bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial of NGR-hTNF in combination with standard chemotherapy in previously untreated non-small cell lung cancer (NSCLC).
Authors: Gregorc Vanesa , Zilembo Nicoletta , Grossi Francesco , De Pas Tommaso M , Rossoni Gilda , Pietrantonio Filippo , Rijavec Erika , Citterio Giovanni , Lambiase Antonio , Bordignon Claudio 
Published: March 2020

8035 Background: NGR-hTNF, a selective antivascular agent, induces at low dose an initial vascular normalization that greatly enhances the intratumoral chemotherapy uptake, with synergistic effects that were noted especially in combination with cisplatin and gemcitabine. Methods: Chemo-naive patients (pts) with advanced NSCLC were stratified by histology (nonsquamous or squamous) and PS (0 or 1) and randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) for 6 cycles, with (arm A) or without (arm B) NGR-hTNF given at 0.8 μg/m2/d1/q3w until progression. Progression-free survival (PFS) was primary aim (1-β=80%, 1-sided α=10%, n=102). Secondary aims comprised adverse events (AEs), response rate (RR), and overall survival (OS). Results: Baseline characteristics in arm A (n=62) vs B (n=59) were: median age: 62 vs 63 years; men: 37 vs 39; PS 1: 23 vs 23; squamous: 18 v 17; smokers: 41 vs 43. For the nonsquamous stratum, 299 cycles were given in arm A (mean 7.0; range 1-20) and 192 in arm B (4.8; 1-6), while for the squamous stratum, 113 in arm A (6.7; 1-31) and 52 in arm B (3.5; 1-6). Rates of grade 3/4 AEs were similar (arm A vs B): neutropenia 13% vs 18%, anaemia 7% vs 4% and fatigue 7% vs 11%. No grade 3/4 AEs related to NGR-hTNF or bleeding/pulmonary hemorrhage events were reported in the squamous subset. With median follow-up time of 24.2 months, median PFS (5.8 vs 5.6 months; HR=0.92), RR (25% vs 21%) and 1-year OS (53% vs 53%) were similar between the two treatment arms. However, by predefined analysis in the squamous stratum, median PFS was 5.6 months for arm A and 4.3 months for arm B (hazard ratio, HR=0.75) and median OS was 14.2 months for arm A and 9.7 months for arm B (HR=0.49; p=0.07). In pts with squamous histology, RR was 38% for arm A and 27% for arm B (odds ratio=1.6), while the median changes in tumor size on treatment from baseline to 2nd, 4th and 6th cycle for arm A vs B were -32% vs -20%, -41% vs -19%, and -42% vs -14%, respectively. Conclusions: Clinical tolerability and benefit were noted in squamous NSCLC with NGR-hTNF plus cisplatin and gemcitabine, which deserve further investigation. Clinical trial information: NCT00994097.
Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies.
Authors: Falconi Adam , Lopes Gilberto , Parker Jayson L. 
Published: March 2020

8040 Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.
Retrospective evaluation of RET biomarker status and outcome to vandetanib in four phase III randomized NSCLC trials.
Authors: Platt Adam , Elvin Paul , Morten John , Ji Qunsheng , Donald Emma , Womack Chris , Su Xinying , Zheng Li , Gladwin Amanda , Vasselli James Robert , Lee Jin Soo , De Boer Richard H. , Herbst Roy S. ,   The RET Analysis Team
Published: March 2020

8045 Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been estimated at 0.2–6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from 4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling, to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel ± V 100mg), ZEAL (NCT00418886; pemetrexed ± V 100mg), ZEPHYR (NCT00404924; V 300mg vs placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234 had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944 and 1102. RET fusions (in >10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n=3; comparator, n=4), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanib-treated RET fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor shrinkage in 2. Overall, 2.8% (n=26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in >10% tumor cells), 8.1% (n=76) had lower RET gene copy number gain (4–6 copies in ≥40% tumor cells) and 8.3% (n=92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). There was no difference in ORR between vandetanib and comparator for the RET amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1% [3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44], respectively). Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886; NCT00404924.
Predictors of survival for younger patients (pts) less than 50 years of age with non-small cell lung cancer (NSCLC): A California Cancer Registry (CCR) analysis.
Authors: Lara Matthew Stephen , Brunson Ann , Tomlinson Ben Kent , Wun Theodore , Qi Lihong , Cress Rosemary , Lara Primo , Gandara David R. , Kelly Karen 
Published: March 2020

8049 Background: Lung cancer is often seen in older pts, with a median age at diagnosis of 70 years (yrs). Epidemiology and outcomes are reportedly different among younger NSCLC pts (< 50 yrs). We hypothesized that these pts have longer cause-specific survival (CSS) and that baseline clinical features prognostic for CSS would be identified. Methods: NSCLC pts in the CCR diagnosed between 1/98 through 12/09 were included. The primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts <50 years, adjusted for baseline variables. Results: We identified 132,671 lung cancer pts: 114,451 (86.3%) had NSCLC. 6,389 (5.6%) were < 50 yrs (median, 46 yrs). Demographics: White (3,557, 56%); Histology: AdenoCA (AC) (3,406, 53%), Squamous (781, 12%), BAC (291, 4.6%); Stage IV (3,655, 57%). Fewer pts < 50 yrs were diagnosed in later yrs: from 37% in ‘98-’01 to 29% in ‘06-‘09. Results of Cox PH models for all ages and < 50 years are shown. Conclusions: The relative proportion of pts < 50 yrs has declined by 22% over the past decade. Age < 50 years was an independent predictor of improved CSS (HR 0.83, p<0.001). In younger pts, AC histology was not prognostic for CSS (versus squamous) despite known differences in clinical and biologic behavior between subtypes.Importantly, clinical variables strongly prognostic for CSS were identified in pts < 50 yrs. [Table: see text]
A comparison of bronchofiberscopic (BFS) washing cytology (BWC) and formalin-fixed paraffin-embedded tissue (PPFE) in the analysis of EGFR mutations in advanced non-small cell lung cancer (NSCLC).
Authors: Hida Naoya , Misumi Yuuki , Agemi Yoko , Sato Akira , Ishii Mari , Shimokawa Tsuneo , Okamoto Hiroaki 
Published: March 2020

8054 Background: In the treatment of advanced NSCLC, EGFR mutation status is one of the most predictive factors for the efficacy of EGFR tyrosine kinase inhibitors, and the evaluation of EGFR mutation status using the PPFE has been widely used for this analysis throughout the world. However, whether BWC can be used as an alternative for PPFE in the analysis of EGFR mutations is unknown. The largest study evaluating these 2 methods included only around 20 samples. Therefore, in the current study, we compared the freeze stock solution of BWC with PPFE for the determination of EGFR mutation status in a large sample set. Methods: In diagnostic BFS examinations, after curetting or brushing and biopsy to target lesions, subsequent bronchial washing by saline was performed. Thereafter, the saline fluid in which the forceps were washed and the bronchial washing fluid were mixed in a sterilized tube and were immediately frozen in a -20°C freezer. EGFR mutation testing for both BWC and PPFE was performed using high-sensitivity PCR (BML, PCR-Invader). Results: A total of 440 BFS examinations were performed from Aug 2010 to Nov 2011 in our hospital. The BWCs of 268 suspected cases of lung cancer were successfully obtained. Of these, 51 cases that were pathologically confirmed as adenocarcinoma based on both BWC and PPFE were analyzed in this study. EGFR mutations were identified in 25 cases, while the remaining 26 cases had wild-type EGFR. In 49 of 51 cases, the results of EGFR mutation status were the same for BWC and PPFE, and the concordance rate was 96%. In one case, an exon-18 mutation was detected only by BWC. In another case an exon-21 mutation was detected only by PPFE. In 24 of 25 cases of EGFR mutation, the mutation site was the same in both samples. The kappa coefficient was 0.92. Conclusions: This is the largest genetic study to date demonstrating a head-to-head comparison of BWC and PPFE for the evaluation of EGFR mutations. Both methods showed high reliability and concordance using high-sensitivity PCR. BWC is considered a simple, rapid method and represents an effective alternative for PPFE in EGFR mutation testing.
BIM deletion polymorphism to predict systemic treatment outcome in advanced non-small cell lung cancer.
Authors: Lee Jih-hsiang , Lin Yu-lin , Chen Hsuan-Yu , Chang Yeun-Chung , Yu Chong-Jen , Shih Jin-Yuan , Chen Kuan-Yu , Yang Pan-Chyr , Yang Chih-Hsin 
Published: March 2020

8055 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and chemotherapies are treatments for EGFR mutant non-small cell lung cancer (NSCLC) patients. We explored the predictive factors for progression-free survival (PFS) and overall survival (OS) on first-line EGFR-TKIs and second-line chemotherapies in NSCLC patients. Methods: One hundred and six chemonaïve NSCLC patients who received first line gefitinib in a phase II study were prospectively followed until death. Clinical and molecular biomakers were correlated with PFS and OS. Results: The OS and PFS of first-line gefitinib treatment were 19.4 (95% CI 15.6-23.3) months and 7.4 (95% CI 6.7-8.1) months, respectively. Sixty-nine patients (65%) received subsequent second-line chemotherapy. Median PFS and OS of second-line chemotherapy were 5.7 (95% CI 4.8-6.6) and 15.1 (95% CI 10.5-20.2) months. Bcl-2-like protein 11 (also named as BIM) deletion polymorphism was found in 17 out of 101 (16.8%) patients tested. The median PFS from first-line gefitinib in patients carrying normal BIM and deletion polymorphism were 8.1 months and 3.6 months, respectively (p<0.001), and the median OS were 22.1 months and 14.1 months, respectively (p=0.041); in 44 patients with common EGFR mutations (del 19 or L858R), the PFS for patients carrying normal BIM and deletion polymorphism were 9.6 months and 7.4 months, respectively (p=0.034). A multivariate analysis suggested that BIM deletion polymorphism and EGFR mutational status were independent predictors for gefitinib PFS (hazard ratio 2.83, p=0.001, and 0.63, p=0.03, respectively). Conclusions: BIM deletion polymorphism predicts shorter PFS in EGFR mutation NSCLC patients treated with first line gefitinib.
Final efficacy and safety results of pemetrexed (pem) continuation maintenance (mtc) therapy in the elderly from the PARAMOUNT phase III study.
Authors: Gridelli Cesare , Thomas Michael , Prabhash Kumar , El Kouri Claude , Blackhall Fiona Helen , Bustin Frederique , San Antonio Belen , Zimmermann Annamaria , Chouaki Nadia , Visseren-Grul Carla , Paz-Ares Luis 
Published: March 2020

8068 Background: The PARAMOUNT phase III trial showed that mtc pem after pem-cisplatin induction was well tolerated and effective for patients (pts) with advanced nonsquamous NSCLC. Here we present the final OS and safety data from this study in elderly (≥70 yrs) vs. non-elderly (<70 yrs) pts. Methods: In this double-blind study, 539 pts with a PS of 0/1 were randomized (2:1, stratified for stage, PS and induction response) to receive mtc pem (n=359, 500 mg/m2, day 1, 21 day cycle) or placebo (plc) (n=180). The study was powered for PFS (previously reported) and key secondary OS. Subgroup analyses were done for pts ≥70 yrs and <70 yrs. Results: Subgroups (≥70: n=92, 17%; <70: n=447, 83%) had similar baseline characteristics except for PS and sex (elderly, PS 0/1: 22%/77%, M/F: 66%/34%; non-elderly, PS 0/1: 34%/65%, M/F: 56%/44%). The median ages were 73 yrs (≥70) and 60 yrs (<70). The mean cycles received for pts ≥70 were 7.4 (range 1-36, dose intensity (DI) 91%) for pem and 4.5 for plc, and for pts <70 were 8.0 (range 1-44, DI 94%) for pem and 5.1 for plc. The OS HRs (pem vs. plc) were 0.89 (95% CI: 0.55-1.4) for ≥70 yrs and 0.75 (95% CI: 0.60-0.95, p=0.015) for<70 yrs. The median OS (95% CI) (≥70) was 13.7 mo (10.4-19.4) for pem and 12.1 mo (8.4-16.9) for plc; the median OS (95%CI) (<70) was 13.9 mo (12.5-16.1) for pem and 10.8 mo (9.5-12.9) for plc. The 1 and 2 yr OS rates (95% CI) for the elderly were 60% (45-71%) and 34% (21-47%) for pem vs. 52% (36-66%) and 28% (15-43%) for plc, respectively. For non-elderly pts, the 1 and 2 yr OS rates were 58% (52-63%) and 31% (26-37%) for pem vs. 43% (35-52%) and 19% (13-27%) for plc, respectively. The Table shows a subset of drug-related AEs. Conclusions: Continuation mtc pem had comparable survival and toxicity profiles in the ≥70 and <70 yrs subgroups. However, Gr 3/4 anemia and neutropenia were numerically higher for pts ≥70 yrs. Clinical trial information: NCT00789373. [Table: see text]
Prognostic impact of tumor (T) and lymph node (N) status in patients with metastatic non-small-cell lung cancer (NSCLC).
Authors: Devarakonda Siddhartha , Xia Bing , Gao Feng , Govindan Ramaswamy , Morgensztern Daniel 
Published: March 2020

8076 Background: Although commonly reported in databases and clinical trials, T and N status do not affect the final stage or overall treatment plan for patients with metastatic NSCLC. Since there is limited data on the impact of T and N status on outcomes in this population, we conducted a Surveillance, Epidemiology, and End Results (SEER) study to address this question. Methods: The SEER database was searched for patients with stage M1b NSCLC, with known T and N status, diagnosed between 2004 and 2008. Patients with T0 and malignant pleural effusion were excluded. Overall survival (OS) was estimated by the Kaplan-Meier method, while the hazard ratios (HR) were estimated and compared using Cox proportional hazard models. Results: Among the 25,919 patients included, the frequencies of T1, T2, T3, and T4 were 15.8%, 28.2%, 33.6% and 22.4% respectively, whereas N0, N1, N2, and N3 were observed in 28.0%, 9.3%, 47.1% and 15.6% respectively. One-year OS ranged from 21.1% in T4 to 35.8% in T1, and 23.1% in N2 to 33.2% in N0 disease (Table). Both T and N were also identified as independent predictors for OS in multivariable analysis adjusted for age, gender, race, and histology. Conclusions: Both T and N status are important clinical prognostic factors that should be taken into consideration when evaluating patients with metastatic NSCLC. If confirmed in prospective studies, clinical trials and analyses of either clinical or molecular prognostic factors in the future may need to be adjusted according to the complete TNM staging. [Table: see text]
Differences in mutation patterns of diagnostic versus post-chemotherapy samples in patients with metastatic non-small cell lung cancer (NSCLC).
Authors: William William Nassib , Erickson Heidi S. , Wei Caimiao , Hanson Nana , Tang Ximing , Rodriguez Jaime , Kalhor Neda , Lee J. Jack , Hong Waun Ki , Kim Edward S. , Wistuba Ignacio Ivan 
Published: March 2020

8079 Background: Many clinical trials in metastatic NSCLC patients who failed first-line chemotherapy have utilized pre-treatment, diagnostic tissues for marker assessment. BATTLE was a randomized, biopsy-driven clinical study in patients with metastatic NSCLC previously treated with systemic therapy. Fresh biopsies were obtained at the time of enrollment for biomarker evaluation. We hypothesized that molecular abnormalities found at the time of enrolment in BATTLE would differ from baseline, pre-chemotherapy, diagnostic tissue. Methods: We isolated DNA (SPRI-TE-based DNA recovery and cleanup methodology) from 82 matched pre-chemotherapy and BATTLE formalin-fixed paraffin-embedded specimens. Mutations were assessed by MALDI-TOF MS (MassArray, Sequenom Inc) using a lung cancer panel of 16 genes/140 assays (AKT1, BRAF, CTNNB1, EGFR, ERBB2, FGFR3, HRAS, KRAS, MEK1, MEK2, MET, NRAS, PIK3CA, PIK3R1, PTEN, and STK11) and were compared between pre-chemotherapy versus BATTLE samples. Results: Mutations were identified in 25 pre-chemotherapy samples (14 K-RAS, 5 EGFR, 3 PIK3CA, 1 STK11, 1 PTEN, 1 HRAS, 1 CTNNB1). Conversely, 29 BATTLE samples had at least one mutation (14 K-RAS, 7 EGFR, 5 PIK3CA, 2 STK11, 1 PTEN, 1 HRAS, 1 CTNNB1). For the matched pair analysis, 46 patients had wild-type tumors both in pre-chemotherapy and BATTLE samples. 11 patients had wild-type tumors in pre-chemotherapy samples, but had a mutation identified in BATTLE samples (4 K-RAS, 4 EGFR, 2 PIK3CA, 1 STK11). 7 patients had a mutation in pre-chemotherapy samples, but no mutations in BATTLE samples (4 K-RAS, 2 EGFR, 1 HRAS). The remaining 18 patients had mutations in both the pre-chemotherapy and BATTLE samples; of these, 2 had different mutations in the paired samples (both within the same genes, 1 KRAS, 1 PIK3CA). Overall, there was a 24% gene mutation discordance rate between pre-chemotherapy and BATTLE samples. Conclusions: Profiling of fresh biopsies may more accurately reflect molecular abnormalities present in the tumor at the time of initiation of salvage therapy, underscoring the importance of real time tissue collection in biomarker-driven studies in this setting (V Foundation, DoD).
Comparison of two chemotherapy regimens in non-small cell lung cancer patients relapsing after surgery and peri-operative chemotherapy (IFCT-0702 study).
Authors: Moro-Sibilot Denis , Audigier-Valette Clarisse , Merle Patrick , Quoix Elisabeth A. , Souquet Pierre Jean , Barlesi Fabrice , Chouaid Christos , Molinier Oliver , Lavole Armelle , Mazieres Julien , Baudrin Laurence , Morin Franck , Zalcman Gerard ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

8081 Background: To evaluate the benefit of adding cisplatin or carboplatin (P) to docetaxel (D) chemotherapy (CT) in patients with the first metastatic relapse after perioperative chemotherapy and surgery. Methods: Patients (Pts) with histologically or cytologically confirmed inoperable non-small cell-lung cancer not eligible for curative radiotherapy (local or metastatic relapse), disease progression after perioperative chemotherapy and surgery and PS 0-1. Pts were randomized to D 75 mg/m² combined with cisplatin 75 mg/m² or carboplatin AUC5 every 3 weeks (Arm A) or alone (Arm B). The primary endpoint was progression-free survival (PFS). Results: Due to low accrual the trial was interrupted after inclusion of 88 patients. From November 2007 to August 2012, 68 males and 20 females, median age (range) 61 (41-75), ECOG PS 0/1/ 49%/50%, squamous histology 39%, Arm A and Arm B 44 patients each, were enrolled. Interval from last cycle of perioperative CT ou last cycle of adjuvant CT was ≥ 12 months in 69% of pts. 79.5% of patients received DP full treatment. A non-statistically significant increase in PFS favoring combined CT was observed with a HR of 0.73 (95% CI: 0.46-1.15; p = 0.18), median PFS 8 months vs 5.6. Objective response rate was increased in the P-containing arm; p <10-4). However, overall survival was not improved by the addition of P to D; the HR for death was 0.90 (95% CI: 0.55-1.48; p = 0.68) median OS 15.9 months vs 12.4 months. Overall grade 3/4 toxicity was observed in 36 pts (DP) vs 30 (D) : neutropenia (32 pts vs 26), febrile neutropenia (8 vs 3), non-hematological toxicities (18 vs 6). Conclusions: PFS and OS weresurprisingly longer than expected in this cohort of NSCLC patients with metastasis, and comparable with that observed in historical cohorts of NSCLC treated in first-line. DP resulted in a non significant 27% reduction of hazard of progression as compared to D alone. A reduced statistical power related to a slow and insufficient accrual may explain this lack of significance. Considering survival data and toxicity profile, we suggest that these patients behave like first-line patients and may probably be treated accordingly with a platinum-based doublet. Clinical trial information: NCT00535275.