FDA: Oncologic Drugs Advisory Committee

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on Dec. 7 voted that peginesatide, a new erythropoiesis-stimulating agent, has a favorable risk-benefit profile when used to treat anemia associated with chronic renal failure in patients who are on dialysis.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee, it voted 15-1 with one abstention on the risk-benefit question. One of the two cardiologists on the panel voted no; the other abstained. The panel did not vote specifically on whether to recommend approval.

Affymax Inc., the manufacturer of peginesatide – a long-acting erythropoiesis-stimulating agent (ESA) administered intravenously or subcutaneously – has proposed that it be approved for the treatment of anemia associated with chronic kidney disease (CKD) in adults who are on dialysis, but not in CKD patients who are not on dialysis or in cancer patients. Peginesatide is administered once a month, which is less frequently than the two ESAs approved in the United States: epoetin alfa, marketed as Epogen and Procrit, and darbepoetin alfa, marketed as Aranesp. A pegylated epoetin beta (Mircera) is not available in the United States.

In two phase III studies of patients with anemia due to CKD who were on dialysis, 1,066 subjects were treated with peginesatide once a month and 542 were treated with epoetin administered one to three times a week. The effectiveness of peginesatide in maintaining hemoglobin levels at 10-12 g/dL through weeks 29-36 of treatment was similar to that of epoetin, with similar low transfusion rates in both groups. The safety profiles, including serious adverse events, deaths during the study, and adverse events resulting in permanent discontinuation of treatment, were similar in both treatment groups.

But in two phase III studies of patients with anemia due to CKD who were not on dialysis, peginesatide appeared to be less safe than darbepoetin. In these two studies, the rates of adverse events, serious adverse events, deaths during the study, adverse events leading to discontinuation as well as adverse cardiovascular outcomes were higher among those on peginesatide than among those on darbepoetin.

Panelists expressed concerned about this safety signal in the patients not on dialysis, but those who voted in favor of peginesatide for the proposed indication agreed that the safety and efficacy of peginesatide were comparable with epoetin in two large randomized studies and cited the convenience of once-a-month dosing for patients. They recommended postmarketing follow-up of these patients to provide longer-term data, since the average length of ESA treatment in patients with CKD is about 5 years and patients in the studies were followed for a little more than 1 year.

The two cardiologists on the panel cited concerns about the studies not being blinded and the possibility that the differences in toxicity in the two patient groups might not be explained pathophysiologically but instead might be the result of stricter entry criteria in the study of patients on dialysis. They also cited the potential for misuse of these drugs in patients.

Targeting higher hemoglobin levels with ESA treatment has been associated with an increased risk of MI and other adverse cardiovascular outcomes in several large clinical trials, which led to changes in treatment recommendations.

In 2007, a boxed warning about the increased risk of deaths and serious cardiovascular events when higher hemoglobin levels are targeted was added to the labels of ESAs, with the recommendation to individualize dosing to target and maintain hemoglobin levels within the 10-12 g/dL range. In 2009, a warning about the increased risk of stroke based on the results of a study of patients with diabetes and CKD who were not on dialysis was added to ESA labels.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on Dec. 7 voted that peginesatide, a new erythropoiesis-stimulating agent, has a favorable risk-benefit profile when used to treat anemia associated with chronic renal failure in patients who are on dialysis.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee, it voted 15-1 with one abstention on the risk-benefit question. One of the two cardiologists on the panel voted no; the other abstained. The panel did not vote specifically on whether to recommend approval.

Affymax Inc., the manufacturer of peginesatide – a long-acting erythropoiesis-stimulating agent (ESA) administered intravenously or subcutaneously – has proposed that it be approved for the treatment of anemia associated with chronic kidney disease (CKD) in adults who are on dialysis, but not in CKD patients who are not on dialysis or in cancer patients. Peginesatide is administered once a month, which is less frequently than the two ESAs approved in the United States: epoetin alfa, marketed as Epogen and Procrit, and darbepoetin alfa, marketed as Aranesp. A pegylated epoetin beta (Mircera) is not available in the United States.

In two phase III studies of patients with anemia due to CKD who were on dialysis, 1,066 subjects were treated with peginesatide once a month and 542 were treated with epoetin administered one to three times a week. The effectiveness of peginesatide in maintaining hemoglobin levels at 10-12 g/dL through weeks 29-36 of treatment was similar to that of epoetin, with similar low transfusion rates in both groups. The safety profiles, including serious adverse events, deaths during the study, and adverse events resulting in permanent discontinuation of treatment, were similar in both treatment groups.

But in two phase III studies of patients with anemia due to CKD who were not on dialysis, peginesatide appeared to be less safe than darbepoetin. In these two studies, the rates of adverse events, serious adverse events, deaths during the study, adverse events leading to discontinuation as well as adverse cardiovascular outcomes were higher among those on peginesatide than among those on darbepoetin.

Panelists expressed concerned about this safety signal in the patients not on dialysis, but those who voted in favor of peginesatide for the proposed indication agreed that the safety and efficacy of peginesatide were comparable with epoetin in two large randomized studies and cited the convenience of once-a-month dosing for patients. They recommended postmarketing follow-up of these patients to provide longer-term data, since the average length of ESA treatment in patients with CKD is about 5 years and patients in the studies were followed for a little more than 1 year.

The two cardiologists on the panel cited concerns about the studies not being blinded and the possibility that the differences in toxicity in the two patient groups might not be explained pathophysiologically but instead might be the result of stricter entry criteria in the study of patients on dialysis. They also cited the potential for misuse of these drugs in patients.

Targeting higher hemoglobin levels with ESA treatment has been associated with an increased risk of MI and other adverse cardiovascular outcomes in several large clinical trials, which led to changes in treatment recommendations.

In 2007, a boxed warning about the increased risk of deaths and serious cardiovascular events when higher hemoglobin levels are targeted was added to the labels of ESAs, with the recommendation to individualize dosing to target and maintain hemoglobin levels within the 10-12 g/dL range. In 2009, a warning about the increased risk of stroke based on the results of a study of patients with diabetes and CKD who were not on dialysis was added to ESA labels.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on Dec. 7 voted that peginesatide, a new erythropoiesis-stimulating agent, has a favorable risk-benefit profile when used to treat anemia associated with chronic renal failure in patients who are on dialysis.

At a meeting of the FDA’s Oncologic Drugs Advisory Committee, it voted 15-1 with one abstention on the risk-benefit question. One of the two cardiologists on the panel voted no; the other abstained. The panel did not vote specifically on whether to recommend approval.

Affymax Inc., the manufacturer of peginesatide – a long-acting erythropoiesis-stimulating agent (ESA) administered intravenously or subcutaneously – has proposed that it be approved for the treatment of anemia associated with chronic kidney disease (CKD) in adults who are on dialysis, but not in CKD patients who are not on dialysis or in cancer patients. Peginesatide is administered once a month, which is less frequently than the two ESAs approved in the United States: epoetin alfa, marketed as Epogen and Procrit, and darbepoetin alfa, marketed as Aranesp. A pegylated epoetin beta (Mircera) is not available in the United States.

In two phase III studies of patients with anemia due to CKD who were on dialysis, 1,066 subjects were treated with peginesatide once a month and 542 were treated with epoetin administered one to three times a week. The effectiveness of peginesatide in maintaining hemoglobin levels at 10-12 g/dL through weeks 29-36 of treatment was similar to that of epoetin, with similar low transfusion rates in both groups. The safety profiles, including serious adverse events, deaths during the study, and adverse events resulting in permanent discontinuation of treatment, were similar in both treatment groups.

But in two phase III studies of patients with anemia due to CKD who were not on dialysis, peginesatide appeared to be less safe than darbepoetin. In these two studies, the rates of adverse events, serious adverse events, deaths during the study, adverse events leading to discontinuation as well as adverse cardiovascular outcomes were higher among those on peginesatide than among those on darbepoetin.

Panelists expressed concerned about this safety signal in the patients not on dialysis, but those who voted in favor of peginesatide for the proposed indication agreed that the safety and efficacy of peginesatide were comparable with epoetin in two large randomized studies and cited the convenience of once-a-month dosing for patients. They recommended postmarketing follow-up of these patients to provide longer-term data, since the average length of ESA treatment in patients with CKD is about 5 years and patients in the studies were followed for a little more than 1 year.

The two cardiologists on the panel cited concerns about the studies not being blinded and the possibility that the differences in toxicity in the two patient groups might not be explained pathophysiologically but instead might be the result of stricter entry criteria in the study of patients on dialysis. They also cited the potential for misuse of these drugs in patients.

Targeting higher hemoglobin levels with ESA treatment has been associated with an increased risk of MI and other adverse cardiovascular outcomes in several large clinical trials, which led to changes in treatment recommendations.

In 2007, a boxed warning about the increased risk of deaths and serious cardiovascular events when higher hemoglobin levels are targeted was added to the labels of ESAs, with the recommendation to individualize dosing to target and maintain hemoglobin levels within the 10-12 g/dL range. In 2009, a warning about the increased risk of stroke based on the results of a study of patients with diabetes and CKD who were not on dialysis was added to ESA labels.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – The data on the kinase inhibitor axitinib support its approval as a second-line treatment for advanced renal cell carcinoma, a Food and Drug Administration advisory panel unanimously agreed at a Dec. 7 meeting.

At the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 13-0 that axitinib has a favorable risk-benefit profile for treating patients with advanced renal cell carcinoma (RCC) after failure of a first-line systemic therapy, based on the results of an international, phase III, open-label, randomized, controlled study comparing treatment with axitinib to sorafenib (Nexavar). Sorafenib was approved in December 2005 as the first targeted therapy for RCC. Both sorafenib and axitinib are selective inhibitors of vascular endothelial growth factor (VEGF) and are administered orally twice a day.

The study enrolled 723 patients with advanced RCC who had failed one prior systemic treatment; their median age was 61 years, almost two-thirds were men, and about two-thirds were white. About 25% of the patients were enrolled in North America, and about half were enrolled in Europe. The median progression-free survival was 6.7 months among those treated with axitinib, compared with 4.7 months among those treated with sorafenib, a highly statistically significant difference.

However, the efficacy findings were driven primarily by the results among patients previously treated with cytokines, a population less likely to be seen in the United States. In this subgroup, the median progression-free survival was 5.6 months, compared with 1.4 months among those previously treated with sorafenib, who are more reflective of the types of patients treated in the United States.

Common adverse events associated with axitinib included diarrhea, nausea, fatigue, asthenia, hypertension, and skin reactions. Although its safety profile is comparable to that of other VEGF inhibitors, the side effect profile is slightly different. (Hypertension and hypothyroidism were more common among those treated with axitinib, while hand-foot-and-mouth syndrome, rash, and alopecia were more likely to occur among those on sorafenib.)

Panelists agreed that the overall toxicity profile of axitinib was comparable to that of sorafenib. And although panelists described the efficacy of axitinib as only marginally or modestly better than that of sorafenib, they agreed it would be useful to have another treatment option within the same class to offer patients who had experienced adverse effects with another agent.

If approved, axitinib will be marketed as Inlyta by Pfizer, and it would be the seventh targeted treatment approved for advanced RCC. Other targeted treatments for advanced RCC approved since December 2005 are the VEGF-receptor inhibitors sunitinib (Sutent) and pazopanib (Votrient), the anti-VEGF antibody bevacizumab (Avastin), and the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (Torisel) and everolimus (Afinitor).

Axinitib has not been approved elsewhere and is under review in the European Union. It is also being studied in a phase III study of patients with treatment-naive and previously treated advanced RCC, and in a phase II study of patients with hepatocellular carcinoma.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. No panelists at this meeting were given a waiver.

SILVER SPRING, MD. – The data on the kinase inhibitor axitinib support its approval as a second-line treatment for advanced renal cell carcinoma, a Food and Drug Administration advisory panel unanimously agreed at a Dec. 7 meeting.

At the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 13-0 that axitinib has a favorable risk-benefit profile for treating patients with advanced renal cell carcinoma (RCC) after failure of a first-line systemic therapy, based on the results of an international, phase III, open-label, randomized, controlled study comparing treatment with axitinib to sorafenib (Nexavar). Sorafenib was approved in December 2005 as the first targeted therapy for RCC. Both sorafenib and axitinib are selective inhibitors of vascular endothelial growth factor (VEGF) and are administered orally twice a day.

The study enrolled 723 patients with advanced RCC who had failed one prior systemic treatment; their median age was 61 years, almost two-thirds were men, and about two-thirds were white. About 25% of the patients were enrolled in North America, and about half were enrolled in Europe. The median progression-free survival was 6.7 months among those treated with axitinib, compared with 4.7 months among those treated with sorafenib, a highly statistically significant difference.

However, the efficacy findings were driven primarily by the results among patients previously treated with cytokines, a population less likely to be seen in the United States. In this subgroup, the median progression-free survival was 5.6 months, compared with 1.4 months among those previously treated with sorafenib, who are more reflective of the types of patients treated in the United States.

Common adverse events associated with axitinib included diarrhea, nausea, fatigue, asthenia, hypertension, and skin reactions. Although its safety profile is comparable to that of other VEGF inhibitors, the side effect profile is slightly different. (Hypertension and hypothyroidism were more common among those treated with axitinib, while hand-foot-and-mouth syndrome, rash, and alopecia were more likely to occur among those on sorafenib.)

Panelists agreed that the overall toxicity profile of axitinib was comparable to that of sorafenib. And although panelists described the efficacy of axitinib as only marginally or modestly better than that of sorafenib, they agreed it would be useful to have another treatment option within the same class to offer patients who had experienced adverse effects with another agent.

If approved, axitinib will be marketed as Inlyta by Pfizer, and it would be the seventh targeted treatment approved for advanced RCC. Other targeted treatments for advanced RCC approved since December 2005 are the VEGF-receptor inhibitors sunitinib (Sutent) and pazopanib (Votrient), the anti-VEGF antibody bevacizumab (Avastin), and the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (Torisel) and everolimus (Afinitor).

Axinitib has not been approved elsewhere and is under review in the European Union. It is also being studied in a phase III study of patients with treatment-naive and previously treated advanced RCC, and in a phase II study of patients with hepatocellular carcinoma.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. No panelists at this meeting were given a waiver.

SILVER SPRING, MD. – The data on the kinase inhibitor axitinib support its approval as a second-line treatment for advanced renal cell carcinoma, a Food and Drug Administration advisory panel unanimously agreed at a Dec. 7 meeting.

At the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 13-0 that axitinib has a favorable risk-benefit profile for treating patients with advanced renal cell carcinoma (RCC) after failure of a first-line systemic therapy, based on the results of an international, phase III, open-label, randomized, controlled study comparing treatment with axitinib to sorafenib (Nexavar). Sorafenib was approved in December 2005 as the first targeted therapy for RCC. Both sorafenib and axitinib are selective inhibitors of vascular endothelial growth factor (VEGF) and are administered orally twice a day.

The study enrolled 723 patients with advanced RCC who had failed one prior systemic treatment; their median age was 61 years, almost two-thirds were men, and about two-thirds were white. About 25% of the patients were enrolled in North America, and about half were enrolled in Europe. The median progression-free survival was 6.7 months among those treated with axitinib, compared with 4.7 months among those treated with sorafenib, a highly statistically significant difference.

However, the efficacy findings were driven primarily by the results among patients previously treated with cytokines, a population less likely to be seen in the United States. In this subgroup, the median progression-free survival was 5.6 months, compared with 1.4 months among those previously treated with sorafenib, who are more reflective of the types of patients treated in the United States.

Common adverse events associated with axitinib included diarrhea, nausea, fatigue, asthenia, hypertension, and skin reactions. Although its safety profile is comparable to that of other VEGF inhibitors, the side effect profile is slightly different. (Hypertension and hypothyroidism were more common among those treated with axitinib, while hand-foot-and-mouth syndrome, rash, and alopecia were more likely to occur among those on sorafenib.)

Panelists agreed that the overall toxicity profile of axitinib was comparable to that of sorafenib. And although panelists described the efficacy of axitinib as only marginally or modestly better than that of sorafenib, they agreed it would be useful to have another treatment option within the same class to offer patients who had experienced adverse effects with another agent.

If approved, axitinib will be marketed as Inlyta by Pfizer, and it would be the seventh targeted treatment approved for advanced RCC. Other targeted treatments for advanced RCC approved since December 2005 are the VEGF-receptor inhibitors sunitinib (Sutent) and pazopanib (Votrient), the anti-VEGF antibody bevacizumab (Avastin), and the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (Torisel) and everolimus (Afinitor).

Axinitib has not been approved elsewhere and is under review in the European Union. It is also being studied in a phase III study of patients with treatment-naive and previously treated advanced RCC, and in a phase II study of patients with hepatocellular carcinoma.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. No panelists at this meeting were given a waiver.