[gdpawel]

In regards to changing endpoints, a summary of clinical trial data presented at the ASCO 2010 Kamofsky Memorial Lecture was presentated at a industry supported symposium at the SGO 2011 meeting on survival benefit associated with biomarker-directed therapy in advanced disease. Participants were to learn about the addition of an ovarian-specific profile testing platform following the publication of the original data in the JCO in October, 2010.

If this was any indication of their previous presentation on breast cancer, they invented another endpoint. A 30% increase in time to progression (TTP) over the most recent prior therapy. If Dr So and So gave the patient XYZ therapy and it provided a 3 day response, then the genetic guided therapy needed only provide a 4 day response to show statistical significance. In the previous data set, the 106 patient accrued had a whopping response rate of 5.6% by intent to treat with an objective response rate in the group of fully tested and treated patients of 10%.

The rather new "accelerated approval" program is based on a surrogate endpoint study rather than the gold standard of overall survival, bona fide clinical efficacy, or quality of life improvement. Surrogate endpoint trials are generally faster than traditional efficacy trials that are required for full drug approval because the surrogate endpoints are typically laboratory readouts that are available before direct measure of effectiveness.

Progression-free survival does not address the patient's quality of life during those additional months of some serious side effects a number of women experience, and it hasn't been shown to correlate with overall survival. So we're back to square one again. Instead of showing a drug can increase survial, all they have to do is show that it can shrink a tumor. Didn't we just come from that neanderthal moment?

The problem with Avastin is that doctors don't know which patients will respond favorably in terms of overall survival. Pharmacogenomics should be used to identify the best candidate patient population and a subsequent studies should then be undertaken to determine biomarkers that have clinical utility in measuring the efficacy of Avastin in those patients.

The introduction of targeted drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of these drugs. There should be an immediate recognition that matchmaking between cancer and cancer treatment is one area in cancer research and treatment which is deserving of much greater attention and utilization.

There should be an inclusive effort to study and utilize technologies which are based on both the sub-cellular (molecular) level and at the cellular (cell function) level. Because what may benefit one individual cancer patient may not benefit another.

Some have suggested that they should use the cell-based functional profiling platform (AngioRx Assay) to identify a potential targeted population of cancer patients that it thinks will benefit from Avastin, and then conduct a randomized clinical trial among this group.

However, unlike some genetic assays that look whether an individual has a particular mutation or amplification, and therefore tests for "theoretical" candidates for a particular targeted drug, the functional profiling technique may find Avastin not synergistic (cooperative) and finds some other VEGF-targeted (or multiple VEGF-targeted) drug may work better in an individual cancer patient and then put that individual into the clinical trial. I can understand they may not want some other drug tested on their dime.

There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.

This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy. There is really nothing wrong with Avastin. It's a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman. There are not perfect drugs. There are simply drugs that work for certain patients. But that's not what pharmaceutical companys like to hear. They like to produce drugs that apply to a broad base of patients. To make the most out of a drug, not just some subsets of patients.