bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program
Authors: Kim E. S. , Herbst R. S. , Lee J. J. , Blumenschein G. , Tsao A. , Wistuba I. , Alden C. , Gupta S. , Stewart D. , Hong W. K. 
Published: August 2020

8024 Background: Treatment for patients (pts) with recurrent NSCLC has limited efficacy despite the use of new targeted agents. Identifying biomarkers to predict tumor response will help personalize therapy for individuals. Methods: Eligible pts had prior chemotherapy, ECOG PS 0–2, and when enrolled, required 2 fresh core needle biopsy specimens to test 11 biomarkers related to 4 molecular pathways in NSCLC: EGFR, Kras, and Braf gene mutation (PCR-based sequencing), EGFR and Cyclin D1 copy number analyses (FISH), and 6 proteins via IHC (VEGF/R and RXR receptors/Cyclin D1). Based on eligibility and tumor biomarker analyses, pts were randomized into 1 of 4 treatments: erlotinib (E) 150 mg qd; sorafenib 400 mg bid, vandetanib 300 mg qd; E 150 mg + bexarotene 400 mg/m2 qd. The primary endpoint is 8-week progression-free status. The first 97 pts were equally randomized, with subsequent pts adaptively randomized under a Bayesian framework. Results: Since 11/2006, 227 pts have been enrolled and 171 randomized and treated (median age 62 yrs, 89 males, 137 Caucasians, 11 Asians, 107 former and 38 never smokers). Accrual has proceeded well (average 9 pts per month). 112 of the biopsied lesions were lung, with a pneumothorax rate of 12.1% (15 of 124 pts; grade 1–2 only; lung, mediastinal and pleural sites). 168 pts (74%) have complete biomarker profiles and 7 (3%) have partial. Histology: adenocarcinoma (75%), squamous (11%), large cell (13%). Mutation frequency was 19% EGFR, 15.4% Kras, and 2.9% Braf. 2 tumors contained both EGFR and Kras mutations, and 2 cases had both Kras and Braf mutations. EGFR polysomy by FISH was 36.4%, and gene amplification 21%. Cyclin D1 amplification was 16.3%. Treatment-related adverse events (grade 3 or more) were 6.5%. Conclusions: We have demonstrated that biopsies are safe and feasible for biomarker-directed studies. The study continues enrollment to 200 evaluable pts at which point the results will be unblinded. BATTLE is one of the first studies in advanced lung cancer to prospectively utilize biomarker analysis of fresh biopsies to direct pt treatment, and is a step towards personalizing therapy in NSCLC. Supported by grant DoD W81XWH-6–1-0303. No significant financial relationships to disclose.
Rebiopsy of patients (pts) with acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC)
Authors: Arcila M. E. , Riely G. J. , Zakowski M. F. , Kris M. G. , Ladanyi M. , Pao W. , Miller V. A. 
Published: August 2020

8025 Background: The EGFR-TKIs erlotinib and gefitinib produce dramatic regressions of tumor in ∼ 70% of NSCLC patients with activating mutations in the EGFR-TK domain. After a median time to progression of ∼1 year, most pts have progressive disease. We undertook this study to search for mechanisms of “acquired resistance” to EGFR-TKIs, to determine the spectrum and frequency of secondary EGFR mutations which arose, and to determine the feasibility of rebiopsy in this setting. Methods: All pts had metastatic or recurrent NSCLC and prior treatment with EGFR-TKI and progressive disease while on EGFR-TKI. Pts must also have had an activating EGFR mutation OR radiographic response (RECIST or WHO) to EGFR-TKI OR significant and durable improvement in cancer-related symptoms as judged by patient's physician. Core biopsies were performed and studied for EGFR mutation (exons 18–21 including PCR-based test for T790M) and MET amplification. Results: From 8/04–12/08 98 pts were consented for rebiopsy and 85 underwent the procedure. Demographics Female/Male=59/39; median age 62 (range 28–88); smoking: never=59, former/current=39. Primary EGFR mutation was exon 19 del-39; exon 21 L858R-11, other/WT-28, pending-7. Median time on EGFR-TKI before biopsy was 12 months (7–28 months). Secondary EGFR mutations: T790M-33, other-2, none detected-31, indeterminate-10, pending-9. MET amplification in 2/16 studied to date. Conclusions: 1) Rebiopsy of patients with NSCLC and acquired resistance to EGFR TKIs is feasible and well-received by pts. 2) Knowledge of EGFR genotype including EGFR T790M and MET status can inform clinical trials of targeted therapies in this population 3) More complete annotation of MET status and exploratory analyses of profiles of specimens by metastatic sites and prior EGFR-TKI versus chemo and EGFR-TKI is ongoing. Supported by the Doris Duke Foundation, the LaBrecque Foundation, Steps for Breath, NIH, and an anonymous donor. No significant financial relationships to disclose.
Cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer (E-SCLC): Final “common arm”: Comparative outcomes analysis of JCOG 9511 and SWOG 0124
Authors: Lara P. , Chansky K. , Shibata T. , Fukuda H. , Tamura T. , Saijo N. , Redman M. , Lenz H. J. , Natale R. , Gandara D. R. 
Published: August 2020

8027 Background: S0124 was a large North American phase III trial (n=651) that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with E-SCLC, contrary to the results of J9511, a phase III trial exclusively in Japanese patients (n=154). As S0124 and J9511 protocols used identical treatment regimens and similar eligibility criteria, we compared demographics, toxicity, and outcomes using patient-level data and a “common arm” analysis to explore potential reasons for the divergent results. Methods: In both trials, patients with documented E-SCLC and adequate end-organ function were randomized to receive either cisplatin 60 mg/m2 day 1 + irinotecan 60 mg/m2 days 1, 8, & 15 Q 4 weeks or cisplatin 80 mg/m2 day 1 + etoposide 100 mg/m2 days 1–3 Q 3 weeks. Demographics and outcomes data were compared among 805 patients enrolled in J9511 and S0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status. Results: Of 671 patients in S0124, 651 were eligible. Patient characteristics (J9511 & S0124, respectively): Mean age - 61 & 62 years; Male sex - 132 (86%) & 370 (57%), p<0.001; Performance status 0 - 19 (12%) & 211 (32%), p<0.001. Efficacy and toxicity comparisons are summarized below. Conclusions: Significant differences in patient demographics, toxicity, and efficacy exist between J9511 and S0124 populations. These results, relevant in the current era of clinical trials globalization, warrant 1) consideration of differential patient characteristics and outcomes amongst populations receiving identical therapy; 2) utilization of the “common arm” model in prospective trials; and 3) inclusion of pharmacogenomic correlates in cancer trials where ethnic/racial differences in drug disposition are expected. [Table: see text] [Table: see text]
Results of a randomized phase II trial of amrubicin (AMR) versus topotecan (Topo) in patients with extensive-disease small cell lung cancer (ED-SCLC) sensitive to first-line platinum-based chemotherapy
Authors: Jotte R. , Conkling P. , Reynolds C. , Klein L. , Fitzgibbons J. F. , McNally R. , Renschler M. , Oliver J. W. 
Published: August 2020

8028 Background: SCLC presents as ED-SCLC in 60%-70% of patients (pts). AMR, a synthetic anthracycline, is approved for these pts in Japan. We compare the efficacy and safety of single-agent AMR vs topotecan in non-Japanese pts with 2nd-line ED-SCLC sensitive to 1st-line platinum-based chemotherapy. Methods: This phase II, open-label, multicenter study enrolled pts with ED-SCLC sensitive to 1st-line platinum-based chemotherapy (recurrence or progression ≥90 days from 1st-line treatment). Pts aged ≥18 years with ECOG performance status (PS) ≤2 and only 1 prior therapy were eligible. Pts were randomized (2:1) to receive IV AMR 40 mg/m2/d (d, 1–3) or IV topotecan 1.5 mg/m2/d (d 1–5) and treated every 21 days until progression, unacceptable toxicity, or withdrawal. The primary endpoint, overall response rate (ORR, complete + partial response), used RECIST criteria. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: In all, 76 pts were randomized to AMR (n=50) or topotecan (n=26) with AMR given for a median of 6 cycles (range 1–16) and topotecan 3 cycles (1–16). AMR significantly improved ORR rates vs topotecan (p<0.012; Table ). Median PFS/OS was 4.3 months (95% CI 2.0, 6.1)/9.3 months (95% CI 5.7, 12.0) with AMR vs 3.5 months (95% CI 2.1, 6.3)/8.9 months (95% CI 4.8, 13.8) with topotecan. There was a higher proportion of ECOG PS 2 pts in the AMR group (n=6) vs the topotecan group (n=2). A trend towards improved OS was observed in the ECOG 0–1 subgroup of 68 pts: median OS was 10.5 months with AMR vs 9.7 months with topotecan. The most common grade ≥3 adverse events with AMR vs topotecan were neutropenia (53% vs 74%), thrombocytopenia (31% vs 52%) and leukopenia (27% vs 30%). Three AMR pts (6%) and 1 topotecan pt (4%) died of neutropenic infection. Conclusions: AMR significantly improves ORR and has acceptable tolerability as 2nd-line treatment in pts with sensitive ED-SCLC. [Table: see text] [Table: see text]
Genome-wide association scan detected candidate polymorphisms associated with overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with carboplatin (CBDCA) and paclitaxel (PTX)
Authors: Sato Y. , Yamamoto N. , Kunitoh H. , Ohe Y. , Katori N. , Sawada J. , Sakamoto H. , Saijo N. , Yoshida T. , Tamura T. 
Published: August 2020

8031 Background: The combination of CBDCA and PTX is one of the standard chemotherapy for patients with advanced NSCLC. Genome-wide association studies (GWAS) are a powerful tool for identifying genes for biomarkers of common diseases. This prospective study was investigated whether candidate polymorphisms in GWAS could influence OS in advanced NSCLC patients treated with CBDCA and PTX. Methods: Chemotherapy naïve stage IIIB or IV NSCLC patients, treated with CBDCA (AUC=6mg/ml/min) and PTX (200mg/m2, 3-hour), were eligible in this study. The DNA samples were extracted from peripheral blood mononuclear cells before treatment and 110,000 SNPs were obtained by Illuimna's Sentrix Human-1 Genotyping BeadChip. Statistical analyses were performed by the log-rank test and Cox proportional hazards model in consideration of the linkage disequilibrium. Results: From July 2002 to May 2004, 117 patients (male/female: 85/32, PS 0/1/2: 22/92/3, stage IIIB/IV: 50/67), aged 29–80 (median: 61) years, received a total of 387 cycles of treatment. The median survival time (MST) of 117 patients was 17.1 months. In the GWAS, four SNPs were associated significantly with shortened OS: rs1656402 in the EIF4E2 Gene (MST for AG [n = 54] + AA [n = 44] and GG [n = 19] were 18.2 and 7.7 months, respectively; p = 4.2× 10-7, HR = 3.58 [2.1–6.1]), rs1209950 in the ETS2 gene (MST for AA [n = 105] and AG [n = 12] + GG [n = 0] were 17.7 and 7.0 months, respectively. p = 9.2×10-8, HR = 4.95 [2.6–9.5]), rs10074374 (MST for CC [n = 114] and CT [n = 3] + TT [n = 0] were 17.1 and 2.2 months, respectively. p = 2.2×10-6, HR = 23.2 [6.3–85.1]) and rs2063681 (MST for CT [n = 45] + CC [n = 61] and TT [n = 11] were 17.8 and 6.6 months, respectively. p = 5.2×10-8, HR = 5.47 [2.8–10.9]). These four SNPs were statistically significant even after multiple comparison adjustment. Conclusions: GWAS is a powerful tool to search for new prognostic biomarkers for patients with stage IIIB or IV NSCLC who receive CBDCA and PTX as the first-line chemotherapy and may unveil an unexplored molecular pathways correlated with the drug response. [Table: see text]
Genetic variants in angiogenesis pathway associated with clinical outcome in NSCLC patients (pts) treated with bevacizumab in combination with carboplatin and paclitaxel: Subset pharmacogenetic analysis of ECOG 4599
Authors: Zhang W. , Dahlberg S. E. , Yang D. , Sandler A. B. , Brahmer J. R. , Schiller J. H. , Carbone D. P. , Johnson D. H. , Lenz H. 
Published: August 2020

8032 Background: E4599 was a randomized phase III study which demonstrated a survival advantage in advanced NSCLC pts treated with bevacizumab (bev) + carboplatin/paclitaxel (BPC) versus carboplatin/paclitaxel alone (PC). Recent studies have shown certain germline polymorphisms (SNPs) are associated with clinical outcome in advanced breast cancer pts treated with paclitaxel plus bev and in advanced colorectal cancer pts treated with first line 5-FU or capecitabine in combination with oxaliplatin and bev. A study also found 2 SNPs in WNK1 gene were associated with bev-induced hypertension. We tested the hypothesis that SNPs involved in angiogenesis pathway (VEGF, EGF, EGFR, IL-8, KDR, ICAM1, FGFR4), DNA repair pathway (ERCC1, XPD, XRCC1, GSTP1) and WNK1 may predict clinical outcome in a subset of pts enrolled on E4599. Methods: Of 878 pts enrolled, samples from 146 pts were available for the current pharmacogenetic study and only 133 of the samples (67 PC, 66 BPC) came from eligible pts. PCR-RFLP assays were performed on genomic DNA extracted from sera of pts. The Kaplan-Meier method was used to estimate time-to-event distributions. Multivariable Cox models adjusted for gender, PS, stage, adrenal, liver and bone mets were separately fitted for each SNP to obtain estimates of hazard ratios. Results: Median OS for the 133 patients was 10.3 mos (8.2–15.6) for PC and 13.0 mos (10.2–16.6) for BPC. Median PFS was 4.6 mos (3.6–5.6) for PC & 6.5 mos (5.4–8.3) for BPC. Pts with mutant homozygote CC genotype for ICAM1 T469C had significantly higher tumor response rate (39%) than heterozygote CT (13%) and homozygote TT (20%) genotype (Fisher's test, p=0.04). Tests for whether treatment effect differs by genotype via interaction terms in the Cox models were statistically significant (p<0.05) for VEGF G-634C, ICAM1 T469C and WNK1-rs11064560 for OS, and for ICAM1 T469C, EGF A-61G and CXCR2 C785T for PFS. Conclusions: Although exploratory, our preliminary results suggest germline SNPs in angiogenesis pathway may predict response, PFS and OS in NSCLC pts treated with BPC. Prospective trials based on these correlative studies are warranted. [Table: see text]
Prospective randomized phase III trial of triplet chemotherapy with paclitaxel + gemcitabine + cisplatin compared to standard doublet chemotherapy with vinorelbine + cisplatin in advanced non-small cell lung cancer
Authors: Sorensen J. , Hansen O. , Vilmar A. , Frank H. 
Published: August 2020

8034 Background: Paclitaxel + gemcitabine + cisplatin showed promising results in phase II with 59% response rate and 48 weeks median survival. Hence, it was compared to a standard doublet regimen to examine for superiority. Methods: Histologically verified inoperable NSCLC patients (pts) aged 18–75 years, performance status 0–2 and normal organ function were randomized to regimen A (paclitaxel 180 mg/m2 and cisplatin 100 mg/m2 day 1 with gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks) or regimen B (cisplatin 100 mg/m2 day 1 and weekly i.v. vinorelbine every 4 weeks) for maximum 6 cycles. Totally 428 pts were needed to detect a 30% median survival increase with 80% power and two-sided type 1-error of 5%. Results: 221 pts.received reg. A and 222 reg. B. Overall, median age was 62 years (range 38–75 yrs), 58% were males, 11% had performance status 2, 62% stage IV disease, 46% adenocarcinoma, and 28% squamous cell carcinoma (SCC), equally distributed between the regimens. Median no. of treatment courses were 4 in both regimens. Frequencies of CTC grade 4 leucocytopenia, thrombocytopenia, or grade 3+4 nausea, neurotoxicity, or nephrotoxicity were 15%, 17%, 19%, 8%, and 8% in reg. A, and 18%, 5% (p=0.001), 17%, 11%(p=0.014), and 7% in reg. B, respectively. Febrile leucopenia episodes were 14% and 10% in reg. A and B, while thrombocytopenic bleedings occurred in 12% and 4% of pts (p=0.008), respectively, with two toxic deaths due to bleeding in reg. A and none in reg. B. Response rates were 52% and 49% in reg. A and reg. B, median response durations were 263 and 217 days (not significant), median times to progressions (TTP) 6.7 and 5.8 months (p=0.453), and median survival times 11.4 and 10.8 months (p=0.415), respectively. In SCC subtype, TTP was higher in reg. A than reg. B (medians 7.0 mths vs. 4.1 mths, p=0.001) and survival was increased (medians 13.5 mths vs 9.7 mths, p=0.020). Conclusions: The triplet regimen A had significantly higher activity in SCC, both with respect to TTP and to survival with median survival in excess of one year and may be preferred in this histologic subtype. [Table: see text]
Final results of a randomized phase II trial of pemetrexed (P) + carboplatin (Cb) ± enzastaurin (E) versus docetaxel (D) + Cb as first-line treatment of patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Obasaju C. K. , Raju R. N. , Stinchcombe T. , Couch L. S. , Jotte R. , Kocs D. M. , Wang Y. , Bromund J. , Treat J. , Socinski M. A. 
Published: August 2020

8037 Background: E is a selective, oral serine/threonine kinase inhibitor. The combination of PCb has shown clinical activity in two phase 2 trials of advanced NSCLC. A phase 3 trial among pts with stage IIIB/IV NSCLC showed that P + cisplatin provides similar efficacy with better tolerability than gemcitabine + cisplatin (Scagliotti, JCO, 2008). The toxicity profile observed with P + platinum doublets makes these regimens attractive for the integration of novel agents with different mechanisms of action. In the TAX 326 trial, D + cisplatin was associated with a median survival of 11.3 mos vs. 10.1 mos for vinorelbine + cisplatin (P=.04). The current open-label three- arm trial was designed to assess PCb ± E versus a control arm of DCb. Methods: Between 3/06 and 5/08, pts with stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, and no prior systemic therapy were enrolled. Pts were equally randomized to 3 arms: (A) P 500 mg/m2 and Cb AUC 6 every 3 wks × 6 cycles with E given orally as a loading dose of 1200 mg or 1125 mg followed by 500 mg daily until disease progression; (B) The same regimen of PCb without E; or (C) D 75 mg/m2 and Cb AUC 6 every 3 wks × 6 cycles. Pts receiving P were administered folic acid, vitamin B12 and steroid prophylaxis. Pts on D also received steroid prophylaxis. Results: See table . Conclusions: First-line treatment with PCb was associated with a significantly longer overall survival than DCb in advanced or metastatic NSCLC. E did not add to the activity of the PCb doublet. PCbE, PCb, and DCb appeared to be well tolerated. Complete results for all patients in the study will be available at the time of the meeting. [Table: see text] [Table: see text]
Clinical course of advanced non-small cell lung cancer (NSCLC) patients (pts) experiencing hypertension (HTN) during treatment (TX) with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) on E4599
Authors: Dahlberg S. E. , Sandler A. B. , Brahmer J. R. , Schiller J. H. , Johnson D. H. 
Published: August 2020

8042 Background: B is a monoclonal antibody that targets VEGF with demonstrated efficacy in combination with PC for the TX of advanced NSCLC. Administration of B is thought to decrease nitrous oxide synthesis and lead to HTN, one of the known toxicities associated with PCB on E4599. This side effect may be a physiological sign that the VEGF pathway is more actively being blocked and indicate differential outcomes between hypertensive and non-hypertensive pts. Methods: Pts randomized to PCB constituted the cohort. Hypertensive pts (HTN of any grade or TX relation reported via a toxicity form, CTCAE v2) were compared to nonhypertensive pts with respect to baseline pt characteristics, overall survival (OS) and progression-free survival (PFS). Blood pressure (BP) data were also collected at each TX cycle; similar comparisons were made for high BP (>150/100). Results: In E4599, 33/417 (7.9%) eligible pts experienced HTN; 30/33 (90.9%) were grade 3 events. Baseline characteristics of the HTN cohort were similar to those in the non-HTN cohort except for a higher proportion of PS 0 pts (70% vs. 38%, p=0.001) and females (67% vs. 48%, p=0.05). Median follow-up was 54.8 mos. The 6-month cumulative incidence of HTN adjusting for death as a competing risk was 6.2% (95% CI: 3.9–8.6%). Landmark analyses measured from the median time to onset of HTN (1.9 mo) suggested higher OS for the HTN pts (14.0 vs. 11.3 mo) as well as higher PFS (8.0 vs. 4.5 mo) although these comparisons did not reach statistical significance. Proportional hazards models for OS and PFS adjusting for HTN as a time-varying covariate resulted in an OS HR=0.64 (0.43–0.96, p=0.03) and PFS HR=0.83 (0.57–1.20, p=0.32). The same modeling adjusting for high BP (>150/100) as a time-varying covariate resulted in OS HR=0.60 (0.44–0.82, p=0.002) and PFS HR=0.71 (0.54–0.95, p=0.02). Results for high BP remained statistically significant after adjusting for sex, PS, histology, adrenal, liver and bone mets. Conclusions: Data from E4599 suggest that onset of HTN during TX with PCB may be associated with improved OS and PFS. Further studies of the downstream effects of VEGF suppression and HTN are needed. [Table: see text]
Vorinostat in combination with gemcitabine and cisplatinum in patients with advanced non-small cell lung cancer (NSCLC): A Phase I dose-escalation study
Authors: Trédaniel J. , Descourt R. , Moro-Sibilot D. , Misset J. , Gachard E. , Garcia-Vargas J. , Roben E. , Zalcman G. 
Published: August 2020

8049 Background: Preclinical data indicate that vorinostat, a histone deacetylase inhibitor, enhances the efficacy of gemcitabine and platinum chemotherapy agents. This study investigated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of vorinostat plus gemcitabine and a platinum agent in patients (pts) with advanced NSCLC. Methods: Eligible pts (aged ≥18 years; stage IIIB/IV NSCLC, ECOG performance status ≤1, no prior systemic chemotherapy [except adjuvant]) were sequentially enrolled on escalating doses of vorinostat plus gemcitabine and a platinum agent (standard 3+3 design) for ≤6 cycles ( Table ). Carboplatin regimens were to be investigated if dose levels 1 or 2 exceeded the MTD. Results: 28 pts enrolled to date (M/F: 22/6; median age: [range] 55 [34–70] years; 20 chemonaïve) at 5 dose levels ( Table ). Two pts had DLTs: elevated creatinine leading to cisplatin dose reduction (dose level 2) and febrile neutropenia (dose level 5) ( Table ). Dose level 5 was achieved without reaching the MTD; however, based on clinical tolerability, dose level 4 was chosen as the recommended dose (RD). 24 pts had adverse events (AEs): 86% mild/moderate, 53% not considered treatment-related. The most common drug-related Grade 3/4 AEs were thrombocytopenia (19 events) and neutropenia (14 events). Serious AEs occurred in 15 pts, and 5 deaths occurred (1 ‘probably‘ and 4 ‘definitely not‘ treatment-related). Of 19 evaluable pts at 5 dose levels, 9 (47%) had a partial response, 8 stable disease, and 2 disease progression ( Table ). Updated results of pts treated at the RD in an expansion cohort will be presented. Conclusions: These phase I data suggest that vorinostat can be administered with standard doses of gemcitabine and cisplatin and the combination is active in the initial treatment of metastatic NSCLC: randomized trials are needed to determine whether addition of vorinostat improves outcomes in such pts. [Table: see text] [Table: see text]