As discussed in the section on TKIs, vascular endothelial growth factor (VEGF) is a signaling protein that helps govern the birth of new blood vessel, a process referred to in the oncological literature as "angiogenesis". Expression of VEGF is essentially limited to vascular endothelial cells, which line the insides of blood vessels. It is these cells that bind VEGF. In the presence of VEGF-ligand, these endothelial cells multiply and new blood vessels are formed. Active tumors secrete VEGF because their continued growth depends on an adequate blood supply to provide the nutrients and oxygen required for cell growth and division. The appeal of VEGF as a target for anticancer agents becomes obvious – if you can block the signals needed for the creation of new blood supplies for tumor cells, you can theoretically "starve" the tumor and perhaps arrest progression or cause tumor death. The first FDA approved anti-VEGF treatment was an antibody against VEGF known as bevacizumab (Avastin) whose first indication was for the first-line treatment of patients with metastatic carcinoma of the colon or rectum, when used in combination with intravenous 5-fluorouracil-based chemotherapy.
The need for tumor cells to sprout new blood vessels for growth makes therapies against the VEGF receptor attractive since they can theoretically be applied to any number of malignancies. Bevacizumab (is a humanized monoclonal antibody and was the first commercially available angiogenesis inhibitor. There are myriad clinical trials investigating bevacizumab across many difference cancers, and a full review is beyond the scope of this article. However, we will learn about the current FDA approved indications for bevacizumab and discuss the major clinical trials that led to those indications.
Bevacizumab was approved following a pivotal phase III study in the New England Journal of Medicine published in June of 2004. Patients with treatment naâ€¢ve metastatic colorectal cancer were randomly assigned to receive either irinotecan, bolus (all at once) 5-fluorouracil, and leucovorin (a regimen known as "IFL") with or without bevacizumab. Results demonstrated clinically significant improvements in the radiographic response rate and progression-free (PFS) response rates in the bevacizumab-containing arm of the trial. Following publication of these data, bevacizumab received FDA approval in combination with 5-fluorouracil for first-line treatment of mCRC.
Since the publication of these data, additional studies have investigated combining bevacizumab with chemotherapeutic regimens that contain short term infusional (as opposed to bolus) 5-fluorouracil (e.g., FOLFIRI, which combines 5-fluorouracil with leucovorin and irinotecan, typically cycled every two weeks). Two studies have been published looking at FOLFIRI/bevacizumab regimens, the BICC-C trial published in the Journal of Clinical Oncology in October of 2007 and the more recently published BEAT study published in April of 2009 in Annals of Oncology. The design of the BICC-C trial was complex but at a median follow-up of 34 months, median survival in the group receiving FOLFIRI/bevacizumab was 28 months while it was 19.2 months with bevacizumab/IFL (bolus 5-fluorouracil). Similar results were noted in the larger BEAT study, in which previously untreated patients with mCRC received bevacizumab plus a chemotherapy regimen chosen by the treating oncologist. Median PFS and OS for the 503 patients treated with FOLFIRI/bevacizumab were 11.6 and 23.7 months. The BEAT study also included patients treated with chemotherapy regimens containing oxaliplatin (e.g., FOLFOX, which is a regimen employing 5-fluorouracil, oxaliplatin and leucovorin and XELOX, which uses an oral form of fluorouracil known as capecitabine (Xeloda) combined with oxaliplatin) and demonstrated improved median PFS and OS in patients receiving bevacizumab-containing regimens
Data from ECOG 3200 published in the Journal of Clinical Oncology in April of 2007 demonstrated that median survival of patients with previously treated mCRC for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone and 10.2 months for those treated with bevacizumab alone. The data from ECOG 3200 provided the basis for FDA approval of bevacizumab in the second line treatment of mCRC.
About 170,000 new cases of lung cancer are diagnosed each year in the U.S., and lung cancer is the leading cause of cancer death worldwide in both men and women. There are two main categories of lung cancer: non-small cell lung cancer (NSCLC), which represents about 80% of cases, and includes both adenocarcinoma and squamous cell carcinoma. The other category is small cell lung cancer (SCLC), which represents the remaining 20%. This distinction of NSCLC versus SCLC is made based on the appearance of the lung cancer cells under the microscope, as well as the clinical behavior and treatment recommendations for the two different types. Unfortunately, the 5-year survival rates for NSCLC are relatively dismal, with about 15-20% of patients surviving at 5 years from diagnosis.
High preoperative blood levels of VEGF have been shown to correlate with a poorer prognosis in patients with early stage NSCLC. A randomized phase II study looking at the combination of bevacizumab with carboplatin/paclitaxel demonstrated increased PFS and OS in the group treated with bevacizumab. This trial was notable for detecting some of the clinical risks of bevacizumab that we will more fully explore in the Ã”toxicities of bevacizumab" section, including an increased risk of life-threatening or fatal hemoptysis (coughing up of blood).
A subsequent phase III ECOG trial (E4599) trial published in the New England Journal of Medicine investigated the addition of bevacizumab to carboplatin/paclitaxel chemotherapy for 878 patients with stage IIIB (plus pleural effusion) or IV NSCLC and demonstrated a two month increased median OS in the bevacizumab-containing group. Side effects were generally well tolerated but there were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage, as compared to 2 in the non-bevacizumab group. This is particularly important, since subsequent trials have largely restricted the use of bevacizumab to patients with non-squamous histologies because of the high rate of fatal pulmonary hemorrhage in this population.
In February 2010, the final results of the AVAiL trial were published. This was a randomized, phase III trial evaluating bevacizumab with cisplatin/gemcitabine, a chemotherapeutic combination widely used in Europe. Patients were similar to those in the ECOG 4599 trial. Patients received cisplatin and gemcitabine for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. PFS was significantly prolonged in the high-dose bevacizumab group compared to placebo although median OS was not statistically improved.
Bevacizumab has shown modest response rates in trials of breast cancer patients previously treated for metastatic breast cancer (MBC), although no overall survival benefit has ever been demonstrated. The benefit of adding bevacizumab to paclitaxel for first-line therapy was explored in two separate trials: ECOG 2100 and the Roche-sponsored phase III AVADO trial. ECOG 2100 was a randomized phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG) and demonstrated a significant improvement in progression-free survival (PFS) and overall response rate (ORR) with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. An independent review published in the Journal of Clinical Oncology in October of 2009 confirmed that the addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in progression free survival (PFS) without an improvement in overall survival (OS). The AVADO trial produced even more modest results and the interim results were presented at the 2008 annual ASCO meeting. The addition of bevacizumab to docetaxel chemotherapy improved median PFS and increased response rates. Although one-year survival rates were also significantly higher in both bevacizumab groups (83 and 78 versus 73% with placebo), median survival data were not mature at the time of the report.
At the 2009 ASCO meeting, the RIBBON-1 study reported preliminary findings from its randomized phase III trial designed to investigate the clinical benefit of combining bevacizumab with various standard first-line chemotherapy regimens for MBC (OncoLink review can be found here). A total of 1,237 patients were examined and were randomized to bevacizumab plus an investigator chosen chemotherapy (capecitabine, a taxane-based, or an anthracycline-based chemotherapy were all options) or placebo plus chemotherapy. This trial was really composed of 2 separate studies conducted in parallel, which makes it difficult to draw comparisons between the two chemotherapy regimens that were analyzed separately. However, the preliminary results demonstrated that the addition of bevacizumab to chemotherapy resulted in a statistically significant improvement in median PFS. In this study, neither chemotherapy group was powered to assess OS, which would require larger numbers of patients. Additionally, about 50-60% of patients crossed-over to other agents in the placebo groups, which is a confounding factor when analyzing survival data. Based on these data, bevacizumab has been approved for the treatment of MBC with paclitaxel for treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.
More recently, on July 20, 2010, the FDA recommended against the use of bevacizumab in combination with chemotherapy for the first line treatment of MBC based on more mature data from ECOG 2100 trial negating their accelerated approval given in February of 2008 based on concerns regarding toxicity from the drug outweighing the progression-free survival benefit seen in these trials. As such, there is no longer any FDA approved use of bevacizumab in MBC, although its use in breast cancer patients is mentioned here given the importance of this reversal.
Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor. Unfortunately, glioblastoma confers a very poor prognosis despite multimodality treatment consisting of surgical removal of as much of the tumor as possible, followed by concurrent or sequential radiation and chemotherapy and symptomatic care with steroids. Other than the brainstem gliomas, it has the worst prognosis of any CNS malignancy. A more recent advent in the treatment of patients with glioblastoma is anti-angiogenic therapy with bevacizumab.
On May 5, 2009, the FDA granted accelerated approval to bevacizumab as a single agent for patients with glioblastoma, following progression after initial therapy based objective response rates observed in two phase II single-arm trials both published in 2009 in the Journal of Clinical Oncology, AVF3708g and NCI 06-C-0064E, partially because of the very limited treatment options that exist if patients have disease recurrence. In the smaller AVF3708g study, 48 patients that had been heavily pretreated had improvement in their six-month PFS from 29 to 57%. The larger NCI study assigned 167 patients with recurrent disease to bevacizumab, either as a single agent or at the same dose in conjunction with irinotecan. Response rates with bevacizumab alone or in combination with irinotecan were 28 and 38%, respectively, and the six-month PFS and OS were 43 and 50%, and 9.2 and 8.7 months, respectively. This combination treatment with bevacizumab or bevacizumab plus irinotecan was generally well tolerated, and toxicity was limited to expected side effects with these agents. Importantly, almost all patients were able to wean off their dosing of oral steroids.
Renal cell carcinomas, actually comprise two different malignancies: 1) renal cell carcinomas (RCC), which arise in the renal cortex and comprises 80-85% of total kidney cancers, and transitional cell carcinomas, which arise in the renal pelvis and represent the remainder of cases. The incidence of kidney and renal pelvis malignancies has increased over the past three decades, although they still only account for about 2% of all cancers. Although surgical resection of these tumors is the standard of care for patients without advanced or locally metastatic disease, many patients unfortunately present with more advanced disease or subsequently develop metastases following resection of the primary tumor. Prior to the approval of TKIs for metastatic renal cell carcinoma (mRCC), the only option was cytokine treatment with interleukin-2 (IL-2) or interferon alpha (IFNα), both of which are associated with significant adverse reactions.
We will discuss two phase III trials which have helped pave the way for the approval of bevacizumab for the treatment of metastatic renal cell carcinomas. CALGB 90206 reported their results in the November 2008 issue of the Journal of Clinical Oncology and randomized patients with previously untreated, metastatic clear-cell RCC to receive either bevacizumab plus interferon alfa-2a (a cytokine-based therapy). The results were recently updated at the annual 2009 ASCO meeting: PFS was significantly increased in patients treated with the bevacizumab plus interferon group compared to interferon alone (median 8.5 versus 5.2 months) and there was also a statistically significant increase in the objective response rate (25.5 versus 13.1%). Although there was a trend towards increased OS, the result was not statistically significant.
More recently, the results from the AVOREN trial using bevacizumab in the treatment in mRCC were published at the ASCO 2009 meeting (OncoLink review here). In the AVOREN trial (first published in The Lancet in December 2007), 649 patients with previously untreated mRCC were randomized to receive either interferon alfa-2a and bevacizumab (n=327) or placebo and interferon alfa-2a (n=322). Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group. However, in the recent 2009 update, at the time of final OS analysis, the bevacizumab-containing arm failed to demonstrate a survival benefit and actually underperformed compared to the TKI sunitinib. Therefore, although bevacizumab and interferon represent a possible approach to the treatment of mRCC, there is no compelling reason to select this regimen over interferon plus sunitinib. However, the improvement in PFS in these trials did lead to the approval of bevacizumab by the FDA July 2009 for use in combination with interferon alfa for the treatment of patients with mRCC. It should be noted that both of these phase III trials excluded patients with brain metastases because of the concerns about intracerebral hemorrhage.
Overall, bevacizumab is well tolerated. Most of the clinical experience with bevacizumab is in metastatic colorectal cancer, where its use is complicated by hypertension (2-16% with grade 3/4 hypertension), proteinuria (1% in colorectal trials), bleeding, problems with wound healing, and arterial thrombosis. Bevacizumab, when administered concurrently with bisphosphonates, may also increase the risk for developing jaw osteonecrosis. As detailed in the section on NSCLC, the use of bevacizumab in lung cancer is restricted to patients with non-squamous histologies because of the high rate of fatal pulmonary hemorrhage in this population. The use of bevacizumab also increases the risk of surgery and wound healing complications and use of the drug is discouraged for at least 28 days prior and following surgery. Bevacizumab should be avoided in patients with known bleeding disorders. Patients with brain metastasis from tumors potentially responding to bevacizumab should be treated with external beam radiation or resected, as appropriate, prior to beginning therapy with bevacizumab. Another very serious potential side effect of bevacizumab therapy is gastrointestinal perforation, which can occur in up to 2.4% of treated patients and may be fatal. Non-gastrointestinal fistulas are another potential side effect, which is an abnormal connection between two internal structures that are not normally connected, which can lead to infection and other complications. Rare complications such as reversible posterior leukoencephalopathy syndrome have also been reported. As with any antibody-based therapy, infusion reactions are also possible and require monitoring at the time of infusion in the oncology clinic.
In summary, here are the currently approved FDA indications for bevacizumab:
Dosing recommendations for bevacizumab: