Breast Cancer

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The second day of the Avastin hearing at the Food and Drug Administration has started. Following the FDA's presentation yesterday, representatives for Genentech will argue why the drug should be approved for breast cancer treatment. Following a question-and-answer session, the FDA's independent advisory board will announce its vote this afternoon.

Naseem S. Miller and Elizabeth Mechcatie contributed to this report.

The second day of the Avastin hearing at the Food and Drug Administration has started. Following the FDA's presentation yesterday, representatives for Genentech will argue why the drug should be approved for breast cancer treatment. Following a question-and-answer session, the FDA's independent advisory board will announce its vote this afternoon.

Naseem S. Miller and Elizabeth Mechcatie contributed to this report.

The second day of the Avastin hearing at the Food and Drug Administration has started. Following the FDA's presentation yesterday, representatives for Genentech will argue why the drug should be approved for breast cancer treatment. Following a question-and-answer session, the FDA's independent advisory board will announce its vote this afternoon.

Naseem S. Miller and Elizabeth Mechcatie contributed to this report.

The first day of the Food and Drug Administration’s hearing on Avastin (bevacizumab) came to an end with a question-and-answer session between FDA officials and representatives from Genentech, the maker of the drug.

Earlier in the day, the Center for Drug Evaluation and Research (CDER) presented its position and stood by its proposal to withdraw approval for the breast cancer indication for Avastin.

The first day of the Food and Drug Administration’s hearing on Avastin (bevacizumab) came to an end with a question-and-answer session between FDA officials and representatives from Genentech, the maker of the drug.

Earlier in the day, the Center for Drug Evaluation and Research (CDER) presented its position and stood by its proposal to withdraw approval for the breast cancer indication for Avastin.

The first day of the Food and Drug Administration’s hearing on Avastin (bevacizumab) came to an end with a question-and-answer session between FDA officials and representatives from Genentech, the maker of the drug.

Earlier in the day, the Center for Drug Evaluation and Research (CDER) presented its position and stood by its proposal to withdraw approval for the breast cancer indication for Avastin.

During a two-day meeting at the Food and Drug Administration offices outside of Washington, Genentech will provide evidence to support the company’s contention that the metastatic breast cancer approval of bevacizumab, in combination with paclitaxel, should not be withdrawn.

In December, the FDA proposed that the accelerated approval for this indication be pulled after two studies failed to show the magnitude of benefit on progression-free survival seen in an earlier study. Moreover, none of the trials showed an improvement in overall survival. 

In an unprecedented move, Genentech appealed the decision, and the FDA granted the company the hearing.

During a two-day meeting at the Food and Drug Administration offices outside of Washington, Genentech will provide evidence to support the company’s contention that the metastatic breast cancer approval of bevacizumab, in combination with paclitaxel, should not be withdrawn.

In December, the FDA proposed that the accelerated approval for this indication be pulled after two studies failed to show the magnitude of benefit on progression-free survival seen in an earlier study. Moreover, none of the trials showed an improvement in overall survival. 

In an unprecedented move, Genentech appealed the decision, and the FDA granted the company the hearing.

During a two-day meeting at the Food and Drug Administration offices outside of Washington, Genentech will provide evidence to support the company’s contention that the metastatic breast cancer approval of bevacizumab, in combination with paclitaxel, should not be withdrawn.

In December, the FDA proposed that the accelerated approval for this indication be pulled after two studies failed to show the magnitude of benefit on progression-free survival seen in an earlier study. Moreover, none of the trials showed an improvement in overall survival. 

In an unprecedented move, Genentech appealed the decision, and the FDA granted the company the hearing.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Just one day ahead of the Food and Drug Administration’s hearing on the fate of Avastin’s breast cancer claim, the New England Journal of Medicine has published two articles on the event – and both take the agency to task for its past, and potentially future, actions on Genentech’s VEGF inhibitor.

Both perspective pieces take a dim view of retaining Avastin’s claim for metastatic breast cancer (MBC). One author questions the FDA’s decision to grant Avastin accelerated approval on the basis of progression-free survival, suggesting it has muddied the evidentiary threshold for future approvals. Meanwhile, writers of the second piece warn against the precedent established if FDA were to bow to political and public pressure and reverse course, allowing the MBC claim to remain on Avastin’s label pending a new confirmatory trial.

One article was contributed by a member of previous FDA advisory committee panels on Avastin. The other was authored by a group from Harvard University, Boston, with particular interests in pharmaceutical regulatory policy and outcomes research.

The NEJM articles, published online June 27, reflect the importance of the Avastin proceedings to the agency and biopharmaceutical industry going forward.

The hearing on the Center for Drug Evaluation and Research’s proposal to withdraw Avastin’s accelerated approval in MBC starts on June 28. The 2-day proceeding will take place at the agency’s White Oak campus in Silver Spring, Md., with Center for Biologics Evaluation and Research Director Dr. Karen Midthun serving as the presiding officer. The hearing panel will be drawn from fewer than half of the members of the agency’s Oncologic Drugs Advisory Committee (ODAC).

The hearing, which will kick off with 2 hours of public testimony, is expected to draw a large crowd of patients advocating for Avastin’s continued use in MBC. Freedom of Access to Medicines, a patient group affiliated with the Abigail Alliance, has announced plans to protest outside the White Oak campus before its representatives testify at the hearing.

An ODAC Veteran Weighs In on PFS. Writing in the NEJM, statistician Ralph D’Agostino Sr., Ph.D., of Boston University, criticizes the agency’s original reliance on progression-free survival (PFS) in approving the MBC indication. Dr. D’Agostino served as a temporary voting member at ODAC’s two previous reviews of Avastin for MBC in July 2010 and December 2007. He voted against the claim on both occasions, siding with the majority of panel members each time.

In "Changing End Points in Breast-Cancer Drug Approval – The Avastin Story," Dr. D’Agostino reiterated many of the same concerns he raised during the previous ODAC reviews about the wisdom of relying upon PFS, rather than overall survival, to support approval. By granting Avastin accelerated approval for MBC in February 2008, the FDA implicitly recognized PFS as a surrogate end point for survival, he said.

The E2100 trial, which served as the basis for accelerated approval, demonstrated a 5.5-month benefit in median PFS with bevacizumab in combination with paclitaxel compared with paclitaxel alone. Two confirmatory trials, AVADO and RIBBON-1, studied bevacizumab in combination with different chemotherapy agents. These trials showed considerably smaller, though still significant, median PFS benefits ranging from less than a month to 2.9 months, with no difference in overall survival. "The data demonstrate that progression-free survival did not act as a surrogate for overall survival," Dr. D’Agostino said of the confirmatory trials.

He argued that the initial MBC approval served to lower the evidentiary standard for subsequent cancer therapies, undermining the ability to truly understand whether they extend overall survival.

"Whatever FDA finally does, many researchers and clinicians see this case as supporting the use of progression-free survival as the primary end point for cancer studies in which overall survival has been the norm," he said. "The argument over whether progression-free survival is a meaningful clinical end point will and should continue, but if its use becomes standard for accelerated or even final approval, it will be more difficult, if not impossible, to obtain solid data on overall survival. Unfortunately, the role of a survival benefit in the FDA approval process is now unclear."

Others Warn About Damage to the FDA’s Reputation. A separate article focused on the damage to the FDA’s reputation, and the integrity of the accelerated approval pathway, if FDA Commissioner Margaret Hamburg were to reverse CDER’s decision and decide not to pull the indication.

Harvard’s Daniel Carpenter, Ph.D., Dr. Aaron Kesselheim, and Dr. Steven Joffe authored the perspective, titled "Reputation and Precedent in the Bevacizumab Decision."

Dr. Carpenter is a professor of government, with work including the Harvard Project on U.S. Pharmaceutical Regulation, "a.k.a. The FDA Project." In 2010, he published a book titled "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA." Dr. Kesselheim is a researcher in the department of health policy and management. Dr. Joffe, a pediatric oncologist, is involved with the Dana-Farber Cancer Institute’s Center for Outcomes and Policy Research, Boston.

The three described accelerated approval as "a medium-term stopover en route to full approval or market withdrawal."

If the FDA lacks a genuine ability to withdraw accelerated approval due to inadequate or unfavorable data from confirmatory trials, the regulator would have few tools to ensure that companies provide the new data they promised in exchange for accelerated approval, they said. "Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions."

In its written summary of the evidence it intends to present at the hearing, Genentech argued that CDER’s withdrawal decision rests upon a new standard – one requiring either an overall survival benefit or PFS of an unspecified magnitude – that may deter development of new treatments for MBC.

However, Dr. Carpenter and his colleagues found this argument unpersuasive.

"The FDA often removes indications from labeling and commonly rejects new drug applications. Yet there is no consistent evidence that such actions deter the development of clinically valuable therapies," they said. "Indeed, the relationship might be the reverse: if bevacizumab offers little promise for patients with metastatic breast cancer, then removing the indication may create a clinical and market niche that provides other companies with an incentive to develop a better product for, or test available products in, that population."

The credibility of both the agency and the accelerated approval process hangs in the balance, the Harvard professors asserted.

"Underlying the back-and-forth about bevacizumab’s trial performance is a larger issue: the precedent that will be established if the FDA reverses its decision on withdrawing bevacizumab’s labeling for metastatic breast cancer not because of changing scientific evidence, but in response to philosophical and political counterarguments," they wrote.

"If the FDA demonstrates that it is unable or unwilling to withdraw accelerated approval when the totality of evidence fails to meets its standard for regular approval ... such a precedent risks undermining the basis for accelerated approval mechanisms and, more broadly, the agency’s credibility as it seeks to regulate medical products for the public good."

CDER similarly has warned that it must be able to withdraw approval when confirmatory trials fail to verify clinical benefit or else the accelerated approval process will operate as a lower standard.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

By improving the risk factors of weight, exercise, and alcohol consumption, women could reduce their 20-year risk of breast cancer by more than 4%, depending on age and other risk factors.

A new risk model suggests that a risk reduction of 1.6% could prevent 16,000 cases of breast cancer in a population of 1 million women. On an individual basis, a 55-year-old woman with the most nonmodifiable risk factors could see the biggest benefit, an absolute risk reduction of 4.4%

Even younger women at the highest risk of breast cancer could reduce their risk over 20 years by more than 3% if they optimally improved all three modifiable risk factors, Elisabetta Petracci, Ph.D., reported in the June 24 issue of the Journal of the National Cancer Institute.

Kristan Hutchison (Property of National Science Foundation)/ (Antarctic Photo Library (Image link)), via Wikimedia Commons .

"The absolute risk model developed in this study could help clinicians make decisions about implementing interventions to reduce a patient’s exposure to modifiable risk factors, thereby reducing their absolute risk of breast cancer," wrote Dr. Petracci and her colleagues (J. Natl. Cancer Inst. 2011;103:1-12). "Because programs to encourage less alcohol consumption, increase leisure activity, and encourage some weight control are likely to be safe, they can be widely administered."

The researchers began their model with data from an Italian breast cancer case-control study of 2,569 cases and 2,588 controls who were followed during 1991-1994. To compute absolute risk, they employed 5-year, age-specific, breast cancer incidence rates from the Florence Cancer Registry in 1989-1993. Rates were based on an estimated 2006 population of 1,190,516 women.

Another Italian study provided a validation cohort consisting of 10,083 women who were followed during 1998-2004. This study collected demographic information as well as information on anthropomorphic characteristics, age, physical activity, reproductive history, diet and lifestyle, and a family history of breast cancer.

The team considered all of the risk factors and calculated the 10- and 20-year risk of breast cancer as well as the 10- and 20-year absolute risk reductions if the three modifiable factors improved optimally. They performed the calculations in each study cohort, then averaged the results to confirm the possible reductions.

The risk reduction model divided its cohort into nine profiles, ranging from a young, low-risk group to an older, high-risk group. Including the above characteristics, the model also took into account educational level, alcohol consumption, ages at menarche and first live birth, and the number of lifetime breast biopsies.

In the entire population, if women aged 45 years improved all three modifiable risk factors, they could reduce the overall 20-year risk by 1.4%. The population-based risk for 65-year-olds could drop by 1.6%. The risk reduction is less in the older women because they generally had more favorable nonmodifiable risk factors, the authors noted.

On an individual basis, a 45-year-old woman with a positive family history could decrease her absolute 20-year risk by 2.7%; the reduction could be 3.2% in a woman aged 65 years.

For a younger woman with the highest nonmodifiable risk factors (only 10% of the population), optimally improving exercise, weight, and drinking could reduce the 10-year risk by 1.6% and the 20-year risk by 3.2%. A 55-year-old could reduce her 10-year risk by 2.4% and her 20-year risk by 4.4%. The oldest women in this category could reduce their 10-year risk by 2.5% and their 20-year risk by 4.1%.

But these numbers also need to be viewed in the context of a large population, the authors noted. Although an overall reduction of 1.6% would save 16,000 cases annually in a population of 1 million women, it would save only 2,560 cases annually in the 8% of postmenopausal women who have a family history of cancer.

Despite these limitations, the authors wrote, "Calculations of reductions in absolute risk using our model potentially provide additional perspective in the possible benefits of such prevention strategies."

This research was supported by the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and the Associazione Italiana per la Ricerca sul Cancro. The investigators did not report any conflicts of interest. Dr. Helzlsouer said that she had no relevant financial disclosures.

By improving the risk factors of weight, exercise, and alcohol consumption, women could reduce their 20-year risk of breast cancer by more than 4%, depending on age and other risk factors.

A new risk model suggests that a risk reduction of 1.6% could prevent 16,000 cases of breast cancer in a population of 1 million women. On an individual basis, a 55-year-old woman with the most nonmodifiable risk factors could see the biggest benefit, an absolute risk reduction of 4.4%

Even younger women at the highest risk of breast cancer could reduce their risk over 20 years by more than 3% if they optimally improved all three modifiable risk factors, Elisabetta Petracci, Ph.D., reported in the June 24 issue of the Journal of the National Cancer Institute.

Kristan Hutchison (Property of National Science Foundation)/ (Antarctic Photo Library (Image link)), via Wikimedia Commons .

"The absolute risk model developed in this study could help clinicians make decisions about implementing interventions to reduce a patient’s exposure to modifiable risk factors, thereby reducing their absolute risk of breast cancer," wrote Dr. Petracci and her colleagues (J. Natl. Cancer Inst. 2011;103:1-12). "Because programs to encourage less alcohol consumption, increase leisure activity, and encourage some weight control are likely to be safe, they can be widely administered."

The researchers began their model with data from an Italian breast cancer case-control study of 2,569 cases and 2,588 controls who were followed during 1991-1994. To compute absolute risk, they employed 5-year, age-specific, breast cancer incidence rates from the Florence Cancer Registry in 1989-1993. Rates were based on an estimated 2006 population of 1,190,516 women.

Another Italian study provided a validation cohort consisting of 10,083 women who were followed during 1998-2004. This study collected demographic information as well as information on anthropomorphic characteristics, age, physical activity, reproductive history, diet and lifestyle, and a family history of breast cancer.

The team considered all of the risk factors and calculated the 10- and 20-year risk of breast cancer as well as the 10- and 20-year absolute risk reductions if the three modifiable factors improved optimally. They performed the calculations in each study cohort, then averaged the results to confirm the possible reductions.

The risk reduction model divided its cohort into nine profiles, ranging from a young, low-risk group to an older, high-risk group. Including the above characteristics, the model also took into account educational level, alcohol consumption, ages at menarche and first live birth, and the number of lifetime breast biopsies.

In the entire population, if women aged 45 years improved all three modifiable risk factors, they could reduce the overall 20-year risk by 1.4%. The population-based risk for 65-year-olds could drop by 1.6%. The risk reduction is less in the older women because they generally had more favorable nonmodifiable risk factors, the authors noted.

On an individual basis, a 45-year-old woman with a positive family history could decrease her absolute 20-year risk by 2.7%; the reduction could be 3.2% in a woman aged 65 years.

For a younger woman with the highest nonmodifiable risk factors (only 10% of the population), optimally improving exercise, weight, and drinking could reduce the 10-year risk by 1.6% and the 20-year risk by 3.2%. A 55-year-old could reduce her 10-year risk by 2.4% and her 20-year risk by 4.4%. The oldest women in this category could reduce their 10-year risk by 2.5% and their 20-year risk by 4.1%.

But these numbers also need to be viewed in the context of a large population, the authors noted. Although an overall reduction of 1.6% would save 16,000 cases annually in a population of 1 million women, it would save only 2,560 cases annually in the 8% of postmenopausal women who have a family history of cancer.

Despite these limitations, the authors wrote, "Calculations of reductions in absolute risk using our model potentially provide additional perspective in the possible benefits of such prevention strategies."

This research was supported by the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and the Associazione Italiana per la Ricerca sul Cancro. The investigators did not report any conflicts of interest. Dr. Helzlsouer said that she had no relevant financial disclosures.

By improving the risk factors of weight, exercise, and alcohol consumption, women could reduce their 20-year risk of breast cancer by more than 4%, depending on age and other risk factors.

A new risk model suggests that a risk reduction of 1.6% could prevent 16,000 cases of breast cancer in a population of 1 million women. On an individual basis, a 55-year-old woman with the most nonmodifiable risk factors could see the biggest benefit, an absolute risk reduction of 4.4%

Even younger women at the highest risk of breast cancer could reduce their risk over 20 years by more than 3% if they optimally improved all three modifiable risk factors, Elisabetta Petracci, Ph.D., reported in the June 24 issue of the Journal of the National Cancer Institute.

Kristan Hutchison (Property of National Science Foundation)/ (Antarctic Photo Library (Image link)), via Wikimedia Commons .

"The absolute risk model developed in this study could help clinicians make decisions about implementing interventions to reduce a patient’s exposure to modifiable risk factors, thereby reducing their absolute risk of breast cancer," wrote Dr. Petracci and her colleagues (J. Natl. Cancer Inst. 2011;103:1-12). "Because programs to encourage less alcohol consumption, increase leisure activity, and encourage some weight control are likely to be safe, they can be widely administered."

The researchers began their model with data from an Italian breast cancer case-control study of 2,569 cases and 2,588 controls who were followed during 1991-1994. To compute absolute risk, they employed 5-year, age-specific, breast cancer incidence rates from the Florence Cancer Registry in 1989-1993. Rates were based on an estimated 2006 population of 1,190,516 women.

Another Italian study provided a validation cohort consisting of 10,083 women who were followed during 1998-2004. This study collected demographic information as well as information on anthropomorphic characteristics, age, physical activity, reproductive history, diet and lifestyle, and a family history of breast cancer.

The team considered all of the risk factors and calculated the 10- and 20-year risk of breast cancer as well as the 10- and 20-year absolute risk reductions if the three modifiable factors improved optimally. They performed the calculations in each study cohort, then averaged the results to confirm the possible reductions.

The risk reduction model divided its cohort into nine profiles, ranging from a young, low-risk group to an older, high-risk group. Including the above characteristics, the model also took into account educational level, alcohol consumption, ages at menarche and first live birth, and the number of lifetime breast biopsies.

In the entire population, if women aged 45 years improved all three modifiable risk factors, they could reduce the overall 20-year risk by 1.4%. The population-based risk for 65-year-olds could drop by 1.6%. The risk reduction is less in the older women because they generally had more favorable nonmodifiable risk factors, the authors noted.

On an individual basis, a 45-year-old woman with a positive family history could decrease her absolute 20-year risk by 2.7%; the reduction could be 3.2% in a woman aged 65 years.

For a younger woman with the highest nonmodifiable risk factors (only 10% of the population), optimally improving exercise, weight, and drinking could reduce the 10-year risk by 1.6% and the 20-year risk by 3.2%. A 55-year-old could reduce her 10-year risk by 2.4% and her 20-year risk by 4.4%. The oldest women in this category could reduce their 10-year risk by 2.5% and their 20-year risk by 4.1%.

But these numbers also need to be viewed in the context of a large population, the authors noted. Although an overall reduction of 1.6% would save 16,000 cases annually in a population of 1 million women, it would save only 2,560 cases annually in the 8% of postmenopausal women who have a family history of cancer.

Despite these limitations, the authors wrote, "Calculations of reductions in absolute risk using our model potentially provide additional perspective in the possible benefits of such prevention strategies."

This research was supported by the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and the Associazione Italiana per la Ricerca sul Cancro. The investigators did not report any conflicts of interest. Dr. Helzlsouer said that she had no relevant financial disclosures.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – Carboplatin or cisplatin monotherapy has significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer, according to Dr. Steven J. Isakoff.

The overall response rate to therapy with one of the platinum compounds was 30.2% – 4.7% complete responses and 25.6% partial responses, Dr. Isakoff of Massachusetts General Hospital cancer center, Boston, and his colleagues in the Translational Breast Cancer Research Consortium found.

Subgroup analyses of the multicenter single-arm trial suggested a higher response rate with cisplatin (37%) than with carboplatin (23%), but this was not a head-to-head study, and the results should be interpreted with caution because physicians were allowed to choose one of the two agents at their own discretion, which could introduce bias into the results, Dr. Isakoff said at the meeting.

The drugs were generally well tolerated with manageable toxicities; some patients have received as many as 23 cycles, he said in an interview.

The investigators also looked at the utility of two members of the p53 family of oncogenic transcription factors, p63 and p73, for predicting response to platinum agents in triple-negative breast cancer (tumors lacking receptors for estrogen, progesterone, or HER2/neu that are targeted by other forms of therapy).

"As information about the activity of platinum in BRCA carriers has become recognized, people are thinking about it more in triple-negative breast cancer," Dr. Isakoff said. "We still don’t know whether triple-negative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy, and I think it’s going to take some of the randomized studies that are going on now in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there’s something special about triple negative and platinum."

The TBCRC009 study enrolled 86 patients with triple-negative breast cancer. The patients were assigned on the treating physician’s choice to receive either cisplatin at 75mg/m² IV every 3 weeks, or carboplatin to an area under the curve of 6 every 3 weeks.

In addition to the overall response rates noted here, the authors calculated a clinical benefit rate (a combination of complete and partial response and stable disease) of 34%.

Median progression-free survival (PFS) was 89 days. Thirty-three percent of patients had a PFS of less than 6 weeks, and another 33% had a PFS longer than 6 months. Among responders, a median PFS was 242 days. Responders had a median of nine chemotherapy cycles.

In subgroup analyses, platinum compounds were associated with a 33% response rate when used as first-line agents, and 17% when used in the second line. Only 17 patients received platinum as a second-line therapy, however.

The patients generally tolerated the drugs well. There was one case each of grade 4 neutropenia and hypertension. Grade 3 events included nine cases of fatigue, six of neutropenia, five of anemia, and four of hyponatremia.

"In general, it was well tolerated. We didn’t see unexpected toxicities with platinum, and we modified things with dose reductions as appropriate. It was not a common event to come off therapy due to toxicity," Dr. Isakoff said.

The investigators continue to collect data to determine whether p63/p73 expression can be a biomarker for response to platinum agents. The authors are also conducting BRCA mutation, molecular subtype, and circulating tumor cell analyses.

"This study was well designed with prospective powering for the p63/p73 correlative end point," said Dr. Stephen K.L. Chia of the British Columbia Cancer Agency and the University of British Columbia, in Vancouver, the invited discussant.

The rationale for investigating p63/p73 as a predictive biomarker is sound because these markers can be found in about 35%-40% of triple-negative breast cancers, he said. Questions that need to be addressed include whether there is a change in expression of the markers in metastatic relapse, and whether the heterogeneous group of triple-negative breast cancers can be further refined through molecular subtyping.

The study was funded by the AVON Foundation, Breast Cancer Research Foundation, Susan D. Komen for the Cure, Golfers Against Cancer, the Tracey Davis Breast Cancer Research Fund, and investigator awards from the NCI-AVON Partners for Progress, Harvard-MIT, and the Dana-Farber/Harvard Cancer Center. The authors said they had no other relevant financial disclosures.

CHICAGO – Carboplatin or cisplatin monotherapy has significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer, according to Dr. Steven J. Isakoff.

The overall response rate to therapy with one of the platinum compounds was 30.2% – 4.7% complete responses and 25.6% partial responses, Dr. Isakoff of Massachusetts General Hospital cancer center, Boston, and his colleagues in the Translational Breast Cancer Research Consortium found.

Subgroup analyses of the multicenter single-arm trial suggested a higher response rate with cisplatin (37%) than with carboplatin (23%), but this was not a head-to-head study, and the results should be interpreted with caution because physicians were allowed to choose one of the two agents at their own discretion, which could introduce bias into the results, Dr. Isakoff said at the meeting.

The drugs were generally well tolerated with manageable toxicities; some patients have received as many as 23 cycles, he said in an interview.

The investigators also looked at the utility of two members of the p53 family of oncogenic transcription factors, p63 and p73, for predicting response to platinum agents in triple-negative breast cancer (tumors lacking receptors for estrogen, progesterone, or HER2/neu that are targeted by other forms of therapy).

"As information about the activity of platinum in BRCA carriers has become recognized, people are thinking about it more in triple-negative breast cancer," Dr. Isakoff said. "We still don’t know whether triple-negative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy, and I think it’s going to take some of the randomized studies that are going on now in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there’s something special about triple negative and platinum."

The TBCRC009 study enrolled 86 patients with triple-negative breast cancer. The patients were assigned on the treating physician’s choice to receive either cisplatin at 75mg/m² IV every 3 weeks, or carboplatin to an area under the curve of 6 every 3 weeks.

In addition to the overall response rates noted here, the authors calculated a clinical benefit rate (a combination of complete and partial response and stable disease) of 34%.

Median progression-free survival (PFS) was 89 days. Thirty-three percent of patients had a PFS of less than 6 weeks, and another 33% had a PFS longer than 6 months. Among responders, a median PFS was 242 days. Responders had a median of nine chemotherapy cycles.

In subgroup analyses, platinum compounds were associated with a 33% response rate when used as first-line agents, and 17% when used in the second line. Only 17 patients received platinum as a second-line therapy, however.

The patients generally tolerated the drugs well. There was one case each of grade 4 neutropenia and hypertension. Grade 3 events included nine cases of fatigue, six of neutropenia, five of anemia, and four of hyponatremia.

"In general, it was well tolerated. We didn’t see unexpected toxicities with platinum, and we modified things with dose reductions as appropriate. It was not a common event to come off therapy due to toxicity," Dr. Isakoff said.

The investigators continue to collect data to determine whether p63/p73 expression can be a biomarker for response to platinum agents. The authors are also conducting BRCA mutation, molecular subtype, and circulating tumor cell analyses.

"This study was well designed with prospective powering for the p63/p73 correlative end point," said Dr. Stephen K.L. Chia of the British Columbia Cancer Agency and the University of British Columbia, in Vancouver, the invited discussant.

The rationale for investigating p63/p73 as a predictive biomarker is sound because these markers can be found in about 35%-40% of triple-negative breast cancers, he said. Questions that need to be addressed include whether there is a change in expression of the markers in metastatic relapse, and whether the heterogeneous group of triple-negative breast cancers can be further refined through molecular subtyping.

The study was funded by the AVON Foundation, Breast Cancer Research Foundation, Susan D. Komen for the Cure, Golfers Against Cancer, the Tracey Davis Breast Cancer Research Fund, and investigator awards from the NCI-AVON Partners for Progress, Harvard-MIT, and the Dana-Farber/Harvard Cancer Center. The authors said they had no other relevant financial disclosures.

CHICAGO – Carboplatin or cisplatin monotherapy has significant activity as a first- or second-line treatment against metastatic triple-negative breast cancer, according to Dr. Steven J. Isakoff.

The overall response rate to therapy with one of the platinum compounds was 30.2% – 4.7% complete responses and 25.6% partial responses, Dr. Isakoff of Massachusetts General Hospital cancer center, Boston, and his colleagues in the Translational Breast Cancer Research Consortium found.

Subgroup analyses of the multicenter single-arm trial suggested a higher response rate with cisplatin (37%) than with carboplatin (23%), but this was not a head-to-head study, and the results should be interpreted with caution because physicians were allowed to choose one of the two agents at their own discretion, which could introduce bias into the results, Dr. Isakoff said at the meeting.

The drugs were generally well tolerated with manageable toxicities; some patients have received as many as 23 cycles, he said in an interview.

The investigators also looked at the utility of two members of the p53 family of oncogenic transcription factors, p63 and p73, for predicting response to platinum agents in triple-negative breast cancer (tumors lacking receptors for estrogen, progesterone, or HER2/neu that are targeted by other forms of therapy).

"As information about the activity of platinum in BRCA carriers has become recognized, people are thinking about it more in triple-negative breast cancer," Dr. Isakoff said. "We still don’t know whether triple-negative breast cancer is particularly sensitive to platinum or is just sensitive to chemotherapy, and I think it’s going to take some of the randomized studies that are going on now in Europe, such as the TNT trial comparing carboplatin to docetaxel, to see whether there’s something special about triple negative and platinum."

The TBCRC009 study enrolled 86 patients with triple-negative breast cancer. The patients were assigned on the treating physician’s choice to receive either cisplatin at 75mg/m² IV every 3 weeks, or carboplatin to an area under the curve of 6 every 3 weeks.

In addition to the overall response rates noted here, the authors calculated a clinical benefit rate (a combination of complete and partial response and stable disease) of 34%.

Median progression-free survival (PFS) was 89 days. Thirty-three percent of patients had a PFS of less than 6 weeks, and another 33% had a PFS longer than 6 months. Among responders, a median PFS was 242 days. Responders had a median of nine chemotherapy cycles.

In subgroup analyses, platinum compounds were associated with a 33% response rate when used as first-line agents, and 17% when used in the second line. Only 17 patients received platinum as a second-line therapy, however.

The patients generally tolerated the drugs well. There was one case each of grade 4 neutropenia and hypertension. Grade 3 events included nine cases of fatigue, six of neutropenia, five of anemia, and four of hyponatremia.

"In general, it was well tolerated. We didn’t see unexpected toxicities with platinum, and we modified things with dose reductions as appropriate. It was not a common event to come off therapy due to toxicity," Dr. Isakoff said.

The investigators continue to collect data to determine whether p63/p73 expression can be a biomarker for response to platinum agents. The authors are also conducting BRCA mutation, molecular subtype, and circulating tumor cell analyses.

"This study was well designed with prospective powering for the p63/p73 correlative end point," said Dr. Stephen K.L. Chia of the British Columbia Cancer Agency and the University of British Columbia, in Vancouver, the invited discussant.

The rationale for investigating p63/p73 as a predictive biomarker is sound because these markers can be found in about 35%-40% of triple-negative breast cancers, he said. Questions that need to be addressed include whether there is a change in expression of the markers in metastatic relapse, and whether the heterogeneous group of triple-negative breast cancers can be further refined through molecular subtyping.

The study was funded by the AVON Foundation, Breast Cancer Research Foundation, Susan D. Komen for the Cure, Golfers Against Cancer, the Tracey Davis Breast Cancer Research Fund, and investigator awards from the NCI-AVON Partners for Progress, Harvard-MIT, and the Dana-Farber/Harvard Cancer Center. The authors said they had no other relevant financial disclosures.

A test that measures the number of copies of the HER2 gene in breast tumor tissue has been approved by the Food and Drug Administration, the agency announced on June 14.

If the Inform Dual ISH test is positive, then the patient is a candidate for treatment with trastuzumab, the recombinant monoclonal antibody directed against HER2 that is marketed as Herceptin by Genentech for the treatment of HER-2 overexpressing breast cancer.

The test is manufactured by Tucson, Ariz.–based Ventana Medical Systems, a member of the Roche group, as is Genentech.

"When used with other clinical information and laboratory tests, this test can provide health care professionals with additional insight on treatment decisions for patients with breast cancer," Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health, said in the statement announcing the approval.

The test makes it possible "to see and count copies of chromosome 17 and HER2 genes on the same slide, similar to HER2 amplification measurements that have traditionally only been available using fluorescence microscopes," the statement said. But the new test, "allows lab staff to see the HER2 and chromosome 17 signals directly under a microscope, for longer periods of time."

Approval is based on a study conducted in the United States that evaluated the test in 510 women with breast cancer. The test confirmed that the tumor sample contained more than the normal number of copies of the HER-2 gene, located on chromosome 17, in 96% of the HER-2 positive samples, according to the statement.

The test also excluded the possibility that an excessive number of HER2 genes was present in 92.3% of the HER2-negative samples.

About 20% of women diagnosed with breast cancer are HER2-positive, according to the FDA.

A test that measures the number of copies of the HER2 gene in breast tumor tissue has been approved by the Food and Drug Administration, the agency announced on June 14.

If the Inform Dual ISH test is positive, then the patient is a candidate for treatment with trastuzumab, the recombinant monoclonal antibody directed against HER2 that is marketed as Herceptin by Genentech for the treatment of HER-2 overexpressing breast cancer.

The test is manufactured by Tucson, Ariz.–based Ventana Medical Systems, a member of the Roche group, as is Genentech.

"When used with other clinical information and laboratory tests, this test can provide health care professionals with additional insight on treatment decisions for patients with breast cancer," Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health, said in the statement announcing the approval.

The test makes it possible "to see and count copies of chromosome 17 and HER2 genes on the same slide, similar to HER2 amplification measurements that have traditionally only been available using fluorescence microscopes," the statement said. But the new test, "allows lab staff to see the HER2 and chromosome 17 signals directly under a microscope, for longer periods of time."

Approval is based on a study conducted in the United States that evaluated the test in 510 women with breast cancer. The test confirmed that the tumor sample contained more than the normal number of copies of the HER-2 gene, located on chromosome 17, in 96% of the HER-2 positive samples, according to the statement.

The test also excluded the possibility that an excessive number of HER2 genes was present in 92.3% of the HER2-negative samples.

About 20% of women diagnosed with breast cancer are HER2-positive, according to the FDA.

A test that measures the number of copies of the HER2 gene in breast tumor tissue has been approved by the Food and Drug Administration, the agency announced on June 14.

If the Inform Dual ISH test is positive, then the patient is a candidate for treatment with trastuzumab, the recombinant monoclonal antibody directed against HER2 that is marketed as Herceptin by Genentech for the treatment of HER-2 overexpressing breast cancer.

The test is manufactured by Tucson, Ariz.–based Ventana Medical Systems, a member of the Roche group, as is Genentech.

"When used with other clinical information and laboratory tests, this test can provide health care professionals with additional insight on treatment decisions for patients with breast cancer," Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health, said in the statement announcing the approval.

The test makes it possible "to see and count copies of chromosome 17 and HER2 genes on the same slide, similar to HER2 amplification measurements that have traditionally only been available using fluorescence microscopes," the statement said. But the new test, "allows lab staff to see the HER2 and chromosome 17 signals directly under a microscope, for longer periods of time."

Approval is based on a study conducted in the United States that evaluated the test in 510 women with breast cancer. The test confirmed that the tumor sample contained more than the normal number of copies of the HER-2 gene, located on chromosome 17, in 96% of the HER-2 positive samples, according to the statement.

The test also excluded the possibility that an excessive number of HER2 genes was present in 92.3% of the HER2-negative samples.

About 20% of women diagnosed with breast cancer are HER2-positive, according to the FDA.