In the Pipeline

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.

02/09/12  

---

FROM A MEETING OF THE FOOD AND DRUG ADMINISTRATION'S ONCOLOGIC DRUGS ADVISORY COMMITTEE

---