Randomized, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC)
Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2007
Presenter: C. Maegold Presenter's Affiliation: University Medical Center, Mannheim, Germany Type of Session: Scientific
Bevacizumab (Avastin), a monoclonal antibody directed against the vascular endothelial growth factor receptor, has been shown to increase survival when used in combination with conventional chemotherapy in several types of cancer.
Toxicities, including increased risk of fatal pulmonary hemorrhage, have been observed with the use of bevacizumab in phase II clinical trials.
Overall survival (OS) benefit, as well as progression free survival (PFS) benefit, for patients with advanced non-small cell lung cancer (NSCLC) has been demonstrated with the use of bevacizumab, carboplatin, and paclitaxel when compared with carboplatin and paclitaxel alone [Eastern Co-operative Oncology Group (ECOG) study E4599].
Combination chemotherapy using cisplatin and gemcitabine is commonly used for treatment of advanced NSCLC in Europe.
This study was carried out to evaluate effect on progression-free survival with the addition of bevacizumab to the cisplatin/ gemcitabine regimen used to treat NSCLC in Europe and in other regions outside of the United States.
Materials and Methods
This study accrued patients from 150 centers in 20 different countries, with 1043 patients being enrolled over a 16 month period.
Eligibility criteria included: Pathologic diagnosis of non-squamous NSCLC, disease stage IIIB or IV or recurrent disease, ECOG performance status 0-1.
Patients were excluded from the trial for the following criteria: Grade 2 or greater hemoptysis, brain metastases, cord compression, bleeding or thrombotic disorder, full-dose anticoagulation within 10 days of enrollment, previous exposure to chemotherapy.
All patients were treated with cisplatin (80 mg/ m 2 ) and gemcitabine (1250 mg/ m 2 ) on days 1 and 8 every 3 weeks for up to 6 cycles, and were randomized in a 1:1:1 fashion to receive either concurrent bevacizumab 7.5 mg/ kg every 3 weeks until disease progression, bevacizumab 15 mg /kg every 3 weeks until disease progression, or placebo. No cross-over between the 3 arms was permitted.
Tumor response was assessed radiologically every 3 weeks.
The primary endpoint of this study was progression-free survival, and the study was designed to have 80% power to detect an improvement in PFS from 4.5 months in the placebo arm to 6.4 months in the bevacizumab arms.
This study demonstrated a 25% improvement in PFS (HR 0.75, p = 0.0026) in the bevacizumab 7.5 mg/ kg group and an 18% improvement in PFS (HR 0.82, p = 0.030) in the bevacizumab 15 mg/ kg group when compared to placebo.
PFS was improved from 6.1 months in the placebo group to 6.7 and 6.5 months in the bevacizumab 7.5 mg/ kg group and the bevacizumab 15 mg/ kg group, respectively.
PFS at three months was improved from 78.6% in the placebo group to 88.5% in the bevacizumab 7.5 mg/ kg group and 80.7 in the bevacizumab15 mg/ kg group.
Duration of response was improved from 4.7 months in the placebo group to 6.1 months in each of the bevacizumab groups (p < 0.001).
Improvements were noted by the authors to be consistent across several subgroups, including varied disease region, gender, stage, performance status, age, race, and smoking status.
No significant difference in the incidence of grade 3, 4, or 5 toxicities, serious toxicities, or toxicity-related deaths were observed across the three groups.
Pulmonary hemorrhage occurred in 4.9% of patients in the placebo group, 7.0% in the bevacizumab 7.5 mg/ kg group, and 9.7% in the bevacizumab 15 mg/ kg group (p = 0.040). Fatal pulmonary hemorrhage occurred in 0.3% of patients in the placebo group, 1.2% in the bevacizumab 7.5 mg/ kg group, and 0.9% in the bevacizumab 15 mg/ kg group (p = <0.001).
Of the patients who experienced any pulmonary hemorrhage, 38% had centrally located lesions. Of the patients who experienced severe or fatal pulmonary hemorrhage, 40% (4/10) had centrally located lesions.
This study demonstrated a statistically significant improvement in PFS with the addition of bevacizumab to the cisplatin/ gemcitabine chemotherapeutic regimen.
Improved PFS was noted for patients receiving either bevacizumab 7.5 mg/ kg or 15 mg/ kg.
The treatment was well-tolerated, with no significant increase in the incidence of grade 3-5 toxicities with addition of bevacizumab.
Although the incidence of any pulmonary hemorrhage was increased with use of bevacizumab, no significant increase was observed in the rates of fatal pulmonary hemorrhage.
The authors note that this study was not designed to evaluate differences in outcome between the two doses of bevacizumab.
Overall survival data is noted to be currently pending.
This study represents the second phase III clinical trial demonstrating a benefit in PFS with the addition of bevacizumab to established chemotherapy regimens, and confirms the results of ECOG 4955. However, this benefit is very modest overall.
Benefits in PFS appear to be independent of the concurrent chemotherapy drugs used (carboplatin/ taxol or cisplatin/ gemcitabine).
This study did not evaluate overall survival, nor was it designed as a dose-comparison study. Benefits in PFS and duration of response were similar between the two bevacizumab doses evaluated.
The addition of bevacizumab does not appear to alter the rate of grades 3-5 toxicity, and toxicity rates did not vary significantly between the two doses of bevacizumab evaluated.
The risk of pulmonary hemorrhage does not appear to be increased in patients with central lesions, and these patients should not be exluded from further bevacizumab trials, nor be considered ineligible for treatment with bevacizumab.
The safety profile of bevacizumab in patients excluded from this study, namely those with brain metastases, squamous histology, and need for anticoagulation, may warrant further investigation in future studies.
Further studies to evaluate overall survival and quality of life parameters are needed as the PFS improvement in this study, although statistically significant, may not be clinically meaningful.
Jul 23, 2010 - Bevacizumab used in combination with standard chemotherapy for advanced non-squamous non-small-cell lung cancer (NSCLC) has a generally manageable safety profile, according to an open-label, single group, phase 4 study published online July 21 in The Lancet: Oncology.