bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients (pts) with stage IV non-small cell lung cancer (NSCLC)
Authors: Manegold C. , Vansteenkiste J. , Cardenal F. , Schütte W. , Woll P. , Ulsperger E. , Rüter B. , Picard M. , Eckmayr J. , von Pawel J. 
Published: August 2020

8014 Background: Cilengitide (EMD 121974) is the most advanced compound in clinical development of a new class of oncology drugs, the integrin inhibitors. Integrins (heterodimeric transmembrane receptors) play key roles in cell interactions. Cilengitide selectively inhibits the cell-surface integrins αVβ3 and αVβ5 on activated endothelial cells during angiogenesis and on tumor cells. Methods: Multicenter, open-label, randomized, phase II study in 140 pts with relapsed stage IV NSCLC. Pts received 1 of 3 cilengitide doses (240 [n=35], 400 [n=35], or 600 [n=36] mg/m2) twice weekly or docetaxel 75 mg/m2 (n=34) once every 3-week cycle for 6 months. Responding pts could continue cilengitide for up to 1 year. Primary endpoint: progression-free survival (PFS). Results: Median age (range) was 60 (33–80) years; 94 pts were male (67%); 83% of pts had KPS ≥80%. Median PFS (95% CI) was 54 (43–64), 63 (53–66), 63 (42–67), and 67 (61–123) days for cilengitide 240, 400, 600, and docetaxel 75 mg/m2, respectively. Median OS (95% CI) was 173 (81–197), 117 (92–209), 181 (90–326), and 194 (135–298) days, respectively. One-year survival rate (95% CI) was 13% (1–24%), 13% (0–26%), 29% (12–37%), and 27% (10–43%), respectively. Survival was similar with cilengitide 600 mg/m2 and docetaxel 75 mg/m2: median OS 181 versus 194 days and 1-year survival rate (95% CI) 29% (12–37%) versus 27% (10–43%). Five docetaxel pts (15%) had a partial response. Most pts (98%) had ≥1 adverse event (AE). Most common AEs were dyspnea (33%), nausea (30%), tumor progression (29%), and cough (23%). Dyspnea and tumor progression were more common with cilengitide than with docetaxel. Grade 3/4 treatment-related AEs were more common with docetaxel (n=13, 41%) than cilengitide 240 (n=2, 6%), 400 (n=4, 11%), or 600 (n=4, 11%) mg/m2. For cilengitide, these were nausea, chest pain, dyspnea, and fatigue. Conclusions: PFS in the docetaxel group was greater than that of cilengitide at all doses. However, cilengitide monotherapy at a dose of 600 mg/m2 showed similar OS to docetaxel and better tolerability. Combination studies with standard chemotherapy and cilengitide are warranted. [Table: see text]
K-Ras mutation (mut), EGFR-related, and exploratory markers as response predictors of cetuximab in first-line advanced NSCLC: Retrospective analyses of the BMS099 trial
Authors: Khambata-Ford S. , Harbison C. , Woytowitz D. , Awad M. , Horak C. , Xu L. A. , Dakhil S. , Hermann R. C. , Lynch T. J. , Weber M. R. 
Published: August 2020

8021 Background: This phase III study investigated cetuximab (C) plus taxane/carboplatin (TC) in 1st-line advanced NSCLC. Progression-free survival (PFS) was not significantly different with the addition of C to TC; response rate (RR) was significantly higher; median overall survival (OS) was longer, with a difference (not statistically significant) similar in magnitude to the significant OS improvement from FLEX (cisplat/vinorelb±C). Potential patient-selection markers were analyzed, including mut in K-Ras, EGFR mut and gene copy number (GCN), EGFR protein expression, and gene expression profiles. Methods: Chemonaïve patients (pts) with stage IIIB/IV NSCLC (any histology or EGFR expression status) were randomized to TC±C. K-Ras gene exon 2, and EGFR exons 18–21 were sequenced bidirectionally using formalin-fixed paraffin embedded tissue-derived genomic DNA. EGFR GCN was measured by fluorescence in situ hybridization (FISH) and EGFR protein expression by immunohistochemistry (IHC). Exploratory expression profiling studies using Affymetrix GeneChip are ongoing. Analyses were blinded to clinical outcome. The relationships between biomarker status and efficacy were assessed with log-rank tests per study arm for treatment-specific effects, and across the total evaluable population. Results: Samples from 225/676 randomized pts were available; 35/202 (17%) had K-Ras mut, 17/167 (10%) had EGFR mut, 54/104 (52%) were EGFR FISH+, 131/148 (89%) were EGFR IHC+. There were no significant treatment-specific correlations between any biomarker assessed and PFS, OS or RR, except superior OS with TC for the EGFR FISH+ group (P=0.03). With all pts combined, OS was longer in the EGFR mut subset vs wt (P=0.09); PFS was longer in EGFR IHC- pts vs IHC+ (P=0.048). Results from gene expression profiling studies, including EGFR ligands, will be presented. Conclusions: There was no significant correlation between patient response to C and any molecular marker evaluated to date (K-RAS mut, EGFR mut, EGFR IHC, EGFR FISH), exploratory analyses are ongoing. Additional predictive-marker studies are needed to optimize cetuximab therapeutic use in NSCLC. [Table: see text]
First-line treatment patterns in advanced NSCLC in western Europe (EU), the United States, and Japan including a comparative analysis of younger versus elderly patients
Authors: Vansteenkiste J. F. , Koester M. , Lange M. , Eschbach C. 
Published: August 2020

8053 Background: The latest developments in advanced NSCLC are represented by targeted therapy (TT), treatment decisions based on tumor histology, and biomarker research. A patient (pt) case-based survey was conducted in three regions to study current pt characteristics and treatment patterns. Methods: 629 physicians treating stage III/IV NSCLC provided details on up to 10 of their pts. Results: Overall, 3455 EU pts, 895 US pts, and 600 Japanese pts were monitored. This analysis focuses on the 89% of pts with stage IIIb/IV NSCLC. In each region, median age, gender, and occurrence of malignant pleural effusion were comparable but tumor histology differed slightly. Comparative analyses revealed that monotherapy (MT) with either chemotherapy (CT) or TT agents is used significantly more in elderly pts (≥70 yrs) while combination therapy (CT/TT doublets or triplets) is more frequent in younger pts. This is consistent across all regions and histologies (squamous vs non-squamous). In the EU, 48.3% of elderly and 13.6% of younger pts received MT (39.9% vs 15.1% for US pts, 32.0% vs 9.4% for Japanese pts). CT/TT doublets were used predominantly in younger vs elderly pts (72.3% vs 48.1% in the EU, 47.3% vs 36.9% in the US, and 81.7% vs 65.5% in Japan). Triplets were also more widely used in younger vs elderly pts (14.3% vs 3.6% in the EU, 36.3% vs 22.6% in the US, and 6.5% vs 1.8% in Japan). For both age groups, the leading MTs are erlotinib in the EU and US, and gefitinib in Japan but use is higher in elderly pts. Preferred doublets in the EU are platinum+gemcitabine (28.8%), platinum+vinorelbine (13.6%) and platinum+taxanes (13.5%). Platinum+taxanes is predominant in the US and Japan (27.7% and 55.4%, respectively). The triplets, bevacizumab+platinum+taxanes (27.0%) and bevacizumab+platinum+other (3.5%), are also common in the US while these treatments only represent 5.1% and 3.9%, respectively, in the EU. Conclusions: Important regional differences in 1st-line advanced NSCLC treatment exist with triplets being more common in the US only. MT is more frequent in elderly pts and combination therapy is more common in younger pts. This latter finding is consistent across all regions and histological subsets. [Table: see text]
Interim analysis of a phase II trial of 5-azacitidine (5AC) and entinostat (SNDX-275) in relapsed advanced lung cancer (NSCLC)
Authors: Juergens R. A. , Vendetti F. , Coleman B. , Sebree R. S. , Rudek M. A. , Belinsky S. , Brock M. , Herman J. , Baylin S. , Rudin C. M. 
Published: August 2020

8055 Background: Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Pre-clinical studies suggest that combining inhibitors of DNA methyltransferase (DNMT) with inhibitors of histone deacetylase (HDAC) synergistically induce re-expression of epigenetically-silenced tumor suppressor genes. Clinical studies at our institution combining the DNMT inhibitor, 5AC, with the HDAC inhibitor, entinostat, in hematologic malignancies have shown remarkable clinical activity. We hypothesized a similar effect would be seen in lung cancer. This study aims to assess the response rate and time to progression of 5AC and entinostat in NSCLC. Methods: Patients (pts) include adults with histologically confirmed recurrent NSCLC and progressive disease after ≥1 prior chemotherapy regimen. 40 mg/m2 of 5AC is administered SQ days 1–6 and 8–10 with 7 mg of entinostat PO days 3 and 10 of a 28 day cycle. A standard Simon two stage design is being used. The sample size is calculated with a power of 90% and a two-sided type 1 error allowance of 5%. Stage 1 included 18 pts, with subsequent expansion to a total of 32. Results: 25 pts have enrolled to date. Demographic characteristics include: mean age (range) - 63 (46- 80); M:F - 1:2; 80% former smokers; 80% adenocarcinomas; mean # of previous therapies - 3. One pt. has had a complete response. She remained on therapy for 14 m and came off therapy due to a new nodule which was resected. Molecular analysis suggests a second primary stage I NSCLC. She remains disease free at 20 m. Another man has stabilization of disease (SD) for ≥16 m with marked symptomatic improvement. Another pt had SD for 4 months. The remaining pts have progressed after 2 cycles of therapy. Main toxicities included injection site reactions, nausea/vomiting, constipation, fatigue, and hematologic toxicities. Conclusions: The combination of 5AC and entinostat is safe and well tolerated in advanced NSCLC pts. 2 pts have had durable benefit from treatment, including a complete response. Pharmacodynamic and pharmacokinetic analyses are being conducted to identify characteristics of the subset of pts responding to this novel therapy. [Table: see text]
The relationship between the responses to prior systemic therapies and the efficacy of subsequent pemetrexed (Pem) therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Sun J. , Oh D. , Lee S. , Kim D. , Im S. , Kim T. , Lee J. , Kim Y. , Heo D. S. , Bang Y. 
Published: August 2020

8061 Background: Pem has been used for pts with previously treated advanced NSCLC. We tried to examine whether the response to prior systemic therapy regimen could predict the efficacy of subsequent Pem therapy. Methods: The medical record of clinical stage IIIB or IV NSCLC pts who received Pem as the second-line or further-line treatment were analyzed retrospectively. Prior systemic therapies were divided into 4 types [gemcitabine based (G), paclitaxel based (P), docetaxel based (D), and EGFR tyrosine kinase inhibitors (I)]. Along with that, patients were classified into two response groups, either responders (partial responses or stable disease for 4 months or more) or non-responders to each type of the prior therapy. Response rate (RR) and progression free survival (PFS) for Pem therapy were analyzed according to the response groups for each type of prior therapies. Results: A total of 247 pts received Pem therapy, and their median PFS was 2.3 months. The number of pts who previously received G, P, D and I, was 159, 120, 110, and 139, respectively. The RR for Pem was higher in responders to G therapy than in non-responders to G (15.0% vs 4.3%, p = 0.02). In addition, median PFS after Pem therapy was longer in responders to G therapy than in non-responders (3.0 vs 1.7 months, p = 0.007). However, the responses to prior P, D, I therapies had no impact on the efficacy of subsequent Pem therapy. By univariate analyses, the variables of the responders to G therapy, female, never-smoker, ECOG performance status 0–1 were good predictive factors for Pem therapy in terms of PFS. By multivariate analysis, only the responders to G therapy had a statistical significance (Hazard ratio = 0.55; 95% CI, 0.37–0.82). Conclusions: The response to the prior gemcitabine based therapy was a predictive factor for subsequent pemetrexed therapy for advanced NSCLC. No significant financial relationships to disclose.
Analysis of optimal timing of gefitinib in sensitive non-small cell lung cancer (NSCLC) patients: Should we use gefitinib as first-line chemotherapy?
Authors: Kenmotsu H. , Goto K. , Naito Y. , Nishiwaki Y. , Kubota K. , Ohmatsu H. , Niho S. , Yoh K. , Nagai K. , Saijo N. 
Published: August 2020

8068 Background: In gefitinib-sensitive NSCLC such as Asian origin, adenocarcinoma, and never/light smoker, the superiority of gefitinib relative to carboplatin/paclitaxel as first-line chemotherapy was recently demonstrated (IPASS). However, the optimal timing of this agent is still controversial. Methods: To assess the optimal timing of gefitinib for sensitive NSCLC, we retrospectively reviewed 720 NSCLC patients treated with this agent at National Cancer Center Hospital East between 2002 and 2008. Results: A total of 190 patients responded to gefitinib monotherapy (response rate 26%) were analyzed in this study. Forty-four patients (23%) were treated with gefitinib as first-line chemotherapy, and 146 (77%) as second or more-line chemotherapy. Patient characteristics (first-line/second or more-line) were as follows: median age (range) 68 (44–82)/64 (33–82); female 84/67%; non-smoker 80/57%; PS0–1 84/74%; adenocarcinoma 93/97%; stage IV 43/54%; recurrence after surgical resection 45/26%. There were some imbalances between the two groups in terms of female (p=0.0296) and recurrence after surgical resection (p=0.0187). Although 64% of second or more-line group received platinum-based chemotherapy in their clinical course, only 27% of first-line group received it. Median follow-up time was 17.2 months. Progression free survival (PFS) from the start of gefitinib was similar between first-line and second or more-line groups (median PFS: 11 vs. 11 months, p=0.3085). However, overall survival (OS) from the start of first-line chemotherapy was significantly longer in second or more-line group (median OS: 23 vs. 33 months, p=0.0298). Conclusions: Even if gefitinib is administered to sensitive patients as first-line or second or more-line chemotherapy, it should have similar efficacy. The significantly longer survival in second or more-line group may be on account of more percentage of patients receiving platinum-based chemotherapy. No significant financial relationships to disclose.
Administration of sunitinib to patients with non-small cell lung cancer and irradiated brain metastases: A phase II trial
Authors: Novello S. , Abrey L. E. , Grossi F. , Camps C. , Mazieres J. , Selaru P. , Patyna S. , Torigoe Y. , Chao R. , Scagliotti G. 
Published: August 2020

8077 Background: Sunitinib (SU), an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R, and RET has promising single-agent antitumor activity in refractory non-small cell lung cancer (NSCLC) (Socinski JCO 2008). Brain metastases (BrMs) occur in ≥25% of NSCLC patients (pts); preclinical data suggest that VEGF signaling is required for the growth of BrMs, and that SU can cross the blood-brain barrier. This study assessed the safety and preliminary efficacy of SU in NSCLC pts with BrMs. Methods: NSCLC pts who had received ≤2 prior systemic therapies and prior whole brain radiation therapy (WBRT) were eligible to receive SU at a starting dose of 37.5 mg with continuous daily dosing (CDD) in 4-wk cycles. Antitumor efficacy was based on overall (RECIST) and intracranial (WHO) tumor assessments. Intracranial disease was assessed by MRI. Safety was assessed by monitoring adverse events (AEs) and health-related quality of life was assessed using FACT/NCCN Lung Symptom Index (FLSI) and Brain Symptom Index (FBrSI). Study termination was to occur when 3 cases of intracranial hemorrhage (ICH) associated with neurologic deficit were noted. Results: To date, 47 pts, including 28 with adenocarcinoma and 10 with squamous cell carcinoma, received SU for a median of 2 cycles (range: 1, 9). The median age of pts was 61 yrs (range: 35, 75), most were male (n=26, 55%), were ever smokers (n=36, 77%) and all had good performance status (ECOG 0/1). In total, 25 pts (53%) experienced non-neurologic grade (G) 3/4 AEs; the most frequent were fatigue/asthenia and dyspnea. Neurologic AEs occurred in 4 pts (9%), including intracranial pressure increased, mental impairment, and gait disturbance (each n=1 and G1) and 1 pt with G3 convulsion and peripheral motor neuropathy. Importantly, no cases of ICH were noted. Stable disease occurred in 7 (19%) of 36 measurable pts. Median PFS was 10.9 wks (95% CI: 6.4,15.4). Median OS was 19.6 wks (95% CI:13.1, NR). Mean change from baseline in FLSI and FBrSI scores did not differ significantly at any time point. Conclusions: Oral SU 37.5 mg on a CDD schedule had a manageable safety profile in NSCLC pts with BrMs. These data support the investigation of SU in combination with agents with known antitumor activity in pts with BrMs. [Table: see text]
Racial/ethnic disparities in lung cancer stage of diagnosis and survival
Authors: Raez L. E. , Koru-Sengul T. , Allen G. , Clarke J. , Santos E. S. , Hu J. J. 
Published: August 2020

8080 Background: There are differences in the treatment outcome of non-small cell lung cancer (NSCLC) patients (pts) between non-Hispanic whites (NHW) and African Americans (AA). Little is known regarding the outcomes of Hispanics (H). Methods: Registry data on 2,696 pts with NSCLC treated during 1999–2006 was obtained. The objective of the study was to evaluate differences in NSCLC survival according to different ethnicities. Chi-square was used to compare distribution of tumor stage. Survival curves were compared using log-rank test for each of the tumor stages. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age at diagnosis, and race. Results: Most pts had stage III/IV at diagnosis; majority of the AA or HW presented in advanced stage compared with NHW. Significantly higher proportions of AA and H were diagnosed with stage IV compared to NHW ( Table ). Mean age at diagnosis was 62 yrs (AA 58, H 60, and NHW 66yrs) and it was significantly different among the 3 groups (one-way ANOVA, p<0.0001). AA and H have significantly shorter stage-specific median survival for early stage compared to that in NHW ( Table ). In pts with advanced stages the pattern was similar: AA and H have a significantly shorter median survival than that in NHW. In early-stage pts, significant predictors for OS from multivariate Cox regression model were female gender (AHR=0.65; p<0.001), AA (NHW as the referent group; AHR=2.67; p<0.0001), and H (NHW as the referent group; AHR=2.01; p<0.0001). In late-stage pts, significant predictors for OS were female gender (AHR=0.79; p=0.0002), AA (NHW as the referent group; AHR=1.53; p<0.0001, and H (NHW as the referent group; AHR=1.28; p=0.0006). Conclusions: NHW pts had better OS than H and AA; we will evaluate whether gene expression profiles or presence of EGFR overexpression have an impact on racial/ethnic disparities in the outcome of NSCLC. [Table: see text] No significant financial relationships to disclose.
Simulation of survival with first- and second-line non-small cell lung cancer (NSCLC) therapy using a public domain drug-disease modeling framework
Authors: Bruno R. , Lu J. , Sun Y. , Claret L. 
Published: August 2020

8087 Background: Modeling and simulation approaches are advocated to support drug development decisions. In this study, we evaluated the ability of a drug-disease model recently developed by scientists at the FDA using data from pivotal studies in NSCLC (Wang et al. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008–4351b1–00-index.htm ) to simulate survival and tumor response for approved therapies in NSCLC. Methods: The modeling framework comprises a longitudinal tumor size model and a survival model relating change in tumor size at first visit (week 8) and patient characteristics (tumor size and ECOG performance status at baseline) to survival time. The tumor size and survival models were used to simulate change in tumor size at first visit and expected survival in the carboplatin/paclitaxel (CP) arm of the E4599 study (first-line NSCLC, N Eng J Med. 2006;355:2542–2550) and in the erlotinib arm in the BR.21 study (second-line NSCLC, N Eng J Med. 2005;353:123–132). The predictive distributions (95% prediction interval [PI]) of survival times were derived from multiple replicates (500) of 400 CP patients and 500 erlotinib patients with similar characteristics to patients in the original studies. Results: There was a high level of concordance between the results of the simulation and the observed results in the two arms, indicating that the modeling framework successfully predicted survival and tumor response. Expected median survival was 9.8 (95% PI, 8.2–11.8) months (vs 10.3 months observed) for the CP arm and 6.8 (95% PI, 5.3–8.9) months (vs 6.7 months observed) for the erlotinib arm. The median change in relative tumor size from baseline at week 8 predicted by the model was 12.1% for the CP arm and 9.5% for the erlotinib arm. Conclusions: The modeling framework can be used to perform simulations of survival of approved treatments. These results suggest that the model could be used to simulate survival for investigational treatments based on tumor shrinkage data observed in early clinical studies (e.g. phase II) to support end-of-phase II decisions and the design of phase III studies. [Table: see text]
Tumor response category for the indicator of prognosis: Analysis of survival data in a Four-Arm Cooperative Study (FACS) for advanced non-small cell lung cancer (NSCLC)
Authors: Watanabe H. , Leki R. , Mori K. , Takada Y. , Nishiwaki Y. , Saijo N. , Fukuoka M. 
Published: August 2020

8088 Background: Tumor response, categorized into CR (complete response), PR (partial response), SD (stable disease) and PD (progressive disease), is a surrogate endpoint for survival and could be expected as a possible indicator of the prognosis. To evaluate whether the tumor response category might be used as an indicator of the prognosis, we conducted an analysis of the best overall response and survival data obtained from FACS, a phase III randomized trial comparing four platinum-based regimens for advanced NSCLC. Methods: A total of 602 patients (pts) with advanced NSCLC from 44 hospitals in Japan were registered in FACS. A retrospective review of the FACS database, including the tumor response and survival, was conducted. The tumor response as evaluated by the investigators was applied with and without confirmation of complete or partial responses at the determination of best overall response. Survival was calculated by the Kaplan-Meier method, and differences among prognostic groups were analyzed by Cox regression analysis. Results: Forty-five pts were excluded from the analysis due to nonavailability of sufficient data. The results are shown in the Table . The response categories of CR, PR and SD could not be categorized into prognostic groups, either with or without confirmation. There were, otherwise, two distinct prognostic groups: non-PD (CR, PR and SD) and PD. Conclusions: The disease control rate was a more sensitive indicator of the prognosis than the response rate in pts with advanced NSCLC registered in FACS. [Table: see text] [Table: see text]