You have seen the headlines – “Genentech Shares Jump on FDA Avastin Nod,” “Genentech shares soar after FDA action,” “Genentech rockets on FDA approval for Avastin.” After the FDA approved Avastin for breast cancer, the stock for the biotech company Genentech jumped over 10%. According to some analysts this approval may add over $500 million in sales. Other estimates are over one billion dollars in three years.
But is this drug worthy of approval? A review of the transcript of the FDA’s own Oncologic Drugs Advisory Committee suggests a number of unsettling aspects, including:
• Survival – The drug did not increase overall survival in the breast cancer patients tested.
• Toxicity – More patients died toxic deaths who received Avastin in combination with paclitaxel than those who received paclitaxel alone. In addition there were more life threatening adverse events (side effects) in those breast cancer patients who received Avastin.
• Problems With the Clinical Trial that Led to Approval – There were a number of issues with the clinical trial highlighted by the FDA including lack of data, the subjective nature of the findings, missing information, and protocol violations.
• Committee Voted “No” on Approval – The FDA’s own Oncologic Drugs Advisory Committee voted not to approve Avastin for breast cancer 5-4. Inexplicably, FDA bureaucrats overturned the decision of its own Advisory Committee.
Overall Survival Not Improved by Avastin
On Friday, February 22, 2008, the FDA approved Genentech’s drug Avastin in combination with paclitaxel for first-line treatment of women with HER-2 negative metastatsized breast cancer. The approval is contingent on data to be released later this year from additional trials. Avastin is an anti-angiogenesis antibody that stops the generation and maintenance of blood vessels that feed tumors. Paclitaxel is a chemotherapy drug isolated from the bark of the Pacific yew tree.
This FDA approval was based primarily on one clinical trial organized by the Eastern Cooperative Oncology Group (ECOG). From December 2001 to May 2004, 722 women with breast cancer joined this clinical trial. They were divided into two groups: 368 women received paclitaxel and Avastin (bevacizumab); and 355 patients received paclitaxel alone.
According to the study abstract that appeared in the New England Journal of Medicine, the overall survival rate “was similar in the two groups.” This conclusion was echoed by the FDA’s Oncologic Drugs Advisory Committee which stated that there was no statistical difference in survival between the two groups.
If there was no survival advantage to the breast cancer patients taking Avastin, why was this drug approved for breast cancer? A different measure was used; one that apparently has little bearing on survival. This metric is called “progression free survival.” According to the National Cancer Institute, “Progression-free survival (is) the length of time during and after treatment in which a patient is living with a disease that does not get worse.” Essentially it is the interval from the start of treatment to the time that the tumor returns or starts growing.
The progression free survival of the patients in the paclitaxel/Avastin group and the paclitaxel group was 11.8 months and 5.9 months respectively. This was indeed an improvement. But how meaningful is this measure? Although Avastin contributed to slowing down the recurrence of the disease, the group of women whose breast cancers were slowed down with Avastin died at about the same time as those who did not receive the new drug. There was no statistical survival advantage.
Several of the doctors on the FDA's Oncologic Drugs Advisory Committee voiced their concerns about using progression free survival to approve Avastin (1):
Aman Buzdar, M.D. of the Department of Breast Medical Oncology at The University of Texas M.D. Anderson Cancer Center suggested that better endpoints were needed, that the improvement in progression free survival could be explained by chance, and that an endpoint should not be dependant on the observer. He stated, “I think that [it] will be going backward and we need harder endpoints. As I pointed out in these data that differences in measurable disease between the two groups could even explain all these five months differences by chance alone, even though all the measures and everything is accurate, it could be just that biology of breast cancer is very heterogeneous. And we need endpoints which are harder, fixed, and not observer-dependent.”
Ralph D’Agostino, Chair of the Mathematics and Statistics Department at Boston University suggested that the Committee does not “buy into progression-free survival.” He stated, “So I would think that it’s very, very serious that in this first-line treatment that we do not buy into this progression-free survival.”
And Patricia Cortazar, M.D. of the FDA, stated that time to progression is not an “adequate basis for approval.” She said, “An improvement in overall survival in a randomized control study is the gold standard endpoint in first-line metastatic breast cancer. We have required a meaningful improvement on survival for safety and efficacy reasons….(the) FDA has not considered tumor response or time to progression as adequate basis for approval.”
Toxicity and Deaths Associated with Avastin
The group of breast cancer patients who received Avastin experienced “significantly” more toxicity. According to Lee Pai-Scherf, M.D. of the FDA’s Division of Biologic Oncology Products, “the incidence of serious toxicity was significantly higher in the paclitaxel/bevacizumab arm: 71 percent versus 51 percent. There were more deaths, more Grade 3 and 4 toxicities.” (Bevacizumab is the generic name for Avastin.) Grade 3 toxicity means severe side-effects. Grade 4 toxicity means life threatening or disabling side-effects. These toxicities included: hypertension, proteinuria (protein in the blood), arterial thromboembolic events with cerebrovascular ischemia, cardia ischemia, bleeding/ hemorrhage, congestive heart failure, GI perforation and fistula, and neutropenia and infection. In fact, there was ten times more hypertension in the Avastin/paclitaxel group versus the paclitaxel group (15%compared to 1.4%t) and three times more infection in the Avastin/paclitaxel group (9.3% versus 2.9%).
Furthermore, twelve patients in the paclitaxel/Avastin group died either on study or within 30 days of the end of the study. The transcript from the FDA’s Oncologic Drugs Advisory Committee suggests that none of these deaths were attributed to the treatment by Genentech. According to Lee Pai-Scherf, M.D. of the FDA’s Division of Biologic Oncology Products:
“Seven patients in the paclitaxel arm and 12 patients in the paclitaxel/bevacizumab arm died either on study or within 30 days of the end of the study. None of the deaths were attributed to protocol treatment according to the Applicant. After careful review of the case report forms and case narratives, the FDA disagreed with the Applicant's death
attribution in 13 out of 19 cases. Of importance, the FDA identified five deaths as definite or probably related to protocol treatment in the paclitaxel and bevacizumab arm.”
According to Barbara Klencke, M.D. of Genentech, Inc., “1.7% of percent of patients (who received Avastin and paclitaxel in the clinical trial) likely died due to protocol therapy.”
Problems with the Study
During the Oncologic Drugs Advisory Committee meeting a number of discussions centered around the lack of data, the subjective nature of the findings, missing information, and protocol violations.
Missing Data
Apparently there was missing information on the toxicity of Avastin. According to Lee Pai-Scherf, M.D. of the FDA’s Division of Biologic Oncology Products, “[T]here was incomplete assessment of toxicity profile due to the data collection. Grade 1-2 toxicity was not collected. Laboratory information was not available.” (Grade 1 toxicities are those that are mild. Grade 2 toxicities are those that are moderate.) According to Dr. Laura Lu of the FDA, “Factors negatively impacting FDA's confidence in the treatment effect on progression free survival include the amount of missing data, the number of patients lost to follow-up, and the ability of IRF (Independent Review Facility) and ECOG (clinical trial) investigators to consistently identify disease progression events.”
Scans – Where Are They?
The FDA suggested that Genentech was unable to obtain scans for some patients. According to the FDA’s Dr. Cortazar, “Genentech was unable to obtain scans for percent (sic) of patients.”
The scans were critical. These Xrays, CT’s or MRI’s were the most important means to determine whether a patient’s breast cancer was stable, getting worse, or getting better. Since progression free survival was the measure being used, the timely taking and reading of these scans was critical. Yet, according to the FDA, Genentech was unable to obtain scans for some percentage of the patients.
Findings Not Replicated by Independent Review Facility
The patient’s scans were subsequently analyzed by an Independent Review Facility (IRF). The independent review could not replicate the findings of the investigators involved in the clinical trial. Differences included finding disease progression (cancer growing or spreading) where the original investigators found none and visa-versa. Even where there was agreement, there was disagreement on the dates. In fact, in 24% of the patients (174 out of 720 patients) the IRF did not agree with the findings of the investigators in the clinical trial (ECOG). According to Dr. Laura Lu (Ph.D.) of the Office of Biostatistics for the FDA, “There were 174 patients for which the IRF and ECOG investigators did not agree on disease progression status. Across the entire study population 6 percent of the patients were determined to have disease progression by the IRF, but not to have disease progression by ECOG investigators. And an additional 18 percent were determined not to have disease progression by the IRF, but as having disease progression by ECOG investigators.”
Dr. Lu alludes to the problem with the dates. “The overall discordance rate for the date of disease progression date is 27 percent. In total, the discordance rate is 51 percent for disease progression status or data progression.” Apparently in over half the patients (51%) the Independent Review Facility could not agree with the findings of the investigators who reported the original data for the clinical trial.
Submission Incomplete
Basic protocol information was also missing or incomplete. Lee Pai-Scherf, M.D. of the FDA stated, “The submission was incomplete in regards to documentation of eligibility, baseline tumor description, study violations, drug exposure, and treatment delays/ discontinuation due to toxicity. In summary, the data submitted did not allow a full evaluation of efficacy and safety.”
Protocol Violations
Furthermore, Dr. Pai-Scherf cites key protocol violations where the treatments own rules were not followed. She stated, “Key protocol violations are shown…Of significance, 6 percent of the patients were treated beyond progression with a frequency higher in the bevacizumab arm: 4 in the paclitaxel arm and 7 percent in the paclitaxel/bevacizumab arm.”
An Inexplicable Decision
After discussing the lack of improvement in survival and quality of life, the deaths and toxicities from the treatment, and the problems and inconsistencies with the study, the FDA's Oncologic Drugs Advisory Committee voted 5 to 4 not to approve Avastin for breast cancer. The three Temporary Voting Members, Aman Buzdar, M.D., Ralph D’Agostino, and Natalie Portis all voted “no.” The two regular committee members who voted “no” were Maha H.A. Hussain, M.D. and Virginia P. Mason. It is worth noting that Virginia Mason of the Inflammatory Breast Cancer Research Foundation is the “Consumer Representative” on the Committee and Natalie Portis is the “Patient Representative.” Apparently the two women who represented the interests of patients and consumers most directly decided that it was not in the best interest of their constituents to approve Avastin for this new indication.
Of the four members who voted in favor of approving Avastin at least two (S. Gail Eckhardt and Joanne Mortimer) have had a prior advisory and/or consulting and/or financial relationship with Genentech.
According to the Authors’ Disclosures of Potential Conflicts of Interest for the article Integrating Molecular Oncology Into Clinical Practice: Antiangiogenic Therapy (2) “The following authors or their immediate family members have indicated a financial interest…Consultant…S. Gail Eckhardt, ImClone Systems, Genentech. Research Funding…S. Gail Eckhardt, ImClone Systems, Genentech.” And according to the disclosure appearing in the article Long Term Consequences of Aromatase Inhibitors (3), “Joanne Mortimer, MD, has disclosed that she has received grants for educational activities from Sanofi-Aventis and that she has served as an advisor or consultant for Genentech.”
Nonetheless, despite a narrow margin in favor of not approving Avastin, the FDA went against the recommendation of its own advisory panel and decided to approve the drug.
“All they had was progression-free survival in one trial, no increase in quality of life and patient deaths in the Avastin group,” said Fran Visco of the National Breast Cancer Coalition as quoted by the Associated Press. “We’re very confused why FDA made this decision.”
Many people are confused and some are concerned that this decision opens the door for more cancer drugs to be approved merely for their temporary tumor-shrinking capabilities, a trend that concerns some health experts. “If FDA sets a precedent of approving a drug based on progression free survival, people are afraid they may stop looking at survival as the most important endpoint,” said Dr. Kay Dickersin, director of the Center for Clinical Trials at Johns Hopkins University according to the Associated Press.
According to the Wall Street Journal, Susan Desmond-Hellmann, Genentech’s president of product development, says that marketing Avastin to fight breast cancer is “important from a business perspective.” Indeed.
Sources
(1) Most of the quotations that appear in this article came from ONCOLOGIC DRUGS ADVISORY COMMITTEE MEETING OPEN SESSION held in Gaithersburg, Maryland on Wednesday, December 5, 2007. A transcript of the session is available online at the FDA’s website.
(2) Published in the Journal of Clinical Oncology, Vol 23, No 5 (February 10), 2005: pp. 937-938. Available here.
(3) Published in Medscape Hematology-Oncology 2005;8(2)
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