bluuebunny/crossref_metadata_2025_split huggingface dataset:
CDKN2A/B gene loss and MDM2 alteration as a potential molecular signature for hyperprogressive disease in advanced NSCLC: A next-generation-sequencing approach.
Authors: Giusti Raffaele , Mazzotta Marco , Filetti Marco , Marinelli Daniele , Di Napoli Arianna , Scarpino Stefania , Scafetta Giorgia , Mei Monica , Vecchione Andrea , Ruco Luigi , Marchetti Paolo 
Published: May 2019

e20628 Background: Hyperprogressive disease (HPD) incidence ranges from 8% to 21% in patients treated with anti-PD-1/PD-L1 mAbs in NSCLC and is associated with poor survival. Previously published data underlined a link between HPD across different cancers types and specific genetic alterations, such as MDM2 amplification and EGFR aberrations. We present a single-center cohort of patients with NSCLC and PD-L1 > 50% treated with 1st-line pembrolizumab. We performed NGS, IHC and FISH analysis to evaluate genetic correlations with the clinical phenotype. Methods: Clinical data from 20 patients with diagnosis of advanced NSCLC treated with 1stline immunotherapy pembrolizumab were retrospectively collected. HPD was defined by Time to Treatment Failure ≤2 months and raising in Tumor Burden ≥50% compared with basal CT-scan. MDM2 amplification was investigated by FISH on FFPE tissue sections using the MDM2/CON12 break apart FISH Probe. Positive cases were defined as those with > 10% positive tumor cells. We performed IHC for MDM2 protein on FFPE tissue sections. The staining was semiquantitatively graded for the intensity as: 0, negative; 1+, weak positive; 2+, moderately positive; 3+, strongly positive, and for the extent as 0– < 1% (negative), 1–50% (focal), and > 50% (diffuse). We also performed NGS analysis (FoundationOne CDX, Foundation Medicine Inc.) on 324 preidentified genes. Results: We identified 5 cases of HPD; all five cases showed MDM2amplification by FISH analysis and a focal protein expression by IHC with the strongest nuclear staining observed in the cases showing a higher degree of MDM2 amplification (8/9 dots) and a weaker expression in those with a lower MDM2amplification (4/5 dots). NGS analysis showed MDM2amplification in 1/5 HPD patient and a loss of CDKN2A/B in 4/5 patients. None of the non-HPD patients had IHC expression of MDM2 or amplification of the gene. Among the non-HPD patients no genetic alterations regarding MDM2 and/or CDKN2A/B were found on NGS analysis. Conclusions: Our data suggest a potential role of CDKN2A/B gene loss and alteration of MDM2 on the establishment of HPD in NSCLC patients treated with immunotherapy. Because the HPD logic is not yet clear, more data is needed to better understand the link between this genomic signature and the development of HPD.
Efficacy and safety of Crizotinib in patients with ALK positive non small cell lung cancer (NSCLC): Real-world findings.
Authors: Raposeiras Cristina Azpitarte , De Dios Alvarez Noemi , Garcia Jorge , Areses Manrique Maria Carmen , Fernández Núñez Natalia , Afonso Afonso Francisco J. , Amenedo Margarita , Veiga Nazaret Quiroga , Cebey Victor , Lazaro Quintela Martin , Firvida Jose-luis , Campos Balea Begoña , Ruiz Bañobre Juan , Varela Pose Vanesa , Agraso Busto Sara , Constenla Manuel 
Published: May 2019

e20636 Background: First or second line crizotinib has shown greater efficacy in clinical trials than chemotherapy in patients with NSCLC ALK positive and it was the first approved ALK inhibitor. However, there are limited data describing the use of crizotinib and its outcomes in real-world settings. Methods: This is a retrospective, observational study of patients crizotinib treated ALK positive metastatic NSCLC, who received treatment between 1 January 2013 and 30 november 2018. The primary objective was progression free survival (PFS); secondary objetives were overall survival (OS), response rates and toxicity. Results: Fifty-eight patients with NSCLC ALK+ were recollected, 33 women and 25 men. The median age was 61 years (25-88); 46.6% were never smokers, 31% were former smokers. The majority (96.6%) had confirmed adenocarcinoma histology and 25.9% had brain metastases at inicial treatment. Crizotinib was used as first line 55.2% and second line in 37.9%. Progression disease was the most frequent reason of discontinuation of crizotinib (74%) and in 5 patients was discontinued because of toxicity. The most frequent toxicities were edemas (37.9%), increased transaminases (27.5), diarrhea (24%) and nauseas (20%). Grade 3-4 toxicities were present in 4 cases with increase transaminases, 1 case of neumonitis and 2 patients with diarrhea. The response rate was 63.8%. The median PFS was 12.66 months (95% CI :7.95- 17.38) and median OS was 23.36 months (95%CI: 16.29-30.44).In patients with brain metastases (15) the response rate was 46.6% and median OS decrease to 15.36 months (95%CI: 0.1-30.8). Conclusions: Our findings indicate that the results of crizotinib in the real world are consistent or sightly improved with prior clinical trial in PFS and OS, despite our sample includes patients for first line and second/later line crizotinib and ¼ of patients had brain metastasic at crizotinib initiation.
Real-world treatment patterns, survival, and cost among elderly patients with small-cell lung cancer (SCLC).
Authors: Shao Changxia , He Jinghua , Kachroo Sumesh , Jin Fan 
Published: May 2019

e20647 Background: Given a dearth of literature, this study aimed to investigate real-world use of systemic therapies, survival, and costs among elderly SCLC patients (pts) in U.S. Methods: Pts (65+ years old) with an initial diagnosis of SCLC during 2007-2013 were identified using the SEER-Medicare data. Overall survival (OS), duration of treatment (DOT) and time to next treatment (TTNT) were estimated based on the Kaplan-Meier method. Costs (2016 US dollars) were derived from Medicare claims. Results: A total of 11 812 pts were identified with 7 797 (66%) being stage IV at diagnosis. During an average of 10 months (m) follow-up post diagnosis, 6 509 (55%), 2 238 (19%) and 679 (6%) received first line (1L), 2L and 3L therapy, respectively. The median OS was 9 m from 1L start and 6 m from 2L or 3L start, suggesting existing treatment providing limited survival benefit. Majority pts (93%) received platinum-based therapy for 1L with Car + etoposide (Eto, 59%) being the most commonly used regimen, followed by Cis + Eto (18%) and Car monotherapy (8%). Car + Eto, Top and Pac were the top 3 regimens used in 2L and 3L. Median DOTs were 4-6 m, yet TTNT ranged from 7 to 18 m across lines of therapy. The average per person per month (PPPM) costs were $9.4k for 1L, $8.9k for 2L, and $8.8k for 3L. Conclusions: Advanced SCLC remains an aggressive malignancy with poor prognosis, lack of ideal therapy and high medical cost, which highlighted high unmet medical need of SCLC among elderly pts. [Table: see text]
Health care utilization associated with adverse events (AEs) among metastatic non-small cell lung cancer (mNSCLC) patients treated with immunotherapy or chemotherapy.
Authors: Engel-Nitz Nicole , Ryan Kellie , Johnson Michael P , Bunner Scott 
Published: May 2019

e20655 Background: Chemotherapy and immunotherapy (IO) are associated with increased overall survival in patients with mNSCLC, yet real-world data on AE-associated healthcare utilization are sparse. This study assessed incidence and utilization associated with AEs among patients initiating first-line treatment for mNSCLC with IO, IO with chemotherapy (IC), or chemotherapy alone (CH). Methods: Data were claims from commercial and Medicare Advantage patients (Jan 2008-Feb 2018). Inclusion criteria were mNSCLC, health plan enrollment for ≥6 months pre- (baseline) and ≥1 month post-index date; initiation of recommended systemic therapy for mNSCLC. Excluded were targeted or small-cell lung cancer therapy, and baseline surgery or other systemic therapy. AE incidence and healthcare utilization were measured from start of 1st line therapy until earliest of start of 2nd line therapy or 180 days. AEs evaluated included hematologic, GI, endocrine, infections, infusion reactions, muscle, neurological, and respiratory. Results: Cohorts were 8,818 CH, 482 IO, and 412 IC. Mean age was older for IO (72 yrs, vs. 69 IC, 68 CH; P < 0.001). IOs used were atezolizumab (n = 12), nivolumab (n = 148), and pembrolizumab (n = 673). Common chemotherapies were carboplatin (74%), pemetrexed (30%), and paclitaxel or etoposide (22%). Overall, 74% had ≥1 AE; incidence rate ratios (IRR) vs. IO (95% CI) were IC 1.36 (1.15-1.60) and CH 1.43 (1.28-1.61). Frequent AEs were blood conditions (43%), GI (32%), and infections (29%). IRR vs. IO included infections (1.94 CH), GI (1.71 IC, 1.90 CH), anemia (4.05 IC, 5.68 CH), leukopenia (5.69 IC, 22.28 CH), and thrombocytopenia (3.70 CH). CH had lower rates vs. IO for hyperthyroidism (2% IO; IRR 0.16 CH) and hypothyroidism (12% IO; IRR 0.19 CH). AE overlaps with infection were common; 61% of patients with infection had a hospitalization that involved both infection and another AE. AE-associated visits varied by cohort; ambulatory: 46% (IO), 50% IC, 61% CH; ER: 25% IO, 27% IC, 30% CH; inpatient: 29% IO, 35% IC, 37% CH (P < 0.05 for all CH vs IO). Conclusions: AE-associated visits in mNSCLC were lower for IO-treated than for CH or IC-treated patients.
The role of low dose aspirin, vitamin D, or metformin in EGFR, ALK, and ROS positive non-small cell lung cancer: A single institution retrospective analysis.
Authors: Bernabe Ramirez Carolina , Sharma Sandhya , Sanchez-Escobar Jose G , Sullivan Kevin M. , Seetharamu Nagashree 
Published: May 2019

e20656 Background: Tyrosine kinase inhibitor (TKI) is the backbone therapy for EGFR, ALK and ROS positive (pos) non-small cell lung cancer (NSCLC). Metformin has shown to sensitize EGFR resistant lung cancer cells in vitro through IL-6/STAT pathways. COX-2 overexpression triggers activation of a transcription factor that binds to EGFR that activates MAPK signaling pathway. Vitamin D receptor (VDR) has shown to directly inhibit EGFR transcriptional activity. Some studies have shown that adding metformin, aspirin and vitamin D (MAD) to chemotherapy may improve progression free survival (PFS) and overall survival (OS) in lung cancer. However, data supporting use of MAD is unknown in EGFR, ALK and ROS pos NSCLC. Methods: Patients (pts) with EGFR, ALK, ROS pos NSCLC treated with first line TKI from January 2014 to June 2017 were included. Information on concurrent use of MAD was obtained. Patients were dichotomized based on use of these individual supportive medications. Two sample t-test was used to compare mean PFS and chi-square test to compare proportions of disease control rate (DCR) at 3 months between groups. Results: 74 patients were included. Vitamin D supplementation (n = 38, 51.3%) prolonged PFS by 16 m vs 11 m (p = 0.04; 95%CI 0.23 to 9.34). For those on aspirin (n = 23, 35%), mean PFS was 16m vs 12.5 m (p = 0.72; 95% CI -5.58to 3.88). Mean PFS for pts on metformin (n = 8, 10%) was 14 months (m) vs 13.5 m for those who were not (p = 0.93, 95% CI -7.27 to 7.87). DCR for metformin use was 26.5% vs 89% (p = 0.0001); for aspirin was 50% vs 65% (p = 0.17) and for vitamin D 48.6% vs 43.7% (p = 0.69). Conclusions: To our knowledge, no data has been published regarding use of MAD in NSCLC with driver mutations. In our study, concurrent use of vitamin D with TKI prolonged PFS in these pts. However, this effect was not seen with metformin or aspirin. Our study was limited by retrospective design, possible under-reporting of medication use by patients and small patient population. Further prospective studies using these medications is important to evaluate the synergistic benefit with the approved targeted therapy.
Correlating the effects of VeriStrat result, anti-PD1 therapy, and neutrophil-to-lymphocyte ratio (NLR) on progression-free survival (PFS) in patients with stage IV non-small cell lung cancer (NSCLC).
Authors: Randall Megan , Basu Sanjib , Batus Marta , Borgia Jeffrey Allen , Bonomi Philip D. , Fidler Mary J. 
Published: May 2019

e20660 Background: Biodesix VeriStrat (VS) is a mass spectrometry assay found to be prognostic in previously treated and front-line NSCLC patients. A label assigns a “good” or “poor” result and is believed to in part represent host inflammatory reaction to tumor. This study looks to correlate VS good (VS-G) or poor (VS-P) label with the neutrophil to lymphocyte ratio (NLR) and outcomes in front-line NSCLC patients who were screened for actionable mutations as part of a companion diagnostic. Methods: Retrospective chart review was conducted of 76 patients with advanced NSCLC who had pretreatment VS testing. Included patients had at least 3-month follow up. Chi squared analysis was used to correlate VS label with patient characteristics and Cox proportional hazards was used to correlate PFS with VS label, NLR and other baseline characteristics in patients receiving anti-PD1 targeted therapy as part of their first treatment. Results: Median PFS was 6.31 months (follow up range 3-17 months). Of 76 tested patients, 23 never received treatment and 47 received anti-PD1 therapy. 51 had VS-G and 23 had VS-P (2 indeterminate). Using two standard NLR cutoffs of 3.5 and 5, 29 and 47, and 42 and 34 had values above and below the cutoff, respectively. VS-G vs VS-P correlated with performance status (PS) as well as NLR at both cut points and on a continuous scale. (P = 0.031, 0.043, 0.045, and 0.056 respectively, VS-G correlating with good PS and low NLR). There was no correlation with PDL1 or body mass index. On multivariate analysis VS label and NLR were also associated with PFS and OS (P = < 0.001 and P = 0.046). Among a subset of 47 patients treated with ICIs, VS-G and NLR < 5 were associated with longer PFS (P = 0.010 and 0.010) though PDL1 result was not. Conclusions: This is the first description of the performance of the VS mass spectrometry assay in front-line patients whose regimen included an anti-PD1 agent. The VS label was able to predict for PFS in this patient population despite relatively short follow up. VS-G label also correlated with low NLR by multiple methods analyzed. Further evaluation of the impact of cytotoxic chemotherapy to anti-PD1 is warranted.
A retrospective study of low-dose apatinib combined with S-1 in patients with advanced non-small cell lung cancer.
Authors: Zhou Tong , Zhou Xiaoyue , Li Peng , Wu Changling , Zhang Changsong , Dong Huajie , Lu Hongjun , Qi Martin , Ling Yang 
Published: May 2019

e20666 Background: Currently regimen for advanced non-small cell lung cancer (NSCLC) failing from standard treatment is deficient. This retrospective study aimed to assess the efficacy and safety of low-dose apatinib in combination with S-1 therapy in this NSCLC setting. Methods: In this retrospective study, advanced NSCLC patients who failed from standard treatment in Changzhou Cancer Hospital of Soochow University were screened for eligibility. Progression-free survival (PFS) was set as the primary endpoint. Overall response rate (ORR), disease control rate (DCR), Overall survival (OS) and safety profile were considered to be the secondary endpoints. Results: 31 eligible patients were included in this study. The median PFS (mPFS) was 102 days (95% CI: 57-147). 7 patients (23%; 95% CI: 11-38%) achieved an objective response and the DCR was maintained in 23 patients (75%; 95% CI: 58-86%). The median OS (mOS) was 422 days (95% CI: 148-696).Patients with smoking had a tendency for shorter overall survival without significant differences (HR = 4.105, 95% CI: 0.874-19.288, P = 0.074). Treatment-related grade 3 toxicity was observed in five patients (16%) and the common grade 1 or 2 adverse events were fatigue (42%), hypertension (32%), and hand-foot-skin reaction (23%). Conclusions: Combination of low-dose apatinib and S-1 could be effective and tolerable for advanced NSCLC patients failed from standard treatment, but further exploration in larger clinical trials is needed.
Phase II study of apatinib combined with vinorelbine in second-line treatment failure non-driver gene mutation advanced non-small cell lung cancer (NCT03652857).
Authors: Zhang Yongchang , Wu Fang , Xiong Yi , Zhang Xiangyu , Yang Nong 
Published: May 2019

e20669 Background: There is currently no standard treatment strategy for non-driver gene mutation advanced non-small cell lung cancer (NSCLC) patients experiencing progression after two or more lines of chemotherapy. Our study assessed the efficacy and safety of apatinib combined with vinorelbine in non-driver gene advanced NSCLC patients for whom at least two lines of prior chemotherapy had failed. Methods: This is a Phase II, single arm clinical trial. 30 advanced NSCLC patients who had two or more prior lines of chemotherapy had failed enrolled in this study. All the patients received treatment of apatinib 500mg, po qd plus vinorelbine 60mg/m2 po qweek. The primary endpoint was overall response rate (ORR). Secondary endpoints were overall (OS), progression-free survival (PFS), disease control rate (DCR) and safety. Results: Between January 2016 and November 2018, 30 patients were enrolled. 25 patients finished all the treatment. 5 patients discontinued the treatment for adverse events. The ORR of all the patients was 36.3 %( 11/30). The DCR of all the patients was 76.3 %( 23/30). The median PFS of all the patients was 4.5months (95% CI 2.4-6.6m). The median OS of all the patients was 10months (3.8m-16.2m). The most common grade 3 to 4 adverse events were non-hematologic including hand-foot syndrome. Moreover, medicine reduction seem not be an important role in disease prognosis. Conclusions: These data show that apatinib combined with vinorelbine can be a good choose with an acceptable safety profile in non-driver gene mutation advanced NSCLC patients refractory to two or more lines of prior chemotherapy. Clinical trial information: NCT03652857.
Neoantigen-based personalized DC vaccine for lung cancer: An update of translational study.
Authors: Ding Zhenyu , Yang Li , Xu Heng , Li Qing , Li Qiu 
Published: May 2019

e20674 Background: DC vaccine is a promising strategy for cancer therapy. We conducts a personalized, neoantigen-loaded DC therapy trial in advanced NSCLC (NCT02956551 & ChiCTR-ONC-16009100). Here we provide the updated data. Methods: Advanced lung cancer patients in their later lines of therapy were enrolled. Whole exon dequencing was performed from freshly obtained tumor tissues as well as the peripheral blood, while RNA-seq was performed in tumor-derived RNA. Somatic mutations were submitted ot systematical progream of neoantigen predication, considring personalized MHC affinity, gene expression, tumor herogeneity, and etc. 10-15 peptides with the highest score were synthesized and pulsed in PBMC-dericed DC, which was introduced to patients. All cells were prepared in a GMP workshop. The primary endpoint was safety and toleratility. Results: Totally 11 patients were enrolled up to now. Most (n = 5) were adenocarcinoma, and the rest were squamous cancer (n = 4) and NET (n = 2). They were heavily treated (lines of previous therapy: 2-5, median 2). 1 patient failed in re-biopsy, 1 lacked candidate neoantigen, and another died rapdily during the preparation of DC vaccine. 8 patient finally received vaccination (n = 6, male; n = 2, female). The number of neoantigens identified from each patient vairied greatly (35-441, median n = 68). Totally 37 times of vaccination was performed (5-17, median 5). The cell infusion was safe and highly tolerable and no significant side effects were observed, even for those with poor performance. The treatment achieved SD in 7 patients, and only 1 with PD. The median PFS was 5.7m (range: 3.8-10.0m). 5 patients are now maintained on therapy. Conclusions: The neoantigen based personalized DC vaccine is highly tolerable without obvious side effects. The vaccination strategy shows promise in efficacy. Clinical trial information: NCT02956551.
FDA analysis of outcomes in Asian patients (pts) with metastatic non-small cell lung cancer (mNSCLC) receiving immune checkpoint inhibitors (ICI).
Authors: Chang Elaine , Gong Yutao , Vallejo Jonathon Joseph , LIU QI , Mathieu Luckson Noe , Booth Brian , Sridhara Rajeshwari , Beaver Julia A. , Pazdur Richard , Blumenthal Gideon Michael 
Published: May 2019

e20690 Background: Asian pts tend to be well-represented in mNSCLC clinical trials, and drug development in Asia is growing. We sought to investigate outcomes of Asian pts enrolled in clinical trials testing ICI in mNSCLC. Methods: We identified 11 ICI mNSCLC randomized trials submitted to FDA 2014-2018. We divided the trials into 3 groups: 1st-line monotherapy (1L-M), 1st-line combination with chemotherapy [chemo] (1L-C), and 2nd-line monotherapy (2L-M). Overall survival (OS) and progression-free survival (PFS) were evaluated with Kaplan-Meier methodology. We performed meta-analyses to assess if treatment effect is consistent across Asian and non-Asian populations. Results: There were 3399 patients enrolled in five 2L-M trials, 1579 in two 1L-M trials, and 2500 in four 1L-C trials. Most Asian pts were located geographically in Asia (90%). Asians comprised 15% of patients enrolled in 2L-M trials, 27% in 1L-M, and 11% in 1L-C. Compared to non-Asians, a higher proportion of Asians were never-smokers (32% vs. 13%) and EGFR-mutated (13% vs. 4%). Asian pts had better unadjusted and adjusted OS than non-Asian pts for each treatment in each line of therapy. The 3 covariates with greatest prognostic impact on OS in 2L-M were race, performance status, and histology. The magnitude of ICI treatment effect relative to chemo was similar for Asian and non-Asian pts. Conclusions: Asians appear to have better prognosis than non-Asians; no uniquely better or worse benefit was observed from ICI when compared to chemotherapy. [Table: see text]