Anti-angiogenesis Therapy

What is the impact on length and quality of life? Could treatment be leading to more invasive tumor growth?
Disturbing possibility – anti-angiogenesis agents may promote more invasive tumor growth

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).

It is important to note that the mouse models were not treated with a chemotherapy agent, and it remains unclear whether bevacizumab affects tumors in patients as seen in these mouse models and wether in combination with chemotherapy patients gain benefit of the anti-angiogenic agents without promoting subsequent invasiveness and metastasis.

Update 12/16/2010

The FDA announced today it is beginning the process of removing Bevacizumab (Avastin®) approval for metastatic breast cancer.

Background

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.

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.

Toxicities

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.

Based on these data, whether PFS in this setting is an effective surrogate for clinical benefit such as survival remains questionable.

Yet, 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.

A Second ODAC Panel: Will History Repeat Itself?

Earlier this year, it was announced that data from the AVADO and RIBBON 1 trials wereas being submitted to the FDA with the purpose of converting the previous accelerated approved to a “full” approval. The application noted that both trials “met their primary endpoints” (PFS), that adverse events were consistent with previous data, and that “no new safety signals” were observed. The FDA again convened an ODAC panel in July of this year to discuss the submitted, supplemental Biologics License Applications (sBLAs) for bevacizumab for the first-line treatment of locally advanced or metastatic breast cancer.

The first study, AVADO, compared treatment with bevacizumab administered either 7.5 mg/kg or 15 mg/kg every 3 weeks with docetaxel against docetaxel alone in 736 patients with previously untreated, locally recurrent or metastatic HER2-negative breast cancer. In contrast to the E2100 trial, in both groups that received treatment with bevacizumab, the median improvement in PFS was less than one month compared with the group that received docetaxel alone.
In the second study, RIBBON 1, 1,237 women received taxane- or anthracycline-based chemotherapy or capecitabine (based on their physician’s discretion) and were randomized on a 2-to-1 basis to receive bevacizumab or placebo. In RIBBON 1, when compared with placebo, the improvement in median PFS was 1.2 months for women treated with taxane- or anthracycline-based chemotherapy in combination with bevacizumab and 2.9 months for those treated with capecitabine (Xeloda) combined with bevacizumab.

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.

Following the ODAC panel, Tthe FDA was expected to make its final decision this September. Yet, in a move that for many was not unexpected, the agency announced that it would be postponing its decision until December. It’s been stated that Roche’s unit Genetech had submitted new data concerning bevacizumab, although the specifics are not yet available to the general public. In arriving at its decision, the FDA takes into account both the expert panel’s recommendations as well as the available data. As noted earlier, although the FDA is not required to adhere to ODAC’s recommendations, it typically does—but will the FDA’s second decision regarding Avastin in HER-2 negative metastatic breast cancer once again prove a surprise and again lower the bar for drug approval?


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