bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant chemotherapy for pathological stage I non-small cell lung cancer with high-risk factors for recurrence: A multicenter study.
Authors: Tsutani Yasuhiro , Imai Kentaro , Ito Hiroyuki , Mimae Takahiro , Miyata Yoshihiro , Ikeda Norihiko , Nakayama Haruhiko , Okada Morihito 
Published: March 2020

8500 Background: The role of adjuvant chemotherapy for pathological stage I non-small cell lung cancer (NSCLC) is controversial. The purpose of this study was to investigate the effect of adjuvant chemotherapy for pathological stage I NSCLC with high-risk factors for recurrence. Methods: Prospectively collected data from 1,278 patients with pathological stage I (8th edition) NSCLC undergoing lobectomy were retrospectively analyzed. High-risk factors for recurrence were determined by multivariable Cox proportional hazards model for recurrence-free survival (RFS). RFS, overall survival (OS), and cancer-specific survival (CSS) were compared between patients who received adjuvant chemotherapy and those who did not. Results: In multivariable analysis, age (≥70 y; hazard ratio [HR], 2.14), invasive component size ( > 2 cm; HR, 1.60), visceral pleural invasion (HR, 1.81), lymphatic permeation (HR, 1.67), and vascular invasion (HR, 2.78) were identified as independent factors for RFS. In patients with high-risk factors for recurrence such as invasive component size of > 2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion (high-risk group; n = 641), RFS was significantly different between patients who received adjuvant chemotherapy (n = 222; 5-y RFS, 81.4%) and those who did not (n = 418; 5-y RFS, 73.8%; P = 0.023). OS and CSS were also significantly better in patients who received adjuvant chemotherapy (5-y OS, 92.7%; 5-y CSS, 95.0%) than in those who did not (5-y OS, 81.7%; P < 0.0001; 5-y CSS, 89.5%; P = 0.012). In patients without any high-risk factors for recurrence (low-risk group; n = 637), RFS was not significantly different between patients who received adjuvant chemotherapy (n = 83; 5-y RFS, 98.1%) and those who did not (n = 554; 5-y RFS, 95.7%; P = 0.30). OS and CSS were also not significantly different between patients who received adjuvant chemotherapy (5-y OS, 98.0%; 5-y CSS, 100%) and those who did not (5-y OS, 95.6%; P = 0.35; 5-y CSS, 99.4%; P = 0.52). Conclusions: Adjuvant chemotherapy may improve survival in patients with pathological stage I NSCLC who have high-risk factors for recurrence such as invasive component size of > 2 cm, visceral pleural invasion, lymphatic permeation, or vascular invasion.
The role of EGFR inhibitors as adjuvant therapy for EGFR mutation positive non-small cell lung cancer.
Authors: Xie Peng , Tang Wenjie , Li Xiaolin , Sun Xindong , Yu Jinming 
Published: March 2020

8508 Background: Cisplatin-based chemotherapy as adjuvant therapy for resected NSCLC has reached its plateau, and was limited by high risk of recurrence and significant toxicities. The clinical value of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected non-small cell lung cancer (NSCLC) harboring EGFR mutations remains controversial. In this study, we performed a meta-analysis to evaluate the role of EGFR inhibitors as adjuvant therapy for targeted patients. Methods: Studies were identified via an electronic search on Pubmed, EMBASE, ISI Web of Science, ScienceDirect, SpringerLink, The Cochrane library and so on. Pooled odds ratio (OR) for disease-free survival (DFS) and overall survival (OS) were calculated for meta-analysis. Registration number: PROSPERO (CRD42018093144). Results: There were 11 trials (1,152 resected NSCLC patients with EGFR sensitive mutations) in this meta-analysis. Results showed that adjuvant treatment with EGFR-TKIs can prolong both OS and DFS when compared to treatment without TKIs as adjuvant therapy (OS: OR, 0.63; 95% CI, 0.46 to 0.87, P = 0.004; heterogeneity I2= 61%, P = 0.008; DFS: OR, 0.56; 95% CI, 0.43 to 0.72, P < 0.00001; heterogeneity I2= 37%, P = 0.1). Results of predefined subgroup analyses in this meta-analysis suggested a greater DFS with EGFR-TKI mono compared with chemotherapy, whereas the OS benefit failed to show a similar difference between the two arms (p = 0.3). And we also find that treatment with EGFR-TKI plus chemotherapy was associated with significantly longer DFS as well as OS than chemotherapy mono in patients with completely resected EGFR-mutant NSCLC (DFS: OR, 0.48; 95%CI, 0.34-0.68; P < 0.00001; heterogeneity I2= 15%, P = 0.29; OS: OR, 0.50; 95% CI, 0.31-0.78; P = 0.003; heterogeneity I2 = 57%, P = 0.05). And less grade 3 or higher AEs were observed in the TKIs group (OR, 0.22; 95% CI, 0.14 to 0.37, P < 0.00001; heterogeneity I2= 22%, P = 0.28). Conclusions: Adjuvant EGFR-TKIs may be a potential treatment option compared to adjuvant chemotherapy in completed resected patients with EGFR mutation-positive NSCLC. This project was supported by the National Natural Science Foundation of China (Grant No. 81502667), Key Research and Development Plan of Shandong, China (Grant No. 2016GSF201167).
A randomized phase II study of tremelimumab and durvalumab with or without radiation for patients with relapsed small cell lung cancer (SCLC).
Authors: Owonikoko Taofeek Kunle , Higgins Kristin Ann , Chen Zhengjia , Zhang Chao , Pillai Rathi Narayana , Steuer Conor Ernst , Saba Nabil F. , Pakkala Suchita , Shin Dong Moon , Zhang Guojing , Wang Shuhua , Hossain Mohammed S , Beardslee Tyler , Engelhart Anne , Revenig Janine , Khuri Fadlo , Curran Walter John , Lonial Sagar , Waller Edmund K. , Ramalingam Suresh S. 
Published: March 2020

8515 Background: The combination of PD-1 and CTLA-4 inhibition has demonstrated activity in the second line therapy setting for SCLC. Radiotherapy enhanced the effectiveness of immunotherapy in NSCLC. We conducted this signal finding study to assess the efficacy of combined ICI with or without radiation in relapsed SCLC. Methods: Patients with relapsed SCLC who have received not more than 2 lines of therapy were enrolled and randomized to either Arm A: [Tremelimumab (T) 1500mg/durvalumab (D) 75mg i.v. every 4 weeks without SBRT] or Arm B: T/D with immune sensitizing SBRT to one selected tumor site (9 Gy x 3 fractions). Treatment continued until progression or maximum of 2 years. Paired tumor biopsies and serial samples of peripheral blood were employed for correlative endpoints (changes in intratumoral and circulating lymphocyte repertoire and immune cytokines). The study was designed to show a promising efficacy signal in either Arm with a hypothesized median PFS of 7 months (10 patients give 87% power at 1-sided alpha of 0.1). Results: Study randomized 17 patients to Arm A (8 patients) or B (9 patients); median age of 70 yrs; females 41.2%; White, 70%, Black 17.6%. Best response in 14 overall evaluable patients was PD in 9 (64.3%), PR in 2 (14%) and SD in 3 (21.4%); median PFS of 2.76 months and OS of 4.47 months. There was no significant difference in efficacy between Arms A and B but a trend of improved PFS and OS with T/D plus SBRT (see table): Median PFS of 2.1 vs. 3.3 months [HR: 2.44 (0.75-7.93); p = 0.122] and median OS of 2.6 vs. 5.7 months [HR: 1.50 (0.45-4.99); p = 0.5068]. Observed grade ≥ 3 adverse events were: Cytopenia (4), Dyspnea (1), and endocrine disorders (3) in Arm A; diarrhea (3) and cytopenias (1) in Arm B. There was an increase in circulating CD8(+) lymphocytes on treatment versus baseline in patients with objective tumor response. Conclusions: The study did not show sufficient signal of efficacy for ICI with or without SBRT in relapsed SCLC. Detailed result of the biomarker analysis will be available at the meeting. Clinical trial information: NCT02701400. [Table: see text]
Ph1/2 study of Rova-T in combination with nivolumab (Nivo) ± ipilimumab (Ipi) for patients (pts) with 2L+ extensive-stage (ED) SCLC.
Authors: Malhotra Jyoti , Nikolinakos Petros , Leal Ticiana , Lehman Jonathan , Morgensztern Daniel , Patel Jyoti D. , Wrangle John M. , Curigliano Giuseppe , Dansin Eric , Greillier Laurent , Johnson Melissa Lynne , Ready Neal , Robinet Gilles , Lally Satwant , Wong Shekman , Avsar Emin , Valenzuela Ricardo , Scripture Charity D. , Selvaggi Giovanni , Besse Benjamin 
Published: March 2020

8516 Background: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, a Notch ligand expressed in SCLC but not normal tissue. Nivo ± Ipi has activity in 2L+ SCLC. Preliminary data suggest Rova-T may result in immunogenic cell death, complementing effects of Nivo ± Ipi. Methods: Eligibility: DLL3 expression (DLT phase only), progression after ≥1 line of therapy including a platinum-based regimen; ECOG 0-1; no prior immunotherapy. All pts received 0.3 mg/kg Rova-T IV on Day 1 of two 6-wk cycles. Cohort 1 (C1) also received two 3-wk cycles of 360 mg Nivo beginning on wk 4. Cohort 2 (C2) received four 3-wk cycles of 1 mg/kg Nivo and 1 mg/kg Ipi beginning on wk 4. Both cohorts then received 480 mg Nivo q4wks until PD. Primary objective: safety. Secondary: antitumor activity by RECISTv1.1, OS. Exploratory: PK. Results: As of Sep 7, 2018, 30 pts were dosed in C1 and 12 in C2. 55% were DLL3 high (≥75% DLL3 expression). 28 (67%) completed 2 planned cycles of Rova-T. 4 pts (1 in C1, 3 in C2) experienced DLTs including rash (3), pneumonitis (1) and colitis (1). C1 completed recruitment, and C2 enrollment was stopped after DLT evaluation phase. Preliminary PK showed Nivo±Ipi had no substantial effect on Rova-T exposure. Clinical trial information: NCT03026166. Conclusions: Despite activity in 2L+ ED-SCLC, Rova-T with Nivo/Ipi is not appropriate due to DLTs. Rova-T/Nivo demonstrated some durable responses; however, the safety data suggest that optimization of dose and schedule is warranted. NCT03026166.[Table: see text]
Randomized phase 2 study of maintenance pemetrexed (Pem) versus observation (Obs) for patients (pts) with malignant pleural mesothelioma (MPM) without progression after first-line chemotherapy: Cancer and Leukemia Group B (CALGB) 30901 (Alliance).
Authors: Dudek Arkadiusz Z. , Wang Xiaofei F. , Gu Lin , Stinchcombe Tom , Kratzke Robert Arthur , Vokes Everett E. , Kindler Hedy L. 
Published: March 2020

8517 Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.
Clonal tumor evolution under induction chemotherapy and concurrent radiochemotherapy (RCHT) in patients with resectable stage IIIA (N2) and selected IIIb non-small cell lung cancer (NSCLC): Molecular analysis of the ESPATUE randomized phase III trial.
Authors: Hasheminasab Sayedmohammad , Knoll Maximilian , Schwager Christian , Nowrouzi Ali , Pfarr Nicole , Weichert Wilko , Rieken Stefan , Pöttgen Christoph , Gauler Thomas Christoph , Eberhardt Wilfried , Schuler Martin H. , Theegarten Dirk , Aigner Clemens , Debus Juergen , Stuschke Martin , Abdollahi Amir 
Published: March 2020

8543 Background: A better understanding of molecular mechanisms governing clonal tumor evolution under RCHT is of utmost importance for development of novel biomarker and targeted therapies. We report here the first attempt to decipher RCHT induced cellular and molecular perturbation in NSCLC on an integrative multiscale level. Methods: Patients with stage III disease received induction chemotherapy with cisplatin and paclitaxel followed by concurrent RCHT with 45 Gy (1.5 Gy twice daily) and cisplatin/vinorelbine according to the ESPATUE protocol. Tumor tissue was sampled from tumor enriched areas marked by pathologists at diagnosis (biopsies, n= 23) and post RCHT during surgical resection (n=22, ESPATUE-Arm B) corresponding to 16 paired samples (PS). Transcriptome analysis (n=45, 16PS), methylome analysis (n=35, 12PS), deep whole exome sequencing (WES) including copy number variation (CNV) analysis by low-pass whole genome sequencing (WGS, n=34, 13PS) were performed. A confirmatory targeted ultra-deep NGS for 41 genes was conducted (n=20PS). Results: Similarity plots of delta transcriptome data identified three distinct clusters of tumor evolution under RCHT. Cluster 1 was highly enriched for STS (5 out of 7 Pat.) compared to cluster 3 enriched for LTS (4 out of 6), p<0.02. 146 transcripts were differentially expressed as the function of RCHT (FDR <0.05). Among them, 61 genes were upregulated and enriched for ECM and tissue remodeling (COL6A3/4, Col14A1, LAMA2, PAI1, MMP2), p53 signaling (p21, GADD45B) and stress response (FOSB, EGR1) pathways, p<0.01. 39 downregulated genes were enriched for genes attributed to cell cycle- and DDR signaling (FANCI, SLX1A) p<0.05. 4221 CpG were differentially methylated (FDR<0.05). Seven inversely regulated genes were found with SLIT3 and TBX5 being among upregulated and hypomethylated genes. WES analysis revealed patterns of tumor evolution with a range of clonal diversity. In 5/13 pairs the clonal composition remained unchanged after RCHT. Approximately 500 post RCHT exclusive mutations were found. Conclusions: Clonal, transcriptional and methylome dynamic of tumor evolution towards RCHT selection pressure is unrevealed in patients with locally advanced NSCLC. This multi-scale dynamic approach provides novel means for development of biomarker and therapeutic targets. Clinical trial information: ESPATUE.
Immune landscape of the tumor microenvironment to predict prognosis and DNA mutations in patients with lung adenocarcinoma.
Authors: Lee Sunyoung S. , Elkhanany Ahmed , Baird Andrew , Dolan Jillian , Lee Dong Chan , Park Shinyoung , Baird Stuart 
Published: March 2020

8544 Background: The tumor microenvironment (TME) influences prognosis and response to therapy. The correlation between immune profiles in the TME and cancer DNA mutations is not well established. Methods: Clinical outcomes data, mRNA-seq, and DNA mutation of 480 patients (pts) with lung adenocarcinoma (LAD) were obtained from TCGA. Pts were clustered into 4 groups using unsupervised machine learning, based on mRNA expression of genes related to antigen presentation (AP) and cytolytic activity (CA): group (G) 1 with high AP and CA (52 pts); G2, high AP, low CA (82); G3, low AP, high CA (66); G4, low AP and CA (280). Analysis of the immune landscape was performed using mRNA-seq of 191 genes enriched in cellular and structural elements of TME. DNA mutations were analyzed using the R package ggpubr and correlated in G1-G4. Results: Pts in G1 have high expression of genes related to immune activation (IA) and decreased expression of immune suppression (IS) and have the best prognosis. Pts in G2 have intermediate prognosis with decreased IA genes and intermediate expression of genes related to IS and immune checkpoints. Pts in G3 have the worst prognosis with very high expression of genes related to immune checkpoints, desmoplasia, T cell co-inhibition, and IS. They also have low CD39 expression implying low cancer antigen-driven T cells. Pts in G4 have intermediate prognosis with highly depressed IA genes. Out of 70,199 non-synonymous mutations, the top 50 mutated genes in each pt group were identified: 36, 26, 31, and 17 DNA mutations were only found in G1, G2, G3, and G4 (refer to presentation). EGFR mutation was only found in G2; KRAS in G2/4; TP53 in G2/3/4. Conclusions: Our correlation analysis of mRNA-seq and DNA mutation shows that the immune landscape of TME can predict DNA mutations and prognosis. It further demonstrates a close connection between DNA mutations and changes in TME mRNA expressivity which appear to have valuable prognostication potential in the clinical setting with now widely available genomic testing.
Benefit of combining local treatment and systemic therapy for stage IV NSCLC: Results from the National Cancer Database.
Authors: Dendy Case Meaghan , Uhlig Johannes , Blasberg Justin , Boffa Daniel J. , Chiang Anne C. , Gettinger Scott N. , Kim Hyun S. 
Published: March 2020

8545 Background: To determine the potential benefit of combining local and systemic therapy in stage IV non-small cell lung cancer (NSCLC). Methods: Data from stage IV NSCLC patients receiving systemic therapy alone, surgical resection and systemic therapy, or external beam radiation therapy/thermal ablation (EBRT/TA) and systemic therapy were acquired from the 2010-2015 National Cancer Database (NCDB). EBRT and TA patients were combined to enhance the power of the study. Overall survival (OS) was evaluated via multivariable Cox proportional hazards models. Comparison was made between EBRT/TA and systemic therapy alone utilizing 1:1 propensity matching analysis. A multivariable logistic regression model was used to determine variables predictive of lung cancer treatment. Significant variables (p < 0.05) were used to calculate the propensity score, and patients receiving EBRT/TA and systemic therapy were 1:1 matched using a greedy (nearest-neighbor) approach. Results: 46,964 patients from the NCDB database fulfilled inclusion criteria (surgical resection n = 1,235; EBRT/TA n = 12,456; systemic therapy alone n = 33,273.) Treatment differed across patient demographics and disease characteristics. Surgical resection demonstrated superior OS compared to EBRT/TA and systemic therapy alone, even after multivariable adjustment (compared to systemic therapy alone HR = 0.54, 95% CI: 0.50-0.58, p < 0.001; compared to EBRT/TA HR = 0.56, 95% CI: 0.52-0.60, p < 0.001). EBRT/TA treatment demonstrated superior survival compared to systemic therapy alone after accounting for confounders via propensity score matching (HR = 0.95, 95% CI: 0.93-0.98, p = 0.002). Interaction analyses indicated heterogeneous effectiveness of EBRT/TA according to patient demographics and cancer factors: the survival benefit of EBRT/TA over systemic therapy alone was especially pronounced in stage IV squamous cell carcinoma patients with limited nodal and metastatic disease (HR = 0.78, 95% CI: 0.71-0.85, p < 0.001 compared to systemic therapy alone; OS rates at 1-year = 50.9% vs. 42.4%; 2-years = 26.6% vs. 19.8%; 3-years = 17.2% vs. 10.1%). Conclusions: Stage IV NSCLC patients who received EBRT/TA or surgical resection in addition to systemic therapy demonstrated prolonged survival. EBRT/TA in combination with systemic therapy should be preferred in selected patients that are ineligible surgical candidates.
Malignant pleural mesothelioma (MPM) genomic profile in the randomized phase II RAMES Study.
Authors: Pagano Maria , Gnoni Roberta , Bonelli Candida , Zanelli Francesca , Garassino Marina Chiara , Ceresoli Giovanni Luca , Pasello Giulia , Tiseo Marcello , Soto Parra Hector J. , Grosso Federica , Zucali Paolo Andrea , Torricelli Federica , Pinto Carmine 
Published: March 2020

8547 Background: Since MPM is an uncommon neoplasia, its rarity has limited available data on molecular drivers. Methods: RAMES study evaluated the second-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo. From December 2016 to July 2018 (end of enrolment), 164 patients (pts) were admitted to this study, which involved the collection of tumor samples - with diagnosis - to evaluate 34 genes by NGS (ACTB, ACTG1, ACTG2, ACTR1A, BAP1,CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6,-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53,TXNRD1, UQCRC1, XRCC6). We reported the results of the first 87 pts (54%): hystotype was epithelioid in 70 pts (80%), biphasic in 14 pts (16%) and sarcomatoid in 3 pts (4%). Median age was 63 years (range 45-81). 70 pts were male (80%) and 17 pts were female (20%). In the present analysis, we included 55 pts in stage III (63%), 26 pts in stage IV (30%) and 6 pts whose stage was unknown. Median first-line PFS platinum/pemetrexed therapy was for 5.75 months (I.C. 95% 4.75-6.76). PFS was ≤6 months for 40 pts (49%), and 6 months for 41 pts (51%). Results: 187 functional somatic mutations were identified. Genomic alterations/patient were 1 gene in 29 pts (33%), 3 genes in 18 pts (21%) and ≥5 genes in 2 pts (2%). The most frequent somatic mutations were RDX in 35 pts (40%), MXRA5 in 20 pts (23%), BAP1 in 13 pts (15%) and ACTG 1 in 9 pts (11%). When patients were collated by stage, the most frequent mutations were: MXRA5 in 16 pts in stage III (29%), BAP1 in 5 pts in stage IV (19%) and RDX in 16 pts in stage IV (62%). The percentage of somatic mutations in patients with PFS as first-line chemotherapy for ≤6 and >6 months was 2.2 and 1.6 (p=0.032), respectively. The most frequent mutations/patient for ≤6 and >6 months PFS were: RDX in 14 pts (35%) with PFS < 6, RDX in 19 pts (46%) with PFS >6 and MXRA5 in 11 pts (27%) with PFS >6. Conclusions: This preliminary data suggests a possible role that a genetic signature may play in distinguishing MPM with different clinical-pathological features. The results are expected to be clarified further in the second step of the study, which is ongoing. Clinical trial information: 2016-001132-36.