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High hopes, realistic expectations drive bevacizumab treatment
Successes and failures of the drug signal the need for more research to help find its appropriate target.
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The idea of killing a tumor by choking off its blood supply, denying it oxygen and nutrients, was first proposed about 40 years ago in an article published by Judah Folkman, MD, in The New England Journal of Medicine. Therefore, when the antiangiogenic bevacizumab burst onto the scientific scene more than 30 years later in 2004, expectations were high for the vascular endothelial growth factor inhibitor.
“There was tremendous hope in the earlier part of this decade that with targeted therapies, such as bevacizumab, we were going to have drugs that we could expect incredible results from with a lower toxicity profile than we had ever seen with more traditional chemotherapies,” said J. Leonard Lichtenfeld, MD, MACP, deputy chief medical officer for the national office of the American Cancer Society.
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Photo courtesy of USC/Norris Comprehensive Cancer Center |
Just a few years earlier, in 2001, the oncology community had seen the tremendous success in treating chronic myeloid leukemia with imatinib (Gleevec, Novartis), a drug that was being called a “magic bullet” for cancer in the lay press.
“We thought that now that we were able to design drugs specific for a target, these drugs would be incredibly effective,” Lichtenfeld told HemOnc Today. “Perhaps we were a little naive in our hopes, because here we find ourselves several years later, and these success are not at the blockbuster level that we saw with [imatinib].”
Although bevacizumab (Avastin, Genentech/Roche) is not the only targeted cancer therapy that has had some disappointing results in recent years, it seems to get more negative attention, particularly in the lay media. Within recent years, the FDA yanked the drug’s accelerated approval status for metastatic breast cancer; the drug’s tremendous cost and adverse effects have garnered increased scrutiny; a recently published study linked the drug to higher mortality risk; and it demonstrated disappointing trial results in the adjuvant treatment of colorectal cancer.
However, bevacizumab is currently approved for the treatment of metastatic renal cell carcinoma, second-line treatment for glioblastoma, first-line treatment of non–small cell lung cancer, and first- and second-line treatment of colorectal cancer; and it is still being studied in a wide variety of other areas, both inside and outside of oncology.
HemOnc Today spoke with experts across several of bevacizumab’s approved and not-yet-approved cancer indications to examine what the oncologists using this drug think of it, and if their opinions line up with the negative attention that bevacizumab has recently received.
Elephant in the room
In 2008, bevacizumab combined with paclitaxel was granted accelerated approval for the treatment of metastatic HER-2–negative breast cancer. This approval was based on a 5.5-month improvement in PFS seen in the open-label, randomized, multicenter E2100 study and was contingent upon Genentech providing additional data to support the drug’s efficacy and safety in these patients.
In December, the FDA announced that it was recommending the removal of this indication because the follow-up data did not show a similar improvement in PFS and showed no improvement in OS. Genentech has filed for an appeal of the decision.
Much of the breast cancer community is split on this decision, according to Debu Tripathy, MD, professor of medicine and co-leader of the Women's Cancer Research Program at the University of Southern California and Norris Comprehensive Cancer Center in Los Angeles.
“I too am truly split about the decision,” Tripathy told HemOnc Today. “I would, of course, like to have bevacizumab as a treatment option for my patients, but I also agree that the benefit across the board for all patients is a very small one. It is not prolonging life, not improving quality of life, and disease-free survival on its own is a pretty weak endpoint.”
Without a way of determining which patients will benefit from treatment, it is difficult to defend treating an entire patient population with this drug, he said.
Although Tripathy said it seems as though the FDA changed its rules along the way — requiring one result at its initial approval of bevacizumab in breast cancer, and then later requiring more — he understands why this may have occurred in an indication such as breast cancer, in which there are such a wide variety of other treatment options.
"The FDA defends itself by saying, 'We don't use only one endpoint. We look at the totality of the evidence. Is the benefit greater than the harm?' and in this case, they do not think so," said Tripathy, who is also a member of the HemOnc Today Editorial Board.
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Approval based on ORR
Metastatic breast cancer is not the only indication for which bevacizumab was granted accelerated approval. In May 2009, the FDA granted the drug accelerated approval as a single-agent second-line treatment for patients with glioblastoma. This approval was based on improved overall response rate (ORR) seen in two single-arm trials, AVF3708g (ORR=25.9%) and NCI 06-C-0064E (ORR=19.6%).
Unlike metastatic breast cancer, there are no other effective therapies for refractory glioblastoma, making its FDA approval more clear cut, Tripathy said. Within neuro-oncology, bevacizumab’s approval is seen as a significant breakthrough for patients with glioblastoma.
“I would classify it as clearly one of the most major advances in years and years for the treatment of these patients,” said David M. Peereboom, MD, associate professor of medicine at Cleveland Clinic Lerner College of Medicine. “It is probably the first drug that has provided clear-cut evidence of functional improvement in patients with glioblastoma.”
Despite the FDA’s decision about removing the breast cancer indication, Peereboom said there is little concern about the glioblastoma indication having a similar fate. Bevacizumab can decrease cerebral edema in patients with glioblastoma, something that is uniquely important in patients with brain tumors because edema causes the majority of morbidity in these patients, he said.
“Bevacizumab is uniquely suited for improving edema, something that is not really an issue in any other tumor type,” Peereboom said. “As a result of this improvement, there is also an improvement in function and quality of life, as well.”
Significant survival advantages
Unlike in other cancers, bevacizumab’s approval in both first-line NSCLC and first- and second-line colorectal cancer was based on significant improvements in OS.
In 2004, the FDA approved bevacizumab combined with standard chemotherapy for colon cancer based on the results of a study that showed that the addition of the drug extended OS by about 5 months and PFS by about 4 months. Two years later, it extended bevacizumab’s label to second-line treatment of metastatic colorectal cancer combined with 5-FU.
“The early data were tremendously and strongly positive,” said David Ilson, MD, PhD, of the department of medicine, gastrointestinal oncology service at Memorial Sloan-Kettering Cancer Center. “The trials showed the largest survival difference of any study in metastatic colon cancer up until that point. We all thought it was a very big advance.”
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Ilson said some subsequent data have been not entirely consistent, but in the aggregate, the studies show a benefit for the drug in advanced disease.
Upon seeing this benefit in patients with metastatic colorectal cancer, researchers began to look into the use of bevacizumab to treat other gastrointestinal cancers, as well. Unfortunately, a phase 3 trial of bevacizumab in advanced pancreatic cancer and a phase 3 study in advanced gastric cancer failed to show an advantage to treatment with the drug. Most recently, two eagerly awaited trials of bevacizumab in stage II or III colorectal cancer, NSABP-08 and AVANT, also did not show any advantage in DFS for bevacizumab combined with standard 5-FU therapy.
“The drug clearly failed as an adjuvant treatment. About that there is no debate,” said Ilson, who is also a member of the HemOnc Today Editorial Board. “You have a US trial that failed to show benefit and a European trial that showed detriment.”
However, this is not the first time that a drug has shown an effect in metastatic disease and not in the adjuvant setting, Ilson said. “The failure of bevacizumab in the adjuvant setting does not at all diminish my interest or enthusiasm in using it as first-line chemotherapy in metastatic patients because it improves outcomes.”
Cost issues are another huge public issue surrounding the drug, and Ilson said they will always be a problem, especially in an incurable disease in which any treatment can be considered palliative.
“I have been practicing for 20 years, and when I started practice, we had 5-FU alone to treat colon cancer, and patients lived an average of 9 to 10 months. We had nothing else to offer them,” Ilson said. “Now the average survival in patients with metastatic colon cancer exceeds 2 years, and that is because of the advent of drugs like bevacizumab, as well as other new drugs.”
Still hopeful
It is this type of success that leads researchers to continue to examine the use of bevacizumab in other cancer indications. Among the areas being explored is ovarian cancer, in which the results from two ongoing studies, ICON7 and GOG218, have indicated that bevacizumab combined with chemotherapy, and then continued as a single-agent after chemotherapy, improved PFS. However, there is currently no indication that the drug improves OS.
“Bevacizumab is absolutely an active drug in ovarian cancer, and it is more active as a singe agent than in any other malignancy,” said Maurie Markman, MD, vice president of patient oncology services and national director for medical oncology at Cancer Treatment Centers of America.
According to Markman, a HemOnc Today Section Editor, the hypothesis behind bevacizumab’s use in ovarian cancer is that ovarian cancers are very much driven by VEGF. Within the normal physiology of reproduction, the angiogenesis process is important in the monthly cycle and in the damage and repair that occurs every month when an egg is released through the epithelium. In addition, there is fairly strong evidence that VEGF is overexpressed and that this overexpression correlates with poor survival and progression of the disease, he said.
But Markman said the fate of the approval of bevacizumab for the treatment of ovarian cancer may be very much tied up in the fate of its indication for the treatment of metastatic breast cancer.
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“There is still an open hearing to be had to determine the breast cancer indication,” he said. “However, I would suspect that the FDA will not make any determination about ovarian cancer until the issue of breast cancer is resolved.
“I don’t have any direct knowledge of that, but it would seem to me that if the FDA is making the decision at this state to pull back on the breast cancer indication on the basis of PFS and OS, then it would be difficult to imagine that the FDA would then improve bevacizumab for ovarian cancer with the same endpoint,” Markman said.
In addition, a study published in March in the Journal of Clinical Oncology indicated that early data from the GOG 218 study showed that adding bevacizumab to standard treatments was not cost-effective, based on the resulting improvement in PFS.
The question of cost is also a difficult one, according to Markman. “As a doctor, I care about my patients. Giving bevacizumab in a front-line setting is a reasonable thing to do from a medical point of view,” he said. However, cost is an issue that physicians and patients need to come to terms with.
“It is an important drug in ovarian cancer. There is no question about it,” Markman said. “But we also don’t have a biomarker to predict in which women it will work.”
Target needed
Experts have said bevacizumab may not have lived up to the magic bullet expectations that surrounded the drug when it first came onto the scene, but all still acknowledge that it has been very successful in certain areas and has definitely improved or extended the lives of many of the patients treated with it.
The identification of a biomarker that would help narrow the field of patients treated to only those who would benefit the most would be a huge advance for bevacizumab and would help to decrease some of the astronomical spending associated with treating an unselected group of patients.
When recalling the first positive results presentation of bevacizumab in advanced colorectal cancer, Lichtenfeld said he can still remember sitting in the audience that day and observing the survival curves.
“The data were clear cut,” he said. “Today, it is still clear that bevacizumab works. It may not be a cure, it may not even be a great leap forward, but it still represents a significant step forward in the treatment of a disease that is difficult to treat and whose progress has been measured in small, small changes over a great period of time.” – by Leah Lawrence
For more information:
- Cohn DE. J Clin Oncol. 2011;29:1247-1251.
- Folkman J. N Engl J Med. 1971;285:1182-1186.
- Pazdur R. FDA approval for bevacizumab. www.cancer.gov/cancertopics/druginfo/fda-bevacizumab#Anchor-Glioblastoma. Accessed April 12, 2011.
- Ranpura V. JAMA. 2011;305:487-494.
Disclosures: Dr. Ilson reports receiving research support from Genentech and Bayer. Dr. Markman reports serving as a member of a medical advisory board for Genentech. Drs. Lichtenfeld, Peereboom and Tripathy report no relevant financial disclosures. .
Has bevacizumab lived up to expectations?
The answer to this question depends on your perspective.
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When this drug was being developed, it was touted by many as a wonder drug for cancer. It would be fair to say that it has not necessarily lived up to that claim. However, bevacizumab is an important and useful addition to the treatment of many different kinds of solid tumors, such as lung, colorectal, glioblastoma and renal. However, bevacizumab’s efficacy is a bit of a mixed picture.
Bevacizumab is a targeted drug against the vascular endothelial growth factor. I would say that this is part of the limitation of what the drug has been able to do, especially in the case of breast cancer. We just do not have a good handle on the types of biomarkers that we need to understand how biologically relevant the VEGF pathway is in a given person’s cancer.
Within the breast cancer community, part of the argument is that we looked at the results from the E2100 trial and saw a doubling of PFS, but no survival advantage. Some would say that we are talking about survival advantage in women who are receiving multiple lines of therapy after first-line treatment and that some of those survival advantages may be lost in all those different treatments. The issue there is that, when you look at how bevacizumab performed combined with other chemotherapy agents, like docetaxel in the AVADO trial or xeloda in the RIBBON-1 studies or EXCALIBUR, the magnitude of benefit was not as large. The observed benefit depends on the setting in which you are using bevacizumab and what agents it is paired with.
In addition, it may be that the VEGF pathway is easily circumvented in some cancers, so when you block it, the cancer grows around it. In other cases, VEGF is not absolutely critical for the growth of some of the tumors, and they can grow right through bevacizumab. If we had a better handle on being able to identify which patients benefit the most from using the drug, then we could probably say more confidently that we could maximize the potential of the drug.
Bevacizumab is not a cure-all. It is not a wonder drug. It is an incremental step in the treatment of cancer, but the magnitude of that advance or progress would be further enhanced if we actually knew the appropriate patients to use it in. Using it in unselected, large patient populations is likely not going to result in us maximizing the cost-benefit ratio of the drug.
Hatem Soliman, MD, is an assistant member in the Don and Erika Wallace Comprehensive Breast Program at Moffitt Cancer Center. He reports no relevant financial disclosures.
Maybe not, but the drug is still important.
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Bevacizumab remains an outstanding achievement in the annals of oncology drug development, a first-in-class agent that brought to clinical reality the promise of antiangiogenic therapy. But perhaps the initial enthusiasm, and thrill, of having a potent new drug, one that demonstrated such an important new proof of principle mechanistically, set up unrealistic expectations that could not be met long term. Recently, a number of high-profile bevacizumab studies have not met with the same success as earlier trials. One need look only within the gastrointestinal oncology realm to see a string of disappointing results over the past several years. A phase 3 trial of bevacizumab in advanced pancreatic cancer (CALGB 80303) was strikingly negative. An international phase 3 study in advanced gastric cancer (AVAGAST) failed to meet its primary endpoint of improved OS, although the addition of bevacizumab to standard chemotherapy did improve median PFS. Two adjuvant colon cancer trials that had been eagerly awaited, NSABP C-08 and AVANT, each of which enrolled several thousand patients apiece with stage II or III disease, did not demonstrate an improvement in DFS with the addition of bevacizumab to standard fluoropyrimidine-based chemotherapy.
Other events have similarly taken some of the luster off of bevacizumab’s previously impenetrable sheen. Late last year, the FDA reversed course on its previous approval of bevacizumab in advanced breast cancer, based on successor studies in this disease indication failing to demonstrate a similar degree of clinical improvement as had the original study on which its expedited approval was based, including an absence of OS benefit. Then, a meta-analysis published earlier this year in JAMA highlighted the fact that bevacizumab, when added to chemotherapy, was associated with a significantly higher rate of fatal adverse events (RR=1.46). When added to people’s growing concerns about our current health economic crisis, and as a perfect example of this class of (overly) expensive targeted cancer therapies, there is no doubt that bevacizumab has since come back down to earth from its original heyday of unchecked enthusiasm.
The hope that it would prove useful in earlier stages of disease, such as in the adjuvant setting in colon cancer, has not been realized. But bevacizumab found its way into a number of treatment paradigms across several important disease indications, offering meaningful clinical benefit to large numbers of patients. Medical oncologists are glad to have this drug available to prescribe to select patients.
Andrew Ko, MD, is an associate professor in the department of medicine (hematology/oncology), University of California San Francisco, and a HemOnc Today Editorial Board member. Dr. Ko reports having received prior research support from Genentech, but not within the last year.