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Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

ABSTRACT: BACKGROUND:Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). METHODS:Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. RESULTS:Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. CONCLUSIONS:In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients.

SUBMITTER: Philip PA

PROVIDER: S-EPMC3896238 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

Philip Philip A PA Mahoney Michelle R MR Holen Kyle D KD Northfelt Donald W DW Pitot Henry C HC Picus Joel J Flynn Patrick J PJ Erlichman Charles C

Cancer 20110927 9

<h4>Background</h4>Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC).<h4>Methods</h4>Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients re ...[more]

PMID: 21953248

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Project description:ImportanceErlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months.ObjectiveTo determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone.Design, setting, and participantsThis phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018.InterventionsPatients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent.Main outcomes and measuresThe primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months).ResultsAmong 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients.Conclusions and relevanceErlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC.Trial registrationClinicalTrials.gov identifier: NCT01532089.

Project description:BACKGROUND:The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC. METHODS:Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P). RESULTS:Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; p < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm (p = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E). CONCLUSION:In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors. IMPLICATIONS FOR PRACTICE:This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.

Dataset Information

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

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Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

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