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Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial.

ABSTRACT: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04-3.58] and 8.48 months (95% CI, 5.78-10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-?B, and hypoxia pathways were identified potential drivers of sorafenib resistance.Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials.

SUBMITTER: Blumenschein GR

PROVIDER: S-EPMC3905243 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial.

Blumenschein George R GR Saintigny Pierre P Liu Suyu S Kim Edward S ES Tsao Anne S AS Herbst Roy S RS Alden Christine C Lee J Jack JJ Tang Ximing X Stewart David J DJ Kies Merrill S MS Fossella Frank V FV Tran Hai T HT Mao L L Hicks Marshall E ME Erasmus Jeremy J Gupta Sanjay S Girard Luc L Peyton Michael M Diao Lixia L Wang Jing J Davis Suzanne E SE Minna John D JD Wistuba Ignacio I Hong Waun K WK Heymach John V JV Lippman Scott M SM

Clinical cancer research : an official journal of the American Association for Cancer Research 20131028 24

<h4>Purpose</h4>To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.<h4>Patients and methods</h4>Patients with previously treated non-small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were as ...[more]

PMID: 24166906

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Project description:Purpose: To determine the 8-week disease control rate (DCR) of sorafenib monotherapy in patients with advanced non-small-cell lung cancer (NSCLC) in the BATTLE trial. Methods: Patients with pre-treated NSCLC consented to baseline biopsies for pre-specified biomarkers assessment and biomarker discovery. Sorafenib was given at 400 mg orally twice daily until tumor progression or unacceptable toxicity. Outcomes by pre-specified biomarkers were analyzed and a Sorafenib sensitivity signature developed using high-throughput gene expression profiles of NSCLC cell lines and baseline biopsies. Results: 105 patients were eligible and 98 patients were evaluable. Median age was 62 (range 34-81) years, 51% of patients were male, 75% were former/current smokers, and 89% had an ECOG performance status of 0-1. Median prior chemotherapies for stage IV NSCLC were two. Median follow-up was 9.4 (range: 1.3-32.2) months. Overall, 8-week DCR was 58.2%. Patients with EGFR mutations had significantly lower 8-week DCR compared to patients with wild-type tumors (23.1% vs. 64.2%, P=0.0119), and patients with K-RAS mutations had the highest 8-week DCR (67%). Most commonly reported treatment-related adverse events include hand-foot syndrome (59.6%), fatigue (42.3%), rash (40.4%), diarrhea (38.5%), and weight loss (38.5%). Sorafenib sensitivity signature developed in cell lines was associated with an improved outcome. Conclusion: Patients with wild-type EGFR, including those with K-RAS mutation, may benefit from sorafenib as opposed to patients with EGFR mutation. We identify a gene expression signature associated with an improved outcome in patients with wild-type EGFR treated with sorafenib. BATTLE-2 trial is ongoing to validate those results. ClinicalTrials.gov number, NCT00411671. Gene expression profiles were measured in 37 core biopsies from patients with refractory non-small cell lung cancer treated with sorafenib in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We report a Sorafenib sensitivity gene expression signature trained in vitro (separate GEO submission), and tested in baseline biopsies collected in the BATTLE trial.

Project description:BackgroundTyphoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up.MethodsWe did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing.FindingsFrom Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9-88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38-123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262-438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously.InterpretationThe final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever.FundingBill & Melinda Gates Foundation.

Project description:IntroductionSeveral clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034).MethodsPatients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE.ResultsAt the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria.ConclusionsIn TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

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Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial.

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Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial.

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