Source: Robert Langreth Blog

In the wake of the FDA’s decision start the process to revoke Avastin’s approval in breast cancer last week, patients are puzzled and angry over how a drug once touted as a breakthrough  now can be branded as ineffective.  The controversy illustrates just how much the much-vaunted revolution in cancer therapy is driven by hype and high prices.

Selling cancer drugs has become big business, with $52 billion in sales last year, according to IMS.  Some $6 billion of it goes right to Roche’s Avastin, the biggest selling of the new drugs. No wonder companies like Merck and Pfizer are  racing to develop new cancer drugs.

But even as sales reach new heights, and prices keep going up–pretty much any cancer drug now costs $50,000 a year–the results from many trials are getting less and less impressive. Tarceva from Roche extends the life of pancreatic cancer patients by two weeks. Avastin has now failed to extend the lives of breast cancer patients in three giant trials.

The hype about targeted cancer drugs has reached fever pitch thanks in part to baby boomers who don’t want to acknowledge their mortality; companies who need to sell hugely expensive drugs that can cost up to $100,000 a year; and science journalists eager for a positive story about a dread disease.

The truth is that nobody wants to acknowledge the unpleasant fact that progress against most cancers has been grudgingly slow. Oncologists are in the business of providing hope to patients with incurable advanced disease.  Having a fancy new targeted drug to give their patients provides this hope. It can be hard to admit that one drug that you have been giving to a lot of patients may not be doing much of anything at all. Most new drugs extend life by just a couple months, often with lots of very nasty side effects, and always at huge cost.

This is not to say that the revolution in cancer genetics hasn’t produced a handful of real scientific breakthroughs, such as Novartis’s Gleevec for leukemia and Roche’s Herceptin for breast cancer. But most of the progress is surprisingly incremental and doesn’t live up to the level of hype that targeted cancer drugs have gotten. Americans have trouble getting used to the concept that medicine progresses at a far slower rate than the computer industry.

Some people, including cancer researcher Garth Anderson, contend the whole targeted cancer drug revolution is failing for reasons that are obvious in retrospect. He says much more attention needs to be focused on devising better surgical methods that could cure more people. Other top doctors worry that a system of paying huge amounts for trivial improvements in slowing the disease will encourage more mediocre drugs in the future instead of true breakthroughs.

Some doctors argue that the problem is that drug companies are designing enormous trials that show statistically valid but “trivial” differences in survival times . They say that to encourage true innovation doctors need to set higher standards. In one recent commentary in the Journal of the National Cancer Institute, University of Toronto oncologist Ian Tannock argued that a three month survival difference is the minimum clinically meaningful difference for most solid tumors. If regulators set this as a minimum, it would encourage smaller patient trials of a greater number of novel drugs. The result might be more real breakthroughs.

Back to Avastin for metastatic breast cancer.  If it doesn’t help people live longer or improve symptoms, then what does it do?  It makes an X-ray look prettier for a few months.  This is what the fancy term “improves progression free survival” actually means–the cancer’s new growth takes a few months longer to show up on an X-ray. Researchers used to assume that slower X-ray growth would always translate into longer survival. Unfortunately, for reasons that nobody knows, this  has not proven to be the case with Avastin in breast cancer.

A few years ago, Avastin was touted as one of the biggest targeted drug breakthroughs, the first in a new class that choked off tumor blood supply.  It does hit a specific molecular target in the cell called VEGF. But the more researchers study it, the murkier the mechanism behind Avastin looks. Some researchers worry it could create a rebound effect that can make the disease grow faster under some circumstances.

And unlike Gleevec  and Herceptin,  which are aimed at narrow subsets of patients, Avastin isn’t targeted to a specific groups of patients at all.  It is an old fashioned give-it-to-all-comers-and-hope-that-a-few-of-them-will-benefit drug. This may be part of the problem. If researchers could identify a narrow subset of women who truly benefit from Avastin, then doctors could avoid having to expose everyone to its nasty side effects.

According to the FDA, serious or life threatening complications of Avastin include “risk of stroke, wound healing complications, organ damage or failure; and the development of a neurological condition called reversible posterior leukoencephalopathy syndrome.”

The Avastin controversy is destined to continue for quite some while. Roche is expected to ask for a hearing to contest the decision. My question: if this were some obscure old off-patent chemotherapy drug that didn’t have $6 billion in sales or an exotic new mechanism, would anyone care?