Most of the American Society of Clinical Oncology annual meeting is a blurry whirlwind of posters and presentations, but one thing is certainly clear: people are still puzzled by FDA’s approval of Genentech/Roche’s Avastin for first-line treatment of metastatic breast cancer.The approval came in February. Although Genentech had been seeking full approval for additional bevacizumab indication based on the strong progression-free survival results of the E2100 study, FDA took the more traditional option and cleared it under its accelerated approval mechanism. The agency requested the results of the AVADO and RIBBON-1 studies as post-marketing commitments.
ASCO provided the first real look at AVADO. Roche’s study, which used Avastin in combination with docetaxel instead of paclitaxel, showed a modest improvement in PFS. Survival data are not yet mature. (You can read more in “The Pink Sheet” DAILY.)
The data, though, aren’t what people are talking about.
The Saturday press briefing on the highly anticipated, late-breaking study turned into a chance for some of the investigators and breast cancer thought leaders to vent on FDA approval standards.
Progression-free survival (PFS) versus overall survival is a perennial issue for regulators, who are tasked with upholding standards and always keep precedent in mind. PFS is commonly used for approvals in second- and third-line settings, but FDA clings to the gold standard of overall survival for first line indications.
The issue is clearly different for practitioners.
“As a practicing physician,” AVADO lead investigator David Miles said he views PFS as a reflection of the period of time where the disease is controlled and the patient remains relatively well. There is an expectation that the patient is “doing better than if their disease is not controlled,” he told the press briefing.
“We have studies where PFS does reflect overall survival and studies where it doesn’t,” Miles observed. “I think when you have a patient whose disease is well-controlled, there is benefit to that, there is utility to that. Particularly when studies are not powered for overall survival.” None of the Avastin breast cancer studies have been designed for a full survival analysis.
He suggested there are “recurrent problems … in recognizing utility in trials, and perhaps that’s why there is this ambivalence or perhaps uncertainty about what things should be approved on.”
“I don’t think any of us have any question that improvement in overall survival is worth more than an improvement in PFS in the end,” Dana-Farber Cancer Institute’s Eric Winer added. “We are all trying to help people live longer, and a drug that achieves that goal is a drug that we are going to use that much more frequently and has that much more reason to be approved quickly.”
Since it seems unlikely that AVADO will go on to prove a survival advantage, Winer stood by the position that there is intrinsic value in PFS, even if it is only improving quality of life. “With that in mind, I think that it’s fair to say that bevacizumab in treatment of metastatic breast cancer is an advance, but it’s not as big of an advance as it would be if in fact it had changed overall survival,” he stated.
The debate only escalated when the study was presented on Sunday. Breaking from the script of reviewing only the study data and its application, Kathy Albain – a former ODAC member and CDER consultant who filled the role of discussing the AVADO findings – used her time slot to focus on FDA and the approval standards.
She was a staunch advocate for PFS endpoints. “Assuming that there is a real treatment benefit for whatever agent you are testing, I believe that PFS should be accepted as a proper surrogate,” Albain maintained. She pointed out that in metastatic breast cancer in particular, it may never be possible to prove surrogacy for overall survival, given the thousands of patients that would be needed.
Albain took it upon herself to conduct a survey, sending out a questionnaire to a sample of 47 experts. She was overwhelmed by the volume and vehemence of the replies. The clear consensus was that PFS should be considered a meaningful approval endpoint. Getting to “the crux of the matter,” Albain’s group suggested PFS should be used in Phase III trials, but maybe it should be prospectively determined how large a benefit is desired. For full approval perhaps two trials should be required, or perhaps there should be a mandatory cross-over design.
Concluding on a high note, Albain issued a charge for the oncology community and for FDA: to challenge the current methods of study design and approvals. “There is no time like the present,” she said.
-- Mary Jo Laffler
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