FDA Advisory Board Gives Thumbs Up to Gemtuzumab for AML

Roxanne Nelson, BSN, RN

July 12, 2017

Gemtuzumab ozogamicin (Mylotarg, Pfizer) may be returning to the market in the United States after receiving a thumbs up from the Food and Drug Administration's (FDA's) Oncologic Drugs Advisory Committee (ODAC).

In a nearly unanimous decision, the ODAC voted 6 to 1 in favor of allowing the agent to become available once again for adult patients with previously untreated, de novo CD33-positive acute myeloid leukemia (AML).

Gemtuzumab was voluntarily withdrawn by the manufacturer in June 2010. It had received an accelerated approval, but a confirmatory clinical trial revealed no survival advantage and an increase in fatal toxicities.

But evidence from studies conducted since that time show that the addition of gemtuzumab to chemotherapy results in improved event-free survival, overall survival, and relapse-free survival.

A new lower dosing schedule has also reduced the risk for fatal toxicity.

Overall, the voting panel felt that the benefit outweighed the risk for toxicity and that the drug should be returned to the marketplace. Although the FDA usually uses overall survival as the endpoint to confirm clinical benefit for the treatment of AML, the panelists largely agreed that event-free survival was a reasonable endpoint in this setting.

Bruce Roth, MD, professor of medicine at Washington University School of Medicine, St. Louis, Missouri, and chairman of the ODAC, noted that the "toxicity that got the drug pulled in the first place is more tolerable" at the lower doses now used and that in leukemia, "event-free survival has importance onto itself without relationship to overall survival."

Fatal Toxicities, No Benefit

The drug first came onto the US market in 2000, under the FDA's accelerated approval program, for the treatment of patients aged 60 years and older with recurrent AML who were not considered candidates for other chemotherapy.

The initial approval was based on the surrogate endpoint of response rate that was observed in 142 patients with AML across three clinical trials.

At the time of its approval, myelosuppression and infusion-related reactions were identified as major safety concerns, but in the postmarketing period, fatal hepatotoxicity and veno-occlusive disease (VOD) were added as black box warnings to the drug's labeling. There was an increased risk for VOD in patients who received gemtuzumab either before or after undergoing hematopoietic stem cell transplantation.

As per the postmarketing requirement, the manufacturer was required to confirm clinical benefit in a randomized controlled trial that compared gemtuzumab ozogamicin, daunorubicin, and cytarabine to chemotherapy alone as induction therapy in patients with de novo CD33-positive AML.

The SWOG S0106 study was used to fulfill that criteria. It was a randomized trial (n = 637) using a gemtuzumab dose of 6 mg/m2 for induction and then 5 mg/m2 up three 3 doses given 28 days apart. Previous studies had used doses of 9 mg/m2 on days 1 and 14.

The primary endpoint was the complete response rate post induction and disease-free survival post consolidation. The findings showed the addition of gemtuzumab yielded no improvement in any of the primary or secondary endpoints.

In addition, there was a higher rate of fatal induction toxicities in the gemtuzumab cohort (5.8% vs 1.3%).

The FDA concluded that the clinical benefit of the agent had not been confirmed and that there was a potential safety problem related to an increased rate of early death. Gemtuzumab was voluntarily removed from the market in October 2010.

Lower Dose, New Endpoints

Since then, several research groups conducted investigator-led studies with gemtuzumab, with encouraging results. One of these trials, the ALFA-701 study, was submitted to the FDA to support the new marketing application for gemtuzumab.

The ALFA-701 study used a low fractionated dose of gemtuzumab 3 mg/m2 on days 1, 4, and 7. It included 271 patients aged 50 to 70 years with newly diagnosed AML. Patients were randomly assigned to receive either chemotherapy plus gemtuzumab or chemotherapy alone.

The primary endpoint was event-free survival, and the addition of gemtuzumab improved both event-free and overall survival. There were 76 events in the gemtuzumab group and 104 events in the control group (P = .00018). The median overall survival was 34 months vs 19.2 months (P = .046).

Although the analysis showed a statistically significant improvement in event-free survival, with a hazard ratio (HR) of 0.56 (P < .001), analysis of the secondary endpoint of overall survival did not show statistically significant improvement (HR, 0.81; P = .16).

The results also showed superiority of gemtuzumab in a sensitivity analysis that used different definitions of event-free survival and a time-to-event endpoint that only considered relapse and death as events.

There was no significant difference in 30-day mortality between the two groups (3.8% vs 2.2%), but in patients who received gemtuzumab, the rate of hemorrhage was higher and the time to recovery of platelets was prolonged. There were also a few rare episodes of VOD; it developed in three of the 139 patients who received gemtuzumab and culminated in two deaths.

"Bring It Back"

Giving a clinical perspective, Jorge E. Cortes, MD, deputy chair in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, pointed out that the benefit outweighs the risk for this agent.

There is a great need for improved therapies for this disease, he emphasized. "Outcome had not changed much, considering that we are using the same treatment that we used in the 1970s with no new therapies available for most patients.

"The majority of patients who fail frontline therapy will usually not achieve remission, and median overall survival is only about 6 months," he added.

Dr Cortes noted that even in the SWOG study, there was a higher response rate among patients who received gemtuzumab, and the study did not report event-free survival.

The trend for survival was also confirmed in a meta-analysis that was conducted by the manufacturer of five randomized studies with patient-level data. In this meta-analysis, the HR was 0.91, with an estimated 2.1-month increase in overall survival.

Dr Cortes acknowledged that VOD is still a problem, but rates of this complication have declined. "There are now ways to mitigate risk of VOD in patients receiving transplant, and management has evolved over time with new protocols in place."

Overall, Dr Cortes would add gemtuzumab to standard chemotherapy and would "welcome having it back as an option for my patients."

Richard Stone, MD, chief of staff and director of the Adult Acute Leukemia Program at the Dana Farber Cancer Institute in Boston, Massachusetts, also believes that gemtuzumab should be back on the market. "Event-free survival is an intrinsically valuable endpoint in AML."

He reiterated that there have been no new therapies in AML. "Gemtuzumab can be used for most AML patients, which has a frontline standard of care that has changed little in 40 years."

Event-Free Survival Is "Meaningful"

In their statistical analysis, the FDA did not find event-free survival to be strongly correlated with overall survival.

Chia-Wen Ko, PhD, statistical reviewer, Division of Biometrics, Center for Drug Evaluation and Research, FDA, noted that the "surrogacy of event-free survival for overall survival may be influenced by salvage therapy, so the lack of correlation was not unexpected.

"The FDA has accepted progression-free survival for drug approvals for diseases with similar circumstances," she said.

In this case, the panel was willing to accept event-free survival as an endpoint and felt that the new lower dosing schedule was safe in this patient population.

"I'm convinced that event-free survival is a meaningful clinical endpoint even if not predictive or highly correlated with survival," said panel member David Harrington, PhD, professor of biostatistics at Dana-Farber Cancer Institute, who voted in favor of returning the drug to the market.

Another member, Bernard F. Cole, PhD, a professor of mathematics and statistics at the University of Vermont, opined that "this benefit of gemtuzumab is robust and highly significant and was demonstrated in a high-quality randomized study."

Dr Cole added that the problem of VOD and toxicity remains and that the manufacturer needs to address this issue with additional study and analyses.

FDA briefing. Published online July 11, 2017. Full text

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