FDA Panel Nixes Decitabine for Acute Myeloid Leukemia

SILVER SPRING, MD. – The leukemia drug decitabine didn’t show robust-enough results to convince the majority of an advisory panel to support its approval by the U.S. Food and Drug Administration as a new treatment for elderly patients with acute myeloid leukemia.

Ten members of the independent Oncologic Drugs Advisory Committee (ODAC) voted no, three voted yes, and one member abstained on a question related to the proposed indication. They were asked whether decitabine (Dacogen) demonstrated a favorable risk-benefit profile for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 65 years and older who are not candidates for induction chemotherapy.

Those who voted no said they didn't find the results of a key study convincing and were not comfortable drawing any solid conclusions. The yea-sayers said they looked beyond the fact that the study didn’t meet its end point and instead erred on the side of adding another treatment choice for doctors and their patients.

The FDA considers the panel’s recommendations, but doesn’t necessarily follow them.

Drugmaker Eisai sought the drug’s approval by filing an application to the FDA in May 2011, with the goal of meeting the "unmet medical need" of older adults with AML who are not candidates for induction therapy.

Although the company’s trials didn’t reach a statistically significant result, its officials made the argument that aggregate clinical data from a randomized trial and a single-arm study showed that the drug was well tolerated, had good efficacy and safety profiles, and would provide a clinically meaningful benefit to older patients with AML who are not candidates for induction chemotherapy.

But FDA officials made the case that the "primary end point of overall survival was not met and any further analyses are expiatory and inflate the false-positive rate." They also pointed out that they defined efficacy as a statistically significant survival rate or a rigorous analysis that shows noninferiority.

AML is mainly a disease of the elderly, with an onset at the median age of 69 years. Because of poorer outcomes among this age group, one-third of patients don’t receive chemotherapy.

Decitabine, a hypomethylating agent, was FDA approved in 2006 for the treatment of myelodysplastic syndromes.

A 2009 randomized, open-label, multinational phase III trial, conducted by Eisai, enrolled 485 patients, with a median age of 73. Patients were randomized to decitabine (242) or treatment of choice (low-dose cytarabine or supportive care) (243), with the primary end point of overall survival, prespecified as a 25% reduction in mortality risk.

Patients in the decitabine arm had a median overall survival of 7.7 months, compared with 5 months in the treatment of choice group, (hazard ratio, 0.85; P = .11). A 2010 post hoc analysis showed the median overall survival was unchanged, but the difference became statistically significant (HR, 0.82; P = .037).

FDA officials argued that, "given the final analysis results, post hoc analysis results could be due to chance," adding that the false-positive rate is greater than 5%.

Eisai also conducted a phase II supportive study, which was a single-arm trial that enrolled 55 patients with a median age of 60 years or older. The efficacy and safety results were similar to those of the randomized trial. The safety profile of decitabine was comparable to that in the label for myelodysplastic syndrome, Eisai officials reported.

"Elderly patients [with AML] are desperate for new treatments," said Dr. Mikkael Sekeres, an ODAC member from the department of hematologic oncology and blood disorders at the Cleveland Clinic Taussig Cancer Institute who voted no. "Unfortunately this drug didn’t do the job."

Dr. Wyndham Wilson, ODAC chair and chief of the lymphoma therapeutics section at the National Institutes of Health, voted yes and said he looked at the totality of the data and thought that they favored its approval.

"I see it as a rare setting, where we really have no good drugs. I couldn’t get stuck on that the primary end point wasn’t met. I feel that I wanted to err on the side of choice," he said. "For me the data was sufficiently robust to approve the drug and have the choice available for physicians and patients."

Dr. Ralph Freedman of the University of Texas M.D. Anderson Cancer Center in Houston – the only ODAC member who abstained from voting – said it was his first time doing so, and he expressed his ambivalence on the risks and benefits of the drug based on the study’s results.

Meanwhile, the issue at hand highlights the fact that the standard of care for treating older adults with AML is not clearly defined, said Dr. Sekeres. Their treatment options currently range from induction chemotherapy to aggressive supportive care, with low-dose cytarabine therapy as a middle-of-the-road therapy.

There are currently four FDA-approved first-line drugs for AML. The last drug was idarubicin, approved in 1990.

Another issue highlighted during the discussions was the available treatments for the growing aging population. The medical community is entering somewhat of an uncharted territory and such trials are important, said Dr. William Kevin Kelly, a voting member of ODAC and professor of medical oncology and urology at Thomas Jefferson University, Philadelphia who voted no.

Panelists were cleared of potential conflicts before voting on decitabine.

SILVER SPRING, MD. – The leukemia drug decitabine didn’t show robust-enough results to convince the majority of an advisory panel to support its approval by the U.S. Food and Drug Administration as a new treatment for elderly patients with acute myeloid leukemia.

Ten members of the independent Oncologic Drugs Advisory Committee (ODAC) voted no, three voted yes, and one member abstained on a question related to the proposed indication. They were asked whether decitabine (Dacogen) demonstrated a favorable risk-benefit profile for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 65 years and older who are not candidates for induction chemotherapy.

Those who voted no said they didn't find the results of a key study convincing and were not comfortable drawing any solid conclusions. The yea-sayers said they looked beyond the fact that the study didn’t meet its end point and instead erred on the side of adding another treatment choice for doctors and their patients.

The FDA considers the panel’s recommendations, but doesn’t necessarily follow them.

Drugmaker Eisai sought the drug’s approval by filing an application to the FDA in May 2011, with the goal of meeting the "unmet medical need" of older adults with AML who are not candidates for induction therapy.

Although the company’s trials didn’t reach a statistically significant result, its officials made the argument that aggregate clinical data from a randomized trial and a single-arm study showed that the drug was well tolerated, had good efficacy and safety profiles, and would provide a clinically meaningful benefit to older patients with AML who are not candidates for induction chemotherapy.

But FDA officials made the case that the "primary end point of overall survival was not met and any further analyses are expiatory and inflate the false-positive rate." They also pointed out that they defined efficacy as a statistically significant survival rate or a rigorous analysis that shows noninferiority.

AML is mainly a disease of the elderly, with an onset at the median age of 69 years. Because of poorer outcomes among this age group, one-third of patients don’t receive chemotherapy.

Decitabine, a hypomethylating agent, was FDA approved in 2006 for the treatment of myelodysplastic syndromes.

A 2009 randomized, open-label, multinational phase III trial, conducted by Eisai, enrolled 485 patients, with a median age of 73. Patients were randomized to decitabine (242) or treatment of choice (low-dose cytarabine or supportive care) (243), with the primary end point of overall survival, prespecified as a 25% reduction in mortality risk.

Patients in the decitabine arm had a median overall survival of 7.7 months, compared with 5 months in the treatment of choice group, (hazard ratio, 0.85; P = .11). A 2010 post hoc analysis showed the median overall survival was unchanged, but the difference became statistically significant (HR, 0.82; P = .037).

FDA officials argued that, "given the final analysis results, post hoc analysis results could be due to chance," adding that the false-positive rate is greater than 5%.

Eisai also conducted a phase II supportive study, which was a single-arm trial that enrolled 55 patients with a median age of 60 years or older. The efficacy and safety results were similar to those of the randomized trial. The safety profile of decitabine was comparable to that in the label for myelodysplastic syndrome, Eisai officials reported.

"Elderly patients [with AML] are desperate for new treatments," said Dr. Mikkael Sekeres, an ODAC member from the department of hematologic oncology and blood disorders at the Cleveland Clinic Taussig Cancer Institute who voted no. "Unfortunately this drug didn’t do the job."

Dr. Wyndham Wilson, ODAC chair and chief of the lymphoma therapeutics section at the National Institutes of Health, voted yes and said he looked at the totality of the data and thought that they favored its approval.

"I see it as a rare setting, where we really have no good drugs. I couldn’t get stuck on that the primary end point wasn’t met. I feel that I wanted to err on the side of choice," he said. "For me the data was sufficiently robust to approve the drug and have the choice available for physicians and patients."

Dr. Ralph Freedman of the University of Texas M.D. Anderson Cancer Center in Houston – the only ODAC member who abstained from voting – said it was his first time doing so, and he expressed his ambivalence on the risks and benefits of the drug based on the study’s results.

Meanwhile, the issue at hand highlights the fact that the standard of care for treating older adults with AML is not clearly defined, said Dr. Sekeres. Their treatment options currently range from induction chemotherapy to aggressive supportive care, with low-dose cytarabine therapy as a middle-of-the-road therapy.

There are currently four FDA-approved first-line drugs for AML. The last drug was idarubicin, approved in 1990.

Another issue highlighted during the discussions was the available treatments for the growing aging population. The medical community is entering somewhat of an uncharted territory and such trials are important, said Dr. William Kevin Kelly, a voting member of ODAC and professor of medical oncology and urology at Thomas Jefferson University, Philadelphia who voted no.

Panelists were cleared of potential conflicts before voting on decitabine.

SILVER SPRING, MD. – The leukemia drug decitabine didn’t show robust-enough results to convince the majority of an advisory panel to support its approval by the U.S. Food and Drug Administration as a new treatment for elderly patients with acute myeloid leukemia.

Ten members of the independent Oncologic Drugs Advisory Committee (ODAC) voted no, three voted yes, and one member abstained on a question related to the proposed indication. They were asked whether decitabine (Dacogen) demonstrated a favorable risk-benefit profile for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 65 years and older who are not candidates for induction chemotherapy.

Those who voted no said they didn't find the results of a key study convincing and were not comfortable drawing any solid conclusions. The yea-sayers said they looked beyond the fact that the study didn’t meet its end point and instead erred on the side of adding another treatment choice for doctors and their patients.

The FDA considers the panel’s recommendations, but doesn’t necessarily follow them.

Drugmaker Eisai sought the drug’s approval by filing an application to the FDA in May 2011, with the goal of meeting the "unmet medical need" of older adults with AML who are not candidates for induction therapy.

Although the company’s trials didn’t reach a statistically significant result, its officials made the argument that aggregate clinical data from a randomized trial and a single-arm study showed that the drug was well tolerated, had good efficacy and safety profiles, and would provide a clinically meaningful benefit to older patients with AML who are not candidates for induction chemotherapy.

But FDA officials made the case that the "primary end point of overall survival was not met and any further analyses are expiatory and inflate the false-positive rate." They also pointed out that they defined efficacy as a statistically significant survival rate or a rigorous analysis that shows noninferiority.

AML is mainly a disease of the elderly, with an onset at the median age of 69 years. Because of poorer outcomes among this age group, one-third of patients don’t receive chemotherapy.

Decitabine, a hypomethylating agent, was FDA approved in 2006 for the treatment of myelodysplastic syndromes.

A 2009 randomized, open-label, multinational phase III trial, conducted by Eisai, enrolled 485 patients, with a median age of 73. Patients were randomized to decitabine (242) or treatment of choice (low-dose cytarabine or supportive care) (243), with the primary end point of overall survival, prespecified as a 25% reduction in mortality risk.

Patients in the decitabine arm had a median overall survival of 7.7 months, compared with 5 months in the treatment of choice group, (hazard ratio, 0.85; P = .11). A 2010 post hoc analysis showed the median overall survival was unchanged, but the difference became statistically significant (HR, 0.82; P = .037).

FDA officials argued that, "given the final analysis results, post hoc analysis results could be due to chance," adding that the false-positive rate is greater than 5%.

Eisai also conducted a phase II supportive study, which was a single-arm trial that enrolled 55 patients with a median age of 60 years or older. The efficacy and safety results were similar to those of the randomized trial. The safety profile of decitabine was comparable to that in the label for myelodysplastic syndrome, Eisai officials reported.

"Elderly patients [with AML] are desperate for new treatments," said Dr. Mikkael Sekeres, an ODAC member from the department of hematologic oncology and blood disorders at the Cleveland Clinic Taussig Cancer Institute who voted no. "Unfortunately this drug didn’t do the job."

Dr. Wyndham Wilson, ODAC chair and chief of the lymphoma therapeutics section at the National Institutes of Health, voted yes and said he looked at the totality of the data and thought that they favored its approval.

"I see it as a rare setting, where we really have no good drugs. I couldn’t get stuck on that the primary end point wasn’t met. I feel that I wanted to err on the side of choice," he said. "For me the data was sufficiently robust to approve the drug and have the choice available for physicians and patients."

Dr. Ralph Freedman of the University of Texas M.D. Anderson Cancer Center in Houston – the only ODAC member who abstained from voting – said it was his first time doing so, and he expressed his ambivalence on the risks and benefits of the drug based on the study’s results.

Meanwhile, the issue at hand highlights the fact that the standard of care for treating older adults with AML is not clearly defined, said Dr. Sekeres. Their treatment options currently range from induction chemotherapy to aggressive supportive care, with low-dose cytarabine therapy as a middle-of-the-road therapy.

There are currently four FDA-approved first-line drugs for AML. The last drug was idarubicin, approved in 1990.

Another issue highlighted during the discussions was the available treatments for the growing aging population. The medical community is entering somewhat of an uncharted territory and such trials are important, said Dr. William Kevin Kelly, a voting member of ODAC and professor of medical oncology and urology at Thomas Jefferson University, Philadelphia who voted no.

Panelists were cleared of potential conflicts before voting on decitabine.