation with clinical variables were assessed by Wilcoxon two-sample test, t-test, ANOVA, Spearman and Pearson correlation coefficients and Cox regression model. Results: We retrieved 77 cases: carcinoid (16) SCLC (41) and LCNEC (20); median age (61 yrs), gender (62% females). Bcl2 and pBcl2 expression was higher in SCLC and LCNEC compared to benign carcinoid tumor. pBcl-2 showed stronger correlation with adverse features including smoking, malignant histology, higher stage at diagnosis and worse survival. No significant association of Mcl1 or pMcl-1 expression with clinical or pathologic parameters. Conclusions: pBcl-2 expression pattern and correlation with adverse prognostic features indicate a key role in SCLC biology and relevance as a therapeutic target. [Table: see text]
A 19-gene prognostic GEP signature (DecisionDx-Thymoma) to determine metastatic risk associated with thymomas.
Authors: Gokmen-Polar Yesim , Goswami Chirayu Pankaj , Cook Robert W. , Oelschlager Kristen M. , Maetzold Derek , Vladislav Ioan Tudor , Shirar Kristen L , Kesler Kenneth , Loehrer Patrick J. , Badve Sunil S.
Published: March 2020

7106

Background: The treatment of thymomas is predominantly based on the stage of disease. Histologic classification is of limited value as all types of thymomas can give rise to metastases. In order to better predict the metastatic behavior of these tumors, we performed genome-wide gene expression analysis and identified a set of genes associated with presence or absence of metastases. In the current study, we sought to further develop and validate the gene signature using quantitative RT-PCR analysis. Methods: Thymomas with archived blocks and long-term follow-up data were reviewed. This training set study consisted of 50 cases, including 34 cases on which the discovery microarray analysis had been performed. RNA was extracted from 5 x 10-micron thick sections in a CAP-accredited CLIA certified laboratory and analyzed by RT-PCR using custom TLDA cards on an ABI7900HT instrument. Expression data and biostatistical analysis were performed using GeNorm and JMP Genomics (SAS). Predictive modeling using Partition Tree Analysis (PTA) and Logistic Regression Analysis (LRA) was performed. Metastasis-free survival (MFS) was assessed using Kaplan-Meier analysis. Results: A 19-gene expression profile (GEP) signature was developed using a cohort of 50 thymomas for predicting metastasis. PTA yielded ROC of 0.97 (met. accuracy = 96%, non-met. accuracy = 81%), while LRA yielded ROC of 0.895 (met. accuracy = 87%, non-met. accuracy = 85%). PTA classification showed 5-year MFS rates of 100% and 31% for predicted low risk (Class 1) and high risk (Class 2) of metastasis (median MFS = NR and 4.1 yrs, resp., P<0.0001 Log-Rank), respectively. LRA showed 5-year MFS rates of 100% and 17% for predicted Class 1 and high risk Class 2 of metastasis (median MFS = NR and 2.9 yrs, resp., P<0.0001 Log-Rank), respectively. Analysis of additional cohorts is ongoing. Conclusions: We have successfully completed development of a 19-gene signature (DecisionDx-Thymoma) that appears to predict metastatic behavior of thymomas more accurately than traditional staging. If validated in larger cohort, this signature will provide insight for the future management of patients with this rare malignancy.
Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC).
Authors: Brahmer Julie R. , Horn Leora , Antonia Scott , Spigel David R. , Gandhi Leena , Sequist Lecia V. , Wigginton Jon , McDonald Dan , Kollia Georgia , Gupta Ashok Kumar , Gettinger Scott N.
Published: March 2020

7509

Background: BMS-936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T cells. We report here that BMS-936558 mediates antitumor activity in heavily pretreated patients (pts) with advanced NSCLC, a tumor historically not considered to be responsive to immunotherapy. Methods: BMS-936558 was administered IV Q2WK to pts with various solid tumors, including NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Pts with advanced NSCLC previously treated with at least 1 prior chemotherapy regimen were eligible. Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR. Clinical activity was assessed by RECIST 1.0. Results: Of 240 pts treated as of July 1, 2011, 75 NSCLC pts were treated at 1 (n=17), 3 (n= 19), or 10 mg/kg (n=39). ECOG performance status was 0/1/2 in 24/49/2 pts. Tumor histology was squamous (n=17), non-squamous (n=52), or unknown (n=6). The number of prior therapies was 1 (n=9), 2 (n=20), ≥3 (n=45), or unknown (n=1). Ninety-five percent of pts had received platinum-based chemotherapy and 40% had a prior tyrosine kinase inhibitor. Sites of metastatic disease included lymph node (n=50), liver (n=12), lung (n=62), and bone (n=13). Median duration of therapy was 10 wk (max 100 wk). Common related AEs were fatigue (17%), nausea (11%), pyrexia (7%), pruritus (7%), dizziness (7%), and anemia (7%). The incidence of grade 3-4 related AEs was 8%. There was 1 drug-related death due to pulmonary toxicity. Clinical activity was observed at all dose levels (Table) and in multiple histologies. Several pts had prolonged SD. Some had a persistent decrease in overall tumor burden in the presence of new lesions and were not categorized as responders. At the time of data lock, of 10 OR pts, 3 had responses lasting ≥6 mo and 5 were on study with response duration of 1.8-5.5 mo. Conclusions: BMS-936558 is well tolerated and has encouraging clinical activity in pts with previously treated advanced NSCLC. Further development of BMS-936558 in pts with advanced NSCLC is warranted. [Table: see text]
Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC).
Authors: Zhou Caicun , Wu Yi Long , Liu Xiaoqing , Wang Changli , Chen Gongyan , Feng Ji Feng , Zhang Shucai , Wang Jie , Zhou Songwen , Ren Shengxiang , Lu Shun , Zhang Li , Hu Cheng-ping , Luo Yi , Chen Lei , Ye Ming , Huang Jianan , Zhi Xiuyi , Zhang Yiping , Xiu Qingyu
Published: March 2020

7520

Background: The OPTIMAL study demonstrated significant superiority for E versus GC in terms of progression-free survival (PFS), objective response rate, tolerability and quality of life (QoL) in first-line advanced NSCLC patients with EGFR activating mutations (Act Mut+). Here we report OS data from OPTIMAL (ClinicalTrials.gov NCT00874419). Methods: Chemotherapy-naive Chinese patients with advanced NSCLC and EGFR Act Mut+, ECOG performance status (PS) 0–2 and measurable disease were randomized to E (150 mg/day), or GC, and stratified by histology, smoking status and mutation type. OS at final data cut-off (15 Nov 2011) was evaluated for the entire intent-to-treat (ITT) population. Subgroup analysis of OS by gender, histology, smoking status, PS, presence of skin rash and type of mutation was performed. Details of second- or later-line therapy were also documented for each patient. Results: A total of 165 patients were randomized to treatment and 154 patients received at least one dose of study drug (ITT population; E, n=82; GC, n=72). A total of 7 patients are still responding to erlotinib in the E arm. Post-study therapy included chemotherapy (doublet, n=38, or mono, n=8), or experimental drugs in clinical trials (n=10) in the E arm, and EGFR tyrosine kinase inhibitor (TKI) therapy (n=49) or chemotherapy (n=7) in the GC arm. Post-study treatment was not received by 26 and 16 patients in the E and GC arms, respectively. A total of 84 deaths were reported (E, n=47; GC, n=37). OS did not differ significantly between the two treatment arms (HR=1.065, p=0.6849), and no significant difference in OS was observed in the different subgroups. Conclusions: The lack of a statistically significant difference in OS in the OPTIMAL study was possibly due to a high level of cross-over to EGFR TKI therapy in the GC arm. However, the significant benefits reported with E in terms of PFS, QoL and tolerability in this study suggest that E should be considered as one of the standard first-line treatments for patients with advanced EGFR Act Mut+ NSCLC.
Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion mutations within the tyrosine kinase domain of EGFR.
Authors: Costa Daniel Botelho , Yasuda Hiroyuki , Sng Natasha J , Yeo Wee-Lee , Figueiredo-Pontes Lorena Lobo de , Tenen Daniel G. , Kobayashi Susumu
Published: March 2020

7523

Background: Epidermal growth factor receptor (EGFR) mutations (M) define an important subgroup of non-small-cell lung cancer (NSCLC). Most patients whose tumors harbor exon 19 deletions or L858R EGFR M have responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs using site-directed mutagenesis and introduced them into Ba/F3 cells for in vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel malignant pleural effusion-derived cell line. Results: The disease control rate of gefitinib or erlotinib was significantly higher in EGFR exon 20 insertion M located within the C-helix (3/3,100%) when compared to M following the C-helix (1/14, 7%; p=0.00059). The NSCLC with EGFR-A763_Y764insFQEA (located within the C-helix of EGFR) achieved a partial response to erlotinib that lasted 18 months. Most other exon 20 insertion M-positive NSCLCs did not respond (p=0.07). Eight representative exon 20 insertion M were studied (including EGFR-A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV, D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA, were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to nanomolar C of erlotinib. A patient-derived cell line with EGFR-A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion mutations are resistant to EGFR TKIs, and in specific EGFR-A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical implications for the care of the 10,000 cases of EGFR exon 20 insertion M NSCLC diagnosed yearly and points towards the need to define the molecular mechanisms that underlie differential responses to EGFR TKIs.
Continuation of EGFR/ALK inhibition after local therapy of oligoprogressive disease in EGFR mutant (Mt) and ALK+ non-small cell lung cancer (NSCLC).
Authors: Weickhardt Andrew James , Scheier Benjamin , Burke Joseph Malachy , Gan Gregory , Doebele Robert Charles , Bunn Paul A. , Gaspar Laurie E. , Kavanagh Brian D. , Camidge D. Ross
Published: March 2020

7526

Background: This study aimed to investigate the benefits of local treatment of limited disease progression and continuation of crizotinib (C) or EGFR-TKI in patients with ALK+ or EGFR-Mt metastatic NSCLC, respectively. Methods: Patients with advanced ALK+ NSCLC treated with C (n=38) and EGFR-Mt NSCLC treated with EGFR TKIs (erlotinib or gefitinib) (n=27) were identified. Patients were evaluated for initial response, site of first progression (CNS or extra CNS (eCNS)) and median progression free survival (PFS1). A subset of patients with limited sites of progression (oligoprogressive disease) suitable for local therapy received either radiation or surgery to these sites and continued on the same TKI. The subsequent pattern of progression and median progression free survival from the time of first progression (PFS2) were recorded. Results: In 38 ALK+ patients, PFS1=9.0 months on C. In 27 EGFR-Mt patients, PFS1=13.8 months on EGFR-TKI. CNS was the first site of progression in 13/28 (46%) of ALK+ patients and 5/23 (22%) EGFR-Mt patients. 25 of 51 patients who progressed (49%) were deemed suitable for local therapy (15 ALK+, 10 EGFR-Mt; 24 with radiotherapy (Body: 3 XRT, 9 SBRT; CNS: 7 WBRT, 5 SRS), 1 with surgery (adrenalectomy)) and continuation of the same targeted therapy. 19/25 patients progressed post local therapy, median PFS2 = 6.2 months. In patients who progressed at PFS1 only in the CNS, there was a trend to longer PFS2 than patients who progressed at PFS1 in eCNS (7.1 months vs 4.0 months, p=0.26). 60% who progressed only in the CNS at PFS1, progressed eCNS at PFS2 (n=10). Conclusions: Progression of oncogene addicted NSCLC on relevant targeted therapies is often suitable for local therapy (oligoprogressive disease). Continuation of the targeted therapy following local therapy is associated with >6 months of additional disease control. [Table: see text]
Local therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors.
Authors: Yu Helena Alexandra , Sima Camelia S. , Drilon Alexander Edward Dela Cruz , Varghese Anna M. , Pietanza Maria Catherine , Azzoli Christopher G. , Rizvi Naiyer A. , Krug Lee M. , Kris Mark G. , Miller Vincent A. , Riely Gregory J.
Published: March 2020

7527

Background: The utility of EGFR directed therapy for the treatment of EGFR mutant lung cancer is limited by the development of acquired resistance (AR) to EGFR tyrosine kinase inhibitor (TKI) therapy, which occurs after a median of 16 months (mos). There are no approved targeted therapies after disease progression on EGFR TKI therapy. Local therapy for oligometastatic disease is used with regularity in other solid tumors, and can lead to long term survival in selected individuals. EGFR mutant lung cancers with AR to TKI therapy can follow an indolent course that is amenable to local therapy to treat progression of disease when used in conjunction with continued EGFR inhibition. Outcomes following local therapy in this setting have not been assessed. Methods: Patients (pts) with AR to EGFR TKI’s who received local therapy excluding treatment of CNS metastases or local therapy prior to AR were identified in an IRB-approved prospective registry of 184 pts with AR enrolled from August 2004- November 2011. We collected treatments as well as progression free survival (PFS) and overall survival (OS) after local therapy. Results: 18 pts received local therapy. Treatments included surgical resection and radiation to lung, lymph nodes, adrenal gland or bone. Median age was 57, 56% were women, and 61% were never smokers. 14 had EGFR Exon 19 deletions, and 4 L858R. The median time to development of AR on TKI was 19 mo (range 5-33). Known mechanisms of AR included T790M (11 pts), MET amplification (1 pt) and small cell transformation (1 pt). The median PFS after local therapy was 10 mo (95% CI: 4-NA), median time from local therapy until change in systemic therapy was 22 mo (95%CI: 6 - 30), and median OS from local therapy was 41 mo (95% CI: 26-NA). Local therapy was tolerated well, with 85% of pts restarting TKI therapy within one month of completing local therapy. Conclusions: Local therapy is well tolerated and in combination with continued EGFR TKI therapy prolongs time until change in systemic therapy is required and may lead to outcomes that are superior to currently available treatment options in selected individuals.
Concordance of driver mutations in primary and matched metastasis from patients with non-small cell lung cancer (NSCLC) using next-generation sequencing (NGS).
Authors: Vignot Stéphane , Frampton Garrett , Yelensky Roman , Brambilla Christian , Toffart Anne-Claire , Miller Vincent A. , Palmer Gary A. , Cronin Maureen T. , Lazar Vladimir , Soria Jean-Charles , Stephens Philip , Brambilla Elisabeth
Published: March 2020

7529

Background: Progress in treating NSCLC continues to be limited by high recurrence rates after definitive treatment of localized disease and frequent presentation with metastatic disease. In these pts, diagnostic samples are often limited in size and may be inadequate for genotyping necessary in this disease. In applying genomic profiling to aid treatment planning for patients with metastatic NSCLC, it is critical to determine whether archived primary tumor adequately reflects the genomic spectrum of the patient’s metastatic disease or whether biopsy of a metastatic site is required. We undertook this study using NGS technology to characterize paired primary-metastatic biopsy genomic profiles. Methods: Primary and matched metastatic tumor pairs plus adjacent normal tissue from 15 pts with NSCLC (adenocarcinoma 9/squamous 4/large cell 2) and heavy smoking history were analyzed using a targeted NGS assay in a CLIA laboratory (Foundation Medicine). Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 778X with 99% of bases covered >100X. Results: Among the 30 tumors, 373 somatic alterations were identified; 96 were known NSCLC drivers including: TP53 (14 pts), KRAS (4 pts), SOX2 (4 pts), STK11 (2 pts), CDKN2A (2 pts) and SMARCA4 (2 pts) in full agreement with their respective histological type. In all cases (15/15), primary and metastatic tumors from the same patient demonstrated 90% driver mutation concordance (74/82, 95 % CI, 82-95%). For other mutations, the majority of which are likely passengers, the 69% (201/291) concordance rate was significantly lower (p< .001).The total number of alterations between primaries (190) and metastases (183) was remarkably similar. Conclusions: These results suggest that genomic profiles of primary tumor can identify the key somatic alterations present in matched NSCLC metastases and therefore is a suitable specimen for clinical decision making in the majority of cases. Our data does not support the routine need for a new biopsy upon recurrence since variability in mutational status is low.
Native and rearranged ALK copy number and rearranged ALK cell count in NSCLC: Implications for ALK inhibitor therapy.
Authors: Camidge D. Ross , Skokan Margaret , Kiatsimkul Porntip , Helfrich Barbara , Schulte Nathan , Maxson DeLee , Aisner Dara L , Franklin Wilbur A. , Doebele Robert Charles , Varella-Garcia Marileila
Published: March 2020

7534

Background: ALK rearranged NSCLC responds well to ALK inhibitors. Clinically, >15% cells showing rearrangements by break-apart FISH classifies tumors as ALK(+). Native ALK copy number gain has also been reported. We explored the significance of native and rearranged ALK copy number on crizotinib outcomes and whether >15% reflected a clear biological distinction in the frequency of ALK(+) cells. Methods: Copy number and genomic status of ALK assessed by FISH. A total of 1426 NSCLC clinical specimens, 174 ALK(+) and 1252 ALK(-) by standard criteria, and 26 NSCLC cell lines (2 ALK(+) and 24 ALK(-)) were investigated. Results: Native ALK gene mean copy number was significantly higher in ALK(-) than in ALK(+) cases (2.8, SD 0.93, range 1.2-11.4 vs. 1.8, SD 0.79; range 0.6 to 5.2; p<0.01). Frequency of native ALK copy number gain (≥3 copies/cell in ≥40% cells) was 19% in ALK(+) and 62% in ALK(-) tumors (p<0.001). In ALK(-) tumors, abundant focal amplification of native ALK was rare (0.8%); scanty amplification (<10% tumor cells) occurred in 1.1%, and duplication of the entire native ALK or of the ALK 3’ end occurred in 3.5%. Among ALK(-) cell lines, mean native ALK copy number ranged 2.1-6.9 and was not correlated with in vitro crizotinib sensitivity (IC50s 0.34-2.8 uM). In (+) patients, neither native or rearranged ALK copy number, nor percentage cell count correlated with maximal tumor shrinkage or PFS with crizotinib. Clinical specimens with 0-9%, 10-15%, 16-30%, 31-50% and >50% of ALK+ cells were found in 79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Conclusions: Lower native ALK copy number in ALK(+) NSCLC suggests ALK fusion occurs early, preceding chromosomal instability. Elevated native ALK copy number rarely reflects focal amplification and native ALK copy number increases alone are not associated with sensitivity to ALK inhibition in vitro. Neither native or rearranged copy number, nor positive cell count within ALK(+) tumors influences clinical benefit from ALK inhibition. As 8.5% of ALK(-) cases fall within 5% of the established >15% cell positive threshold, further investigation of ALK status by other diagnostic techniques in this subset may be warranted.
Association of epithelial to mesenchymal transition with efficacy of EGFR-TKIs in non-small cell lung cancer patients with EGFR wild type.
Authors: Ren Shengxiang , Su ChunXia , Chen Xiaoxia , Li Jiayu , Li Bing , Li Xuefei , Zhou Caicun
Published: March 2020

7535

Background: The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype, it has a profound impact on cancer progression and treatment. The purpose of this study was to investigate the role of EMT to predict the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) patients. Methods: We evaluated the correlation between EMT and sensitivity to EGFR-TKIs in advanced NSCLC patients. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, fibronectin, N-cadherin and vimentin and ARMs was used to detect the EGFR mutation in tumor specimens obtained before the treatment. The EMT phenotype status was determined according to the expression of E-cadherin, fibronectin, N-cadherin and vimentin. Results: 101 patients enrolled into this study and 97 had enough tissue to perform the EMT examination. The median age was 59 years old, male/female:56/45, never smoker/smoker: 71/30, adenocarcinoma/non-adeno: 73/28, PS 0-1/2-3: 83/18, Stage IIIB/IV: 2/99, 1st /2nd-4th line: 13/88. The response rate and progression free survival(PFS) in the whole population were 45.5% and 7.6 months respectively. EMT test revealed that 46(47.4%) samples were epithelial phenotype, while 51(52.6%) were mesenchymal phenotype. 38 of 79 patients harbour activating EGFR mutation. Among the patients with EGFR wild type or unknown status, patients with an epithelial phenotype had a higher response rate(40% Vs 17.6%, P=0.056) and significantly longer PFS(7.6 m Vs 3.8 m, P=0.045) than these with a mesenchymal phenotype. However, the response rate(85.7% Vs 64.7%, P=0.249) and PFS(15.2 m Vs 12.2 m, P=0.420) were similar in the patients with activated EGFR mutation. Conclusions: Patients with an epithelial phenotype got more benefit from the treatment of EGFR-TKIs in the advanced EGFR wild type NSCLC patients, which indicated that the EMT might be a potential marker to guide the individual therapy of EGFR-TKIs in this subpopulation.
A randomized phase II study of axitinib in combination with pemetrexed/cisplatin (pem/cis) as first-line therapy for nonsquamous non-small cell lung cancer (NSCLC).
Authors: Belani Chandra Prakash , Yamamoto Nobuyuki , Bondarenko Igor , Orlov Sergey V , Tang Jie , Niethammer Andreas G. , Ingrosso Antonella , Kim Sinil , Scagliotti Giorgio
Published: March 2020

7551

Background: Axitinib is a potent and selective second-generation inhibitor of VEGF receptors 1, 2, and 3 that has promising single-agent activity in advanced NSCLC. Efficacy and safety of axitinib (in 2 dosing schedules) combined with pem/ciswere evaluatedfor non-squamous NSCLC. Methods: Patients with confirmed stage IIIB, IV, or recurrent non-squamous NSCLC and ECOG performance status (PS) 0 or 1 were stratified by gender and PS, and randomized 1:1:1 to receive six 21-day cycles of axitinib continuously plus pem/cis (arm I); axitinib on Days 2 through 19 followed by a 3-day interruption plus pem/cis (arm II); or pem/cis alone (arm III). Axitinib was administered at a starting dose of 5 mg BID. Pem/cis (500/75 mg/m2) was infused on Day 1 of each cycle. Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics of patients in arm I (n=55), arm II (n=58), or arm III (n=57) ranged between 59–62 yr median age; 62–65% male; 71–85% White; 73–85% current/ex-smokers; and 43–47% PS 0. There were no significant differences in PFS or overall survival (OS) between axitinib-containing arms I and II compared with pem/cis alone, but objective response rates (ORR) were higher (Table). Most common all causality grade 3 adverse events (AEs) in arm I, II, and III, respectively, were hypertension (20%, 17%, 0%); neutropenia (18%, 10%, 9%); nausea (16%, 5%, 7%); vomiting (13%, 5%, 4%); fatigue (11%,16%,16%); and anemia (7%, 14%, 9%). Grade 4 AEs observed in >1 patient were asthenia and pulmonary embolism (2 patients each in arm II). Conclusions: Axitinib combined with pem/cis was generally well tolerated, but efficacy was not significantly better than pem/cis alone in non-squamous NSCLC. [Table: see text]
A randomized phase III study of a cisplatin (CDDP) and docetaxel (DOC) with or without irinotecan (CPT) in pts with advanced NSCLC: Okayama Lung Cancer Study Group OLCSG 0403 trial.
Authors: Okada Toshiaki , Tabata Masahiro , Segawa Yoshihiko , Kamei Haruhito , Shibayama Takuo , Gemba Kenichi , Takigawa Nagio , Matsuo Keitaro , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

7560

Background: CDDP-based doublet chemotherapy provides a significant but modest survival prolongation in untreated advanced NSCLC with MST of around 12 months. Based on the favorable efficacy profile in our previous phase II trial of triplet chemotherapy with CDDP, DOC, and CPT (response rate: 57.1%, MST: 17 months) (JTO 2007), we conducted a phase III study to compare this regimen with CDDP and DOC doublet therapy in the first-line setting. Methods: Pts were randomly allocated to the triplet therapy (A arm; CDDP 60 mg/m2, day 1; DOC 60 mg/m2, day 1; and CPT 60 mg/m2, day 2; q3 wks, determined based on our phase I study result) or a standard doublet chemotherapy (B arm; CDDP 80 mg/m2, and DOC 60 mg/m2, day 1; q3 wks). The primary endpoint was OS whilst secondary endpoints included response rates, PFS, and toxicity. Results: Between 2004 and 2009, 120 pts were enrolled (A/B: 60 pts each). Objective response was comparable between the arms (18 pts [30%] each, p = 0.571). As for toxicity, grade 3-4 neutropenia, principal toxicity, was observed in 93% vs. 58% (p < 0.001). Although grade 3 febrile neutropenia was observed in 53% and 18% of the pts (p < 0.001), none of whom further developed toxic deaths. At a median follow-up time of 64.2 months, median PFS time and 1-year PFS rate were 5.3 vs. 4.3 months and 13.3% vs. 11.7%, respectively (stratified logrank test; p = 0.872). There was also no difference in OS (MST, 16.8 vs. 12.2 months; 1-year OS rate, 68.0% vs. 53.0%; stratified logrank test; p = 0.846). Subgroup analysis for OS showed that never smokers (HR = 0.366; 95% CI = 0.072-1.866) tended to benefit from the triplet chemotherapy compared with ever-smokers (HR = 1.380; 95% CI = 0.771-2.473) despite no statistical significance (p for interaction = 0.150). Similar trend in interaction between treatment effect and smoking status was also observed in PFS. Conclusions: This triplet chemotherapy failed to produce a significant antitumor activity as compared with the standard doublet therapy.