Genasense Progression-Free Survival Data Do Not Show “Real Effect,” Cmte. Says
Posted May 3 on www.fdaadvisorycommittee.com
Aventis/Genta’s Genasense appears to have a “real effect” on response rates in metastatic melanoma patients but not on progression-free survival or survival, FDA’s Oncologic Drugs Advisory Committee concluded at its May 3 meeting.
The committee voted 11 to 5 that Genasense (oblimersen) plus dacarbazine showed a difference in response rate from dacarbazine in patients with metastatic melanoma. However, the committee then voted 12 to 4 that the Genta pivotal trial did not conclusively show a “real effect” on progression-free survival.
Progression-free survival was 74 days for Genasense plus dacarbazine vs. 49 days for dacarbazine alone (p=.0003). The antitumor response rate was 11.7% and 6.8%, respectively (p=.019).
Genta focused on the secondary endpoints of progression-free survival and response rates when the primary endpoint of overall survival did not show a statistically significant difference between Genasense plus dacarbazine and dacarbazine alone. Patients in the experimental arm had a median survival of 274 days compared to 238 days for dacarbazine alone (p=.18).
While many committee members supported use of progression-free survival as an endpoint for melanoma trials, FDA and other committee members had concerns about missing data and the fact that patients taking Genasense were evaluated slightly later than those taking dacarbazine alone.
"Even a slight difference in assessment schedule between treatment groups could potentially bias the estimation of treatment effect and likely lead to a false positive inference in a large study,” FDA said.
“These were secondary outcomes that we are looking at, so that the way that one would rigorously define these and ascertain them is somewhat missing,” committee voting consultant Ralph D’Agostino, PhD, Boston University, said.
“I am stuck with the…difficulty with progression-free survival and how it can move around depending on assumptions. I am also concerned with the response rate in terms of how rigorous that was. I am quite surprised that the outside independent group was somehow or another only there for quality control….It wasn’t given all the data. I find those aspects of the study really bother me in terms of how do we interpret the relatively small numbers,” D’Agostino added.
On the pivotal approval question, the committee voted 13 to 3 that the data presented by Genta could not be considered substantial evidence of effectiveness.
“There might be something here, but it just isn’t clear,” committee member Stephen George, PhD, Duke University, said. Genasense “might be a promising agent, but probably at a very low level,” he said.
Voting consultant Ronald Bukowski, MD, Cleveland Clinic, noted that in oncology increased response rates have been seen with the addition of agents to chemotherapy. “Unfortunately, those studies have demonstrated no benefit in terms of survival and other secondary effects. We have to keep this in mind as we consider this particular drug. There is an independent response here that may be a signal but we have seen this before.” |
