FDA panel votes against panobinostat as add-on therapy for multiple myeloma

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that the risk-benefit profile of panobinostat as add-on treatment to bortezomib and dexamethasone did not support approval as a treatment for multiple myeloma at this time, citing issues that included toxicity and marginal progression-free survival results.

At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with the proteasome inhibitor bortezomib (Velcade) and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the indication proposed by the manufacturer, Novartis Pharmaceuticals. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival (PFS), and said they hoped the company would continue to study the drug in patients with the disease.

Like other panelists voting no on the risk-benefit question, Dr. James Liebmann, of the division of hematology-oncology at the University of Massachusetts, Worcester, said the vote was a difficult decision “because I do think that this probably has some activity in this disease and probably can be useful.” But in the study presented by the company, “the toxicity outweighed the marginal benefit in progression-free survival,” he added.

Panobinostat, in a capsule formulation, is a histone deacetylase (DAC) inhibitor. It inhibits class I, II, and IV histone DACs, which “are epigenetic modulators and important cancer targets due to the dysregulation of these enzymes in many types of tumors,” and as an epigenetic regulator, the drug “may help restore cell programming in multiple myeloma,” according to Novartis. If approved, it would be the first drug in this class to be approved for multiple myeloma.

In the pivotal phase III, international PANORAMA-1 study, 768 patients with relapsed or relapsed-refractory multiple myeloma were randomized to treatment with panobinostat or placebo, added to bortezomib and dexamethasone. Treatment was given in two 24-week phases (3-week cycles for the first phase and 6-week cycles for the second phase, with a 2 weeks on, 1 week off schedule), with 20 mg of panobinostat three times a week during both phases, and bortezomib (1.3 mg/m²) administered twice a week during the first phase and once a week during the second phase.

The primary endpoint, median PFS assessed by the investigator, was 12 months in the panobinostat arm, compared with 8.1 months in the placebo arm, a 3.9-month difference (hazard ratio, 0.63) that was statistically significant. When an independent review committee conducted an assessment – a prespecified sensitivity analysis – the median PFS benefit was 1.9 months. Among those on panobinostat, the overall response rate was numerically higher (61% vs. 55%), and there was a trend toward an improvement in overall survival, a secondary endpoint (a difference of about 3 months in the median overall survival).

There were more deaths that were not due to progressive disease among those in the panobinostat arm – 7%, compared with 3.5% in the placebo arm­ – and serious adverse events associated with treatment included pneumonia, diarrhea, thrombocytopenia, sepsis, and fatigue. Treatment had to be interrupted or the dose had to be modified because of an adverse event in 89% of those on panobinostat, compared with 76% of those in the placebo arm. Diarrhea was the most common reason for discontinuation in the panobinostat group: About 25% had grade 3/4 diarrhea, compared with almost 8% of those in the placebo arm. The company had no data showing that quality of life was better among those in the panobinostat arm.

The main issue raised by the FDA was the large amount of missing and censored data, and the effect this had on determining the magnitude of the benefit, weighed against the toxicity, which limited the FDA’s confidence in the results.

“This is a drug that has some activity, but progression-free survival alone, particularly when there are issues of missing data and a high rate of censoring” is a concern, said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. She added that she expects that the drug will play a role in the treatment of multiple myeloma, “but potentially in a more narrow population of patients.”

Another panelist, Dr. Tito Fojo, director of the medical oncology fellowship program at the National Cancer Institute, Bethesda, Md., added, “I think this is a drug that likely has activity in this disease and could benefit these patients, but not in this combination.”

Among other concerns raised by panelists were the age of the patients in the study, which was a median of 63 years at enrollment, about 10 years younger than the median age of patients at diagnosis, since toxicity could be worse in older patients, they pointed out.

“While we are disappointed with the committee’s recommendation, we will continue to work with the FDA as it evaluates the application,” Bruno Strigini, Pharm.D., president of Novartis Oncology, said in a statement issued after the vote. The drug is also under review in the European Union and Japan.

The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make the decision this month. No panel members had conflicts of interest to disclose.

Bortezomib was approved as third-line and second-line therapy for multiple myeloma in 2003 and 2005, respectively, and in 2008 it was approved for previously untreated multiple myeloma.

[email protected]

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that the risk-benefit profile of panobinostat as add-on treatment to bortezomib and dexamethasone did not support approval as a treatment for multiple myeloma at this time, citing issues that included toxicity and marginal progression-free survival results.

At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with the proteasome inhibitor bortezomib (Velcade) and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the indication proposed by the manufacturer, Novartis Pharmaceuticals. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival (PFS), and said they hoped the company would continue to study the drug in patients with the disease.

Like other panelists voting no on the risk-benefit question, Dr. James Liebmann, of the division of hematology-oncology at the University of Massachusetts, Worcester, said the vote was a difficult decision “because I do think that this probably has some activity in this disease and probably can be useful.” But in the study presented by the company, “the toxicity outweighed the marginal benefit in progression-free survival,” he added.

Panobinostat, in a capsule formulation, is a histone deacetylase (DAC) inhibitor. It inhibits class I, II, and IV histone DACs, which “are epigenetic modulators and important cancer targets due to the dysregulation of these enzymes in many types of tumors,” and as an epigenetic regulator, the drug “may help restore cell programming in multiple myeloma,” according to Novartis. If approved, it would be the first drug in this class to be approved for multiple myeloma.

In the pivotal phase III, international PANORAMA-1 study, 768 patients with relapsed or relapsed-refractory multiple myeloma were randomized to treatment with panobinostat or placebo, added to bortezomib and dexamethasone. Treatment was given in two 24-week phases (3-week cycles for the first phase and 6-week cycles for the second phase, with a 2 weeks on, 1 week off schedule), with 20 mg of panobinostat three times a week during both phases, and bortezomib (1.3 mg/m²) administered twice a week during the first phase and once a week during the second phase.

The primary endpoint, median PFS assessed by the investigator, was 12 months in the panobinostat arm, compared with 8.1 months in the placebo arm, a 3.9-month difference (hazard ratio, 0.63) that was statistically significant. When an independent review committee conducted an assessment – a prespecified sensitivity analysis – the median PFS benefit was 1.9 months. Among those on panobinostat, the overall response rate was numerically higher (61% vs. 55%), and there was a trend toward an improvement in overall survival, a secondary endpoint (a difference of about 3 months in the median overall survival).

There were more deaths that were not due to progressive disease among those in the panobinostat arm – 7%, compared with 3.5% in the placebo arm­ – and serious adverse events associated with treatment included pneumonia, diarrhea, thrombocytopenia, sepsis, and fatigue. Treatment had to be interrupted or the dose had to be modified because of an adverse event in 89% of those on panobinostat, compared with 76% of those in the placebo arm. Diarrhea was the most common reason for discontinuation in the panobinostat group: About 25% had grade 3/4 diarrhea, compared with almost 8% of those in the placebo arm. The company had no data showing that quality of life was better among those in the panobinostat arm.

The main issue raised by the FDA was the large amount of missing and censored data, and the effect this had on determining the magnitude of the benefit, weighed against the toxicity, which limited the FDA’s confidence in the results.

“This is a drug that has some activity, but progression-free survival alone, particularly when there are issues of missing data and a high rate of censoring” is a concern, said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. She added that she expects that the drug will play a role in the treatment of multiple myeloma, “but potentially in a more narrow population of patients.”

Another panelist, Dr. Tito Fojo, director of the medical oncology fellowship program at the National Cancer Institute, Bethesda, Md., added, “I think this is a drug that likely has activity in this disease and could benefit these patients, but not in this combination.”

Among other concerns raised by panelists were the age of the patients in the study, which was a median of 63 years at enrollment, about 10 years younger than the median age of patients at diagnosis, since toxicity could be worse in older patients, they pointed out.

“While we are disappointed with the committee’s recommendation, we will continue to work with the FDA as it evaluates the application,” Bruno Strigini, Pharm.D., president of Novartis Oncology, said in a statement issued after the vote. The drug is also under review in the European Union and Japan.

The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make the decision this month. No panel members had conflicts of interest to disclose.

Bortezomib was approved as third-line and second-line therapy for multiple myeloma in 2003 and 2005, respectively, and in 2008 it was approved for previously untreated multiple myeloma.

[email protected]

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that the risk-benefit profile of panobinostat as add-on treatment to bortezomib and dexamethasone did not support approval as a treatment for multiple myeloma at this time, citing issues that included toxicity and marginal progression-free survival results.

At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with the proteasome inhibitor bortezomib (Velcade) and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the indication proposed by the manufacturer, Novartis Pharmaceuticals. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival (PFS), and said they hoped the company would continue to study the drug in patients with the disease.

Like other panelists voting no on the risk-benefit question, Dr. James Liebmann, of the division of hematology-oncology at the University of Massachusetts, Worcester, said the vote was a difficult decision “because I do think that this probably has some activity in this disease and probably can be useful.” But in the study presented by the company, “the toxicity outweighed the marginal benefit in progression-free survival,” he added.

Panobinostat, in a capsule formulation, is a histone deacetylase (DAC) inhibitor. It inhibits class I, II, and IV histone DACs, which “are epigenetic modulators and important cancer targets due to the dysregulation of these enzymes in many types of tumors,” and as an epigenetic regulator, the drug “may help restore cell programming in multiple myeloma,” according to Novartis. If approved, it would be the first drug in this class to be approved for multiple myeloma.

In the pivotal phase III, international PANORAMA-1 study, 768 patients with relapsed or relapsed-refractory multiple myeloma were randomized to treatment with panobinostat or placebo, added to bortezomib and dexamethasone. Treatment was given in two 24-week phases (3-week cycles for the first phase and 6-week cycles for the second phase, with a 2 weeks on, 1 week off schedule), with 20 mg of panobinostat three times a week during both phases, and bortezomib (1.3 mg/m²) administered twice a week during the first phase and once a week during the second phase.

The primary endpoint, median PFS assessed by the investigator, was 12 months in the panobinostat arm, compared with 8.1 months in the placebo arm, a 3.9-month difference (hazard ratio, 0.63) that was statistically significant. When an independent review committee conducted an assessment – a prespecified sensitivity analysis – the median PFS benefit was 1.9 months. Among those on panobinostat, the overall response rate was numerically higher (61% vs. 55%), and there was a trend toward an improvement in overall survival, a secondary endpoint (a difference of about 3 months in the median overall survival).

There were more deaths that were not due to progressive disease among those in the panobinostat arm – 7%, compared with 3.5% in the placebo arm­ – and serious adverse events associated with treatment included pneumonia, diarrhea, thrombocytopenia, sepsis, and fatigue. Treatment had to be interrupted or the dose had to be modified because of an adverse event in 89% of those on panobinostat, compared with 76% of those in the placebo arm. Diarrhea was the most common reason for discontinuation in the panobinostat group: About 25% had grade 3/4 diarrhea, compared with almost 8% of those in the placebo arm. The company had no data showing that quality of life was better among those in the panobinostat arm.

The main issue raised by the FDA was the large amount of missing and censored data, and the effect this had on determining the magnitude of the benefit, weighed against the toxicity, which limited the FDA’s confidence in the results.

“This is a drug that has some activity, but progression-free survival alone, particularly when there are issues of missing data and a high rate of censoring” is a concern, said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. She added that she expects that the drug will play a role in the treatment of multiple myeloma, “but potentially in a more narrow population of patients.”

Another panelist, Dr. Tito Fojo, director of the medical oncology fellowship program at the National Cancer Institute, Bethesda, Md., added, “I think this is a drug that likely has activity in this disease and could benefit these patients, but not in this combination.”

Among other concerns raised by panelists were the age of the patients in the study, which was a median of 63 years at enrollment, about 10 years younger than the median age of patients at diagnosis, since toxicity could be worse in older patients, they pointed out.

“While we are disappointed with the committee’s recommendation, we will continue to work with the FDA as it evaluates the application,” Bruno Strigini, Pharm.D., president of Novartis Oncology, said in a statement issued after the vote. The drug is also under review in the European Union and Japan.

The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make the decision this month. No panel members had conflicts of interest to disclose.

Bortezomib was approved as third-line and second-line therapy for multiple myeloma in 2003 and 2005, respectively, and in 2008 it was approved for previously untreated multiple myeloma.

[email protected]