Key FDA Panel Endorses Carfilzomib for Myeloma

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.