Tuesday, June 03, 2008

Avastin for Breast Cancer: Progress for Progression-Free Survival?

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

1 comment:

Greg Pawelski said...

The True Costs And Benefits Of Avastin

What may limit the effectiveness of Avastin is that there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry. The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed.

It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many pathways to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.

Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.

If you find one or more implicated proteins in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You're not going to accomplish this using genetic tests.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
"Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005