Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer
- Study type
- Clinical trial
- Study name
- ECOG 4599
- Phase
- Phase 3
- Design
- Randomised multicentre ECOG study comparing chemotherapy alone with chemotherapy plus bevacizumab
- Sample size
- 878 patients
- Source
- N Engl J Med · 2006
- Trial registration
- NCT00021060
In plain words
In this study, patients with advanced non-small cell lung cancer who met certain conditions were given the drug bevacizumab in addition to standard chemotherapy. This combination helped patients live about two months longer (12.3 versus 10.3 months). On the other hand, the risk of bleeding and of death caused by treatment was higher, so this treatment is suitable only for selected patients and should be discussed with the treating doctor.
Key results
Treatment arms and regimens
Paclitaxel 200 mg/m² IV over 3 hours, then carboplatin AUC 6 IV over 15 to 30 minutes, day 1 every 3 weeks, up to 6 cycles in the absence of progression or unacceptable toxicity (444 patients).
Paclitaxel and carboplatin as in the other arm, then bevacizumab 15 mg/kg IV over 30 to 90 minutes, day 1 every 3 weeks for 6 cycles; thereafter, patients with stable disease or response received single-agent bevacizumab 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity (434 patients).
Source of the regimen details: FDA label for Avastin (DailyMed, section 14, study E4599: doses of paclitaxel, carboplatin and bevacizumab) and ClinicalTrials.gov NCT00021060 (order and duration of infusions, number of cycles and maintenance); the full text of the NEJM paper was not available in PMC.
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Chemotherapy-naive patients with recurrent or advanced (stage IIIB or IV) non-squamous non-small cell lung cancer, ECOG performance status 0 or 1 and adequate organ function (per the FDA label: 11% recurrent disease; among newly diagnosed patients, 12% stage IIIB with malignant pleural effusion and 76% stage IV). Exclusion criteria: predominantly squamous histology (only mixed tumours were allowed), brain/central nervous system metastases, gross haemoptysis (half a teaspoon or more of bright red blood), unstable angina and therapeutic anticoagulation. Enrolment from July 2001 to April 2004.
Endpoints
Primary endpoint: overall survival.
Safety and side effects
Clinically significant bleeding occurred in 4.4% of the bevacizumab group and 0.7% of the chemotherapy-alone group (P<0.001). There were 15 treatment-related deaths in the bevacizumab group, 5 of them from pulmonary haemorrhage. Per the FDA label (only grade 3–5 non-haematological and grade 4–5 haematological events were collected), events at least 2% more frequent with bevacizumab were: neutropenia 27% vs 17%, fatigue 16% vs 13%, hypertension 8% vs 0.7%, infection without neutropenia 7% vs 3%, venous thromboembolism 5% vs 3%, febrile neutropenia 5% vs 2%, pneumonitis/pulmonary infiltrates 5% vs 3%, infection with grade 3 or 4 neutropenia 4% vs 2%, hyponatraemia 4% vs 1%, headache 3% vs 1% and proteinuria 3% vs 0%.
Clinical significance and place in guidelines
This study showed that adding bevacizumab to paclitaxel and carboplatin in selected patients (no squamous histology, brain metastases or significant haemoptysis, and performance status 0 to 1) improves overall survival, but at the cost of more bleeding and more treatment-related deaths. Careful patient selection is important. Current approval status and clinical guideline recommendations should be checked separately.
Limitations
The results apply only to selected patients; patients with squamous tumours, brain metastases, significant haemoptysis and poorer performance status were excluded. An increase in treatment-related deaths, including pulmonary haemorrhage, was reported in the bevacizumab group.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.