Bevacizumab (Avastin®) is the first cancer therapy approved by the Food and Drug Administration (FDA) to inhibit angiogenesis, which refers to the development of new blood vessels needed to carry vital nutrients to a tumor. Bevacizumab inhibits angiogenesis by blocking "Vascular Endothelial Growth Factor" or VEGF (pronounced Veg-F), a protein that is excessively produced by tumor cells and a key factor in the growth of many types of cancer.
This therapeutic agent is a monoclonal antibody, a type of highly specific antibody created in the laboratory that selectively binds to substances in the body, including cancer cells. Each monoclonal antibody is created to find and bind to one specific substance. Bevacizumab selectively binds to VEGF, blocking the protein's ability to bind to its receptors on the surface of endothelial cells, which are the main cells in the inside lining of blood vessels. By blocking the activity of VEGF, bevacizumab can reduce the development of blood vessels and the delivery of oxygen and nutrients needed by the tumor to grow and spread.
Bevacizumab was first approved by the FDA in 2004 and 2006 respectively for the first- and second-line treatment of metastatic cancer of the colon or rectum (colorectal cancer) in combination with 5-fluorouracil (5-FU)-based chemotherapy. In 2006, it was also approved as first-line treatment in combination with chemotherapy (i.e., carboplatin and paclitaxel) for a form of inoperable (unresectable) metastatic lung cancer (i.e., non-squamous, non-small-cell). For both colorectal and lung cancer, bevacizumab was approved by the FDA based on randomized clinical trials that demonstrated improvement in overall survival (OS).
In contrast, in 2008, bevacizumab was FDA approved for another indication, but this time, approval was not on the basis of overall survival as the trial endpoint—which brings us to the story of bevacizumab and metastatic breast cancer.
When the FDA approved bevacizumab for the first-line treatment of metastatic breast cancer in combination with paclitaxel, the agency based such approval on improvement in progression-free survival (PFS). In a Phase III randomized clinical trial called the E2100 study, patients with locally recurrent or metastatic breast cancer who received bevacizumab and paclitaxel (Taxol®) lived approximately twice as long without their cancer worsening when compared to those who were treated with paclitaxel alone. But what does "twice as long" specifically mean? It does not mean that women lived longer, in fact, there was no increase in overall survival. An improvement in PFS means that it took twice as long for the tumor to progress. Patients treated with bevacizumab and paclitaxel demonstrated a median PFS of 11.3 months, whereas those who received paclitaxel alone had a median PFS of 5.8 months—that is, a 5.5 month improvement in the length of time before tumor growth and disease progression. However, a significant improvement in overall survival was not shown. Furthermore, those who received bevacizumab experienced a higher overall incidence of toxicities as well as more severe toxicities.
So in the case of metastatic breast cancer, FDA approval was given to bevacizumab based solely on increased progression-free survival, suggesting the agency's acceptance of such a surrogate endpoint as an appropriate measure of efficacy.
A surrogate endpoint is a physical sign or laboratory finding used in clinical trials that may not itself be a direct measure, but one that is considered reasonably likely to predict therapeutic benefit and a clinically meaningful outcome, such as survival. However, there are few "true" surrogates, and it is crucial to note that a treatment that delays tumor growth and cancer progression may not actually lengthen survival.
What is clear, however, is that treatment with bevacizumab is associated with an increased risk of serious adverse effects and that serious toxicities may very well negatively impact quality of life.
Despite the recommendations of the Oncologic Drugs Advisory Committee (ODAC) and the concerns its members raised regarding lack of survival data, severe toxicities, and trial design, the FDA approved bevacizumab (Avastin®) in 2008 as a first-line treatment in combination with paclitaxel for women with metastatic HER2-negative breast cancer. The approval was extremely controversial and surprised many, particularly since the FDA typically follows the advice of its advisory panel. Instead, on this occasion, the FDA overruled ODAC's recommendation and granted "accelerated approval," showing acceptance of PFS in the absence of overall survival—and, therefore, based on what some consider a lower level of evidence.
The FDA requires confirmatory trials for agents that have received accelerated approval. In this case, as a condition of accelerated approval, submission of data was required from two ongoing randomized placebo-controlled Phase III clinical trials—called AVADO and RIBBON 1—to verify treatment effect on PFS and to provide further data on overall survival. However, importantly, in each of these studies, the primary endpoint was, once again, progression-free survival.
Thus, the data from these confirmatory trials showed a much more modest improvement in PFS with bevacizumab than the original E2100 trial, lack of overall survival benefit, and a higher incidence of serious adverse events requiring medical intervention or hospitalization or resulting in death.
Due to such data, ODAC did not find that the benefits of bevacizumab outweighed the risks, nor that the results of these confirmatory trials were clinically meaningful. They voted that the results of the AVADO and RIBBON 1 trials did not confirm the magnitude of meaningful clinical benefit as shown in the earlier E2100 study results—and voted 12 to 1 to recommend that FDA revoke the approval of bevacizumab as a first-line treatment for HER2-negative metastatic breast cancer.
For women living with metastatic breast cancer, the Food and Drug Administration’s (FDA) decision to withdraw approval of Avastin, is probably the most impactful event of 2011. In November 2011, FDA Commissioner Margaret Hamburg, MD, announced her decision to revoke the agency’s approval of the breast cancer indication for Avastin (bevacizumab).
A crucial consideration is the fact that those who received bevacizumab experienced a significantly higher overall frequency of toxicities that were also more severe than seen in those who received paclitaxel alone. The addition of bevacizumab to paclitaxel was associated with a 20.2% increase in serious side effects classified as "Grades 3-5" Adverse Events. In addition, death occurred in 1.7% of patients (6/363) in the bevacizumab arm compared to 0% (0/348) for those who received paclitaxel alone.
In March 2009, the results from a study in mouse models suggested a disturbing possibility--that although anti-angiogenesis agents may initially shrink tumors, they may later promote more invasive tumor growth as an adaptive response of the cancer as it seeks the necessary oxygen and nutrients (Paez-Ribes, 2009). The investigators studied the effects of the anti-angiogenic drug sunitinib in mouse models of glioblastoma and pancreatic neuroendocrine cancer. They confirmed that the tumors stabilized or shrank during the first weeks of treatment with sunitinib, but later had an adaptive response, with increased invasion into adjacent tissue and metastasis.
The results of this research are similar to those seen in earlier animal studies. They are also consistent with some early results seen in a small number of clinical trials suggesting that anti-angiogenic therapy may alter the natural history of tumors. This includes a clinical trial in which a subset of glioblastoma patients had recurrence at multiple sites confirmed by MRI imaging after initial tumor shrinkage during treatment with bevacizumab (Zuniga, 2009).
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Miller KD, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357:2666-2676.
Paez-Ribes M, Allen E, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220-231.
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