Progression-free survival will have to be validated as a surrogate for survival on a cancer-by-cancer basis for PFS to be considered as a valid endpoint for approval, comments by FDA and members of its Oncologic Drugs Advisory Committee suggest.

The issue arose during a March 13 review of Lilly's Gemzar (gemcitabine) for treatment of ovarian cancer at which the committee voted 9-2 with one abstention against approving the supplemental indication (see ¹ Also see "Gemzar Ovarian Cancer Negative Review Shows Discomfort With Ex-U.S. Data" - Pink Sheet, 20 March, 2006.).

One of the key problems panel members cited with the application was gemcitabine's failure to extend overall survival despite a statistically significant benefit on progression-free survival.

Lilly's application was primarily based on a pivotal trial comparing Gemzar and carboplatin with carboplatin alone in 356 advanced ovarian cancer patients.

The trial met its primary endpoint with the gemcitabine arm demonstrating a statistically significant 2.8 month increase in median PFS (8.6 months vs. 5.8 months). However, there was no difference between the two arms in overall survival (18 months for gemcitabine/carboplatin vs. 17.3 months for carboplatin).

Committee consultant and former ODAC Chair Stacy Nerenstone (Hartford Hospital) said a the two-month improvement in PFS with "soft endpoints" for assessing PFS was unconvincing, because the benefit of increasing PFS in ovarian cancer "is not as clear cut as lung cancer" and "may not be the correct surrogate for survival."

Committee member Bruce Cheson (Georgetown University Hospital) said he was particularly "troubled" that the trial lacked sufficient power to assess PFS as a surrogate for overall survival.

"This is a study looking at progression-free survival as a primary endpoint," he noted. "A study that meets this primary endpoint should be I think considered a positive study and approved."

"The problem here is...that if you look for an endpoint, you have to look at the endpoint and you have to measure it and it seems that this was not done in a sufficient number of patients to satisfy me and probably some of my colleagues," Cheson said.

FDA has been highlighting the value of disease stabilization in oncology in recent months. PFS was the basis for awarding full approval to Bayer/Onyx' Nexavar (sorafenib) for treatment of kidney cancer (² Also see "Magnitude Of Effect, Not Survival, Is Key To Approval For Oncologic Nexavar" - Pink Sheet, 2 January, 2006., p. 10).

As part of a series of meetings on cancer endpoints, ODAC has said that PFS is a valid primary endpoint in colorectal cancer, lung cancer and melanoma trials (³ Also see "Colon Cancer Adjuvant Trials Need 3-Year Disease-Free Survival – FDA Cmte" - Pink Sheet, 17 May, 2004., p. 41).

Office of Oncology Drug Products Medical Team Leader John Johnson said the agency's determination of "whether progression-free survival is an acceptable endpoint for full approval is really specific to the disease setting."

Johnson said that, in accordance with the ODAC recommendation, FDA views PFS as a valid endpoint in lung and colorectal cancers. "The main reason that the committee made that recommendation in those two specific settings was that progression free survival in each of those settings was considered a surrogate for survival," he noted.

OODP Deputy Director Karen Weiss pointed to a number of factors that the agency considers when determining whether PFS is a valid basis for approval such as "the magnitude of the effect, the toxicity of the therapies, [and] the particular scenario that you are dealing with."

Johnson also said it would be difficult for FDA to approve an agent based on PFS without a survival benefit when alternative therapies that have been shown to have a survival benefit in the same setting.

During the meeting, FDA and a Lilly consultant disagreed on whether a 2004 consensus conference on ovarian cancer endpoints said PFS was a valid primary endpoint in the recurrent setting.

FDA will have the chance to address the question at an April 26 workshop on ovarian cancer endpoints (⁴ 'The Pink Sheet' March 13, 2006, In Brief). [Editor's note: To ⁵ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

Progression-Free Survival Must Be Tied To Survival For Oncologic Approval

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