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Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599.

ABSTRACT: PURPOSE Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non-small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. PATIENTS AND METHODS Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. Results In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%). CONCLUSION Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed.

SUBMITTER: Dahlberg SE

PROVIDER: S-EPMC2834434 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599.

Dahlberg Suzanne E SE Sandler Alan B AB Brahmer Julie R JR Schiller Joan H JH Johnson David H DH

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100119 6

PURPOSE Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non-small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. PATIENTS AND METHODS Ea ...[more]

PMID: 20085937

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Project description:A previous randomized trial demonstrated that adding bevacizumab to carboplatin and paclitaxel improved survival in advanced non-small cell lung cancer (NSCLC). However, longer survival was not observed in the subgroup of patients aged 65 years or older.To examine whether adding bevacizumab to carboplatin and paclitaxel chemotherapy is associated with improved survival in older patients with NSCLC.Retrospective cohort study of 4168 Medicare beneficiaries aged 65 years or older with stage IIIB or stage IV non-squamous cell NSCLC diagnosed in 2002-2007 in a Surveillance, Epidemiology, and End Results (SEER) region. Patients were categorized into 3 cohorts based on diagnosis year and type of initial chemotherapy administered within 4 months of diagnosis: (1) diagnosis in 2006-2007 and bevacizumab-carboplatin-paclitaxel therapy; (2) diagnosis in 2006-2007 and carboplatin-paclitaxel therapy; or (3) diagnosis in 2002-2005 and carboplatin-paclitaxel therapy. The associations between carboplatin-paclitaxel with vs without bevacizumab and overall survival were compared using Cox proportional hazards models and propensity score analyses including information about patient characteristics recorded in SEER-Medicare.Overall survival measured from the first date of chemotherapy treatment until death or the censoring date of December 31, 2009.The median survival estimates were 9.7 (interquartile range [IQR], 4.4-18.6) months for bevacizumab-carboplatin-paclitaxel, 8.9 (IQR, 3.5-19.3) months for carboplatin-paclitaxel in 2006-2007, and 8.0 (IQR, 3.7-17.2) months for carboplatin-paclitaxel in 2002-2005. One-year survival probabilities were 39.6% (95% CI, 34.6%-45.4%) for bevacizumab-carboplatin-paclitaxel vs 40.1% (95% CI, 37.4%-43.0%) for carboplatin-paclitaxel in 2006-2007 and 35.6% (95% CI, 33.8%-37.5%) for carboplatin-paclitaxel in 2002-2005. Neither multivariable nor propensity score-adjusted Cox models demonstrated a survival advantage for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel cohorts. In propensity score-stratified models, the hazard ratio for overall survival for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel in 2006-2007 was 1.01 (95% CI, 0.89-1.16; P = .85) and compared with carboplatin-paclitaxel in 2002-2005 was 0.93 (95% CI, 0.83-1.06; P = .28). The propensity score-weighted model and propensity score-matching model similarly failed to demonstrate a statistically significant superiority for bevacizumab-carboplatin-paclitaxel. Subgroup and sensitivity analyses for key variables did not change these findings.Adding bevacizumab to carboplatin and paclitaxel chemotherapy was not associated with better survival among Medicare patients with advanced NSCLC.

Project description:BACKGROUND:BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). METHODS:Patients were randomized to the BTH1677 arm (N?=?61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N?=?31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. RESULTS:ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P?=?.2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. CONCLUSIONS:Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. TRIAL REGISTRATION:ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009.

Dataset Information

Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599.

Publications

Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599.

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