A phase I trial in patients with solid tumors revealed that bevacizumab could be safely combined with standard doses of carboplatin (Paraplatin®
: Bristol-Meyers Squibb; Princeton, NJ, USA) and paclitaxel (Taxol®
; Bristol-Meyers Squibb; Princeton, NJ, USA) (Margolin et al 2001
). This led to the development of a randomized phase II trial in patients with advanced NSCLC. Ninety-nine patients were enrolled in this trial, and all patients received carboplatin area under the curve (AUC) = 6 using the Calvert equation, and paclitaxel 200 mg/m2
every 3 weeks, and patients on the two investigational arms received bevacizumab 7.5 mg/kg (n = 32) or 15 mg/kg (n = 35) every 3 weeks until disease progression (Calvert et al 1989
; Johnson et al 2004
). Patients on all three arms received a median of 6 cycles of carboplatin and paclitaxel and patients on the low-dose and high-dose bevacizumab arms received a median of 8 and 10 doses of bevacizumab, respectively. Treatment with the high-dose bevacizumab resulted in statistically significant longer time to tumor progression in comparison to the control arm (7.4 months vs 4.2 months; p = 0.023). There was no significant difference in the time to tumor progression between the carboplatin and paclitaxel arm and the low-dose bevacizumab arm (). Patients who received carboplatin and paclitaxel could receive single agent therapy with bevacizumab upon disease progression. Nineteen patients received second-line therapy with single bevacizumab, and five patients experienced stable disease. The median survival and one-year survival rate from the time of initiating bevacizumab therapy in this subgroup of patients was 10 months and 47%, respectively.
Table 1 Efficacy results of a three-arm randomized phase II trial with carboplatin and paclitaxel with and without bevacizumab Johnson et al (2004).
This trial revealed several notable bevacizumab related adverse events including hypertension, proteinuria, and episodes of hemorrhage. The episodes of hemorrhage consisted of two distinct clinical entities: minor mucocutaneous hemorrhage, predominantly epistaxis, and life threatening hemorrhage. Six patients experienced life threatening hemoptysis or hemorrhage, and four events were fatal. Squamous histology appears to be associated with the development of this complication since four of the 13 patients with squamous histology (31%) experienced severe hemorrhage versus two of the 54 (4%) of patients with non-squamous histology. Five of the six had cavitation at baseline or tumor necrosis during the therapy. Pulmonary hemorrhage may be associated with central location; however, central location may be a surrogate marker for histology since squamous cell tumors tend to be centrally located. Five of the six episodes occurred on the low-dose treatment arm, and events occurred early (≤60 days) as well as late (≥180 days); thus the events did not appear to be dose- or time-dependent.
If a subset analysis is performed in patients with the non-squamous histology (n = 79) it appears that the addition of bevacizumab to standard chemotherapy improves the response rate, time to tumor progression, and overall survival (). Based on the promising results of this phase II trial, the Eastern Cooperative Oncology Group (ECOG) initiated a phase II/III trail, ECOG 4599, comparing the standard therapy of carboplatin and paclitaxel to the combination of carboplatin, paclitaxel, and bevacizumab (15 mg/kg) every 3 weeks in patients with advanced stage non-squamous histology (Sandler et al 2006a
). Exclusion criteria were: hemoptysis (defined as ≥1/2 a teaspoon of bright red blood); central nervous system metastases; clinically significant cardiovascular disease; medically uncontrolled hypertension; documented hemorrhagic diathesis or coagulopathy; anticoagulation therapy; regular use of aspirin (>325 mg daily), non-steriodal anti-inflammatory agents, or other agents known to inhibit platelet function. Patients could not have received radiation therapy within 21 days of enrollment or major surgery within 28 days of enrollment. Patients were required to have computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain within four weeks of enrollment to evaluate for brain metastases. Importantly, patients with centrally located tumors were not excluded. Of the 878 patients enrolled on the trial, 444 received carboplatin and paclitaxel and 434 received carboplatin, paclitaxel, and bevacizumab.
There was a statistically significant improvement in the response rate, progression-free survival, and overall survival in the bevacizumab containing arm (). This trial led the FDA to approve bevacizumab for the treatment of patients with advanced stage NSCLC with non-squamous histology in combination with carboplatin and paclitaxel. On a subgroup analysis no survival benefit was seen among women with treatment with bevacizumab despite a statistically significant improvement in response and progression free survival (Brahmer et al 2006
). The test for a treatment gender interaction in a proportional hazards model for survival was statistically significant (p = 0.04). It is important to note that this trial was not statistically powered to evaluate the efficacy of bevacizumab in subgroups. The reasons for the lack of a survival benefit in women are unclear, and potential explanations include an imbalance in unrecognized prognostic factors, statistical chances, or a true lack of benefit among women. There were no survival differences in survival related to gender on the previous trial of metastatic colorectal cancer (Hurwitz et al 2004
). Until the potential relationship between gender and overall survival can be clarified, female patients who meet the eligibility criteria for the trial should be considered candidates for treatment with bevacizumab.
The bevacizumab-containing treatment arm did have a significantly higher rate of toxicity than the carboplatin and paclitaxel treatment arm. The bevacizumab containing arm had a higher rate National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 4 neutropenia (25.5% vs 16.8%, respectively; p = 0.002), thrombocytopenia (1.6% vs 0.2%, respectively; p = 0.04), and febrile neutropenia (5.2% vs 2.0%, respectively; p = 0.02). There was a higher rate of non-hematologic toxicity as well including grade 3–5 hypertension (7% vs 0.7%, respectively; p = 0.001), hemorrhage (4.4% vs 0.7%, respectively; p = 0.001), and grade 3 proteinuria (3.1% vs 0%, respectively; p = 0.001). There were seven hemorrhage-related deaths on the bevacizumab arm (pulmonary hemorrhage (n = 5), and gastrointestinal bleeding (n = 2). The other causes of death on the bevacizumab arm were: complications of febrile neutropenia (n = 5), cerebrovascular event (n = 2) and probable pulmonary embolism (n = 1). There were 15 treatment-related deaths on the bevacizumab arm versus two on the standard treatment arm (p = 0.001).
An exploratory retrospective analysis of the episodes of pulmonary hemorrhage occurring <150 days from initiation treatment was performed. (Sandler et al 2006b
) This analysis used a case-control method in an attempt to identify radiographic and clinical risk factors for the development of severe pulmonary hemorrhage. Hemoptysis at baseline, and tumor cavitation were identified as probable risk factors for pulmonary hemorrhage. Central location was not identified as a risk factor. Given the small number of cases involved in this analysis a larger analysis which included patients from ongoing clinical trials may provide additional information about risk factors for pulmonary hemorrhage, and the relative risk associated with each risk factor.
In addition to these two trials, a third trial, known as AVAil (BO17704) has completed enrollment, and the preliminary results were presented at the American Society of Clinical Oncology meeting in June 2007 (Manegold et al 2007
). This was a three arm trial designed to compare the efficacy of chemotherapy and two different doses of bevacizumab versus chemotherapy alone, and was not designed for a comparison of the efficacy of two different doses of bevacizumab. To be eligible for this trial patients were required to have non-squamous histology, a preserved functional status, and chemotherapy-naïve stage IIIB/IV or recurrent NSCLC. The exclusion criteria were: grade ≥2 hemoptysis; radiological evidence of tumor invasion of major blood vessels; brain metastases or spinal cord compression; uncontrolled hypertension; history of thrombotic or hemorrhagic disorders; and therapeutic anticoagulation within 10 days of the first treatment. The initial primary end-point was an improvement in overall survival with the combination of chemotherapy and bevacizumab versus chemotherapy alone; however, after enrollment on the trial had begun the trial was amended and the primary end-point was changed to progression-free survival.
One thousand and forty-three patients were enrolled on the trial, and patients were randomized to three arms: cisplatin (80 mg/m2) on day 1 and gemcitabine 1250 mg/m2 on days 1, 8 and placebo every 3 weeks (n = 347) or the same chemotherapy with either 7.5 mg/kg (n = 345) or 15 mg/kg (n = 351) every 3 weeks. Bevacizumab was continued until disease progression and no crossover to bevacizumab was allowed. Patients on the chemotherapy and bevacizumab arms experienced a statistically significant improvement in the progression-free survival in comparison to the pooled placebo; cisplatin, gemcitabine, and bevacizumab 7.5 mg/kg arm versus pooled placebo (hazard ratio [HR] = 0.75; 95% confidence Interval [CI] 0.62–0.91, p = 0.0026) and cisplatin, gemcitabine and bevacizumab 15 mg/kg versus pooled placebo (HR = 0.82; 95% CI 0.68–0.98, p = 0.0301). The median progression-free survival time for cisplatin and gemcitabine; cisplatin, gemcitabine and bevacizumab 7.5 mg/kg; and cisplatin, gemcitabine, and bevacizumab 15 mg/kg were 6.1 months, 6.7 months, and 6.5 months, respectively. At the time of this analysis the protocol-specified number of events for fully powered survival analysis has not been reached. The rate of grade ≥3 neutropenia, febrile neutropenia hemorrhage, and pulmonary hemorrhage were similar in all treatment arms. The rate of grade ≥3 pulmonary hemorrhage and febrile neutropenia for the cisplatin and gemcitabine, cisplatin, gemcitabine, bevacizumab 7.5 mg/kg and 15 mg/kg arms was 0.3%, 1.2%, and 0.9%, respectively and 1%, 2%, and 2%, respectively. The final results of this trial should provide valuable toxicity data; however, the trial design may limit conclusions that can be made in regards to the survival benefit of bevacizumab and the relatively efficacy of the two doses of bevacizumab.