Action to Cure Kidney Cancer

Since 2003, the direction of kidney cancer clinical research has shifted from almost total reliance on immunotherapies (Interleukin-2 and Interferon), to an emphasis on investigational drugs that target various cellular mechanisms that regulate cancer cell growth and proliferation. Specifically, the new therapies are targeted to work by at least three and perhaps more mechanisms of action:

1. by inhibiting the growth of new blood vessels which in turn nourish the growth of new tumor cells (angiogenesis)
2. by inhibiting cells (pericytes) which stabilize new blood vessels
3. by correcting the normal body mechanism that allow living cells, including cancer cells, to naturally die. The latter is known as apoptosis. Most body cells divide about seven times before they undergo genetically programmed cell death, but cancer cells continue dividing as infinitum

Research has revealed that the vast majority of clear cell kidney cancer is caused by a genetic mutation in the Von Hippau Lindau gene, known as the VHL gene. This abnormal gene in turn produces a deviant protein which causes the accumulation of Hypoxia Inducible Factor (HIF), which in turn induces the production of three other products which are critical to the proliferation of clear cell RCC. These three products are:

1. Vascular Endothelial Growth Factor (VEGF)
2. Platelet Derived Growth Factor (PDGF)
3. Transforming Growth Factor-alpha (TGF-α)

All four of the above cellular products, i.e., HIF, VEGF, PDGF and TGF-α, have been the "targets" of the new "targeted: therapies." The two most studied and promising drugs, Sutent and Sorafenib, both target VEGF and PDGF. Other studies are underway to target HIF, and a widely used combination therapy of Avastin and Tarceva, targets both VEGF and TGF-α. It is widely believed, but not yet proven by researchers, that combining drugs to take a multi-targeted approach will probably lead to the most effective results. In another twist, researchers are beginning to take this approach by combining the new targeted therapies with the older, standard immunotherapies. What follows is a summary of the major results, reported at the 2005 ASCO Conference, of trials involving these targeted drugs.

Kidney cancer investigators are also discussing alternative ways to measure the effectiveness of these new therapies. Heretofore, tumor shrinkage combined with overall survival of RCC patients were the usually accepted measures of effectiveness. However, the end points of some of the clinical studies with targeted drugs have not yet had time to demonstrate clear differences in survival, even though many of these studies demonstrate substantial tumor shrinkage or stabilization of disease with no new growth. A consensus seems to be developing towards using the measures called "progression free survival" and "median time to progression" as alternative measures of effectiveness for these agents. That being said, for the present time, median survival is still the most important widely accepted variable in measuring the effectiveness of a cancer drug.

The following table compares some of the latest results of clinical trials for these targeted agents.

Drug	Mfctr	Pts	PR	SD	PFS	Median Survival	Troubling Side Effects
Sutent (SU011248) Trial One	Pfizer	63	40%	28%	8.7 mos	16.4 mos	See below
Sutent (SU011248) Trial Two	Pfizer	106	39%	23%	Not Yet Reached	Not Yet Reached	As above
AG-013736	Pfizer	52	46%	40%	Not Yet Reached	Not Yet Reached	See below
Bayer 43-9006 (sorafenib)	Bayer/Onyx	335	2%	78%	5.6 mos	Not Yet Reached	Dermatitis
Avastin (Bevacizumab) + Tarceva (Erlotinib)	Genentech	59	22%	61%	11.1 mos	21.4-22.8 mos	See below

Table Definitions

Pts:

number of patients enrolled in the trial

PR:

number and percentage of partial responders; the measurement of partial response is the amount of shrinkage in diameter of the tumor, the standard of which may vary from one trial to another. Usually, PR is defined as a minimum of 30% decrease in the measurement of the longest dimension of a tumor. For example, a tumor that goes from 5.0 cm to 3.5 would qualify as a partial response.

SD:

stable disease; this is a range where the top figure is a measurement that restricts growth of tumor diameter to a maximal amount, say 10%, and the minimum is just below the figure for PR

PFS:

progression free survival; this is shorter of two measurements, i.e., the amount of time that a person remains alive or that a person's tumors do not grow.

Median Survival:

the point in a study at which half the patients who began the study have died. For example, if the median survival is 16.3 months, half the patients died within 16.3 months of initiation of the study and half the patients lived longer than 16.3 months. It does not imply how long those latter patients have lived - see Stephen J. Gould's essay under "Personal Stories" menu item.

Notes

1. Sutent: The data are for the two phase 2 trials reported on at ASCO 2004 and ASCO 2005; the PFS and Median Survival are known only for Sutent Trial One. In Sutent Trial Two, there was one Complete Response. Side effects: Fatigue 8%, Hypertension 6%, Mouth Sores 5%, Dermatitis 5%. Reported by Robert Motzer (Memorial Sloan-Kettering in New York). For presentation, click here.
2. AG-013736: The data for time to progression (TTP), progression free survival (PFS) and overall survival have not yet been reached because more than 50% of the patients who started the trial have not yet had progression in the growth of their tumors. Side effects: Hypertension: 15%, Diarrhea 8%, Fatigue 8%. Reported by Brian Rini (Univ. Cal. SF*). For presentation, click here.
3. Bay 43-9006(sorafenib): The Bayer Phase 3, placebo-controlled trial data as reported at ASCO showed 2% Partial Response, but 78% stable disease. Reported by Bernard Escudier (Institut Gustave-Roussy in Villejuif, France). For presentation, click here.
4. Avastin (Bevacizumab) + Tarceva (erlotinib): There have been 2 Complete Responses; reported by David Spigel (Sarah Cannon Research Institute in Nashville, TN) Median survival: 21.4 mos for prior treatment and 22.8 mos for no prior treatment. Side Effects: Rash 13%, Diarrhea 13%, Nausea/Vomiting 10%, Hypertension 10%, Bleeding 8%, Proteinuria 8% (excessive protein in urine). This report was an update of a Phase II study from last year - see Abstract click here.
   
   * Note that Dr Brian Rini is now at the Cleveland Clinic.

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Pfizer Cuts Short Testing of Promising New Kidney Cancer Drug

AG-013736 versus Sutent

The results of Phase 2 trials for two Pfizer kidney cancer drugs were presented at the American Society of Clinical Oncology (ASCO) conference in Orlando. The newer drug, AG-013736, showed an overall response or no progression (that is, tumor shrinkage or stability) of 86%, while the older drug, Sutent, had a similar response of 68%. AG-013736 compared favorably in toxicity with Sutent. This should be excellent news for the over 10,000 Americans stricken with metastatic kidney cancer each year, but Pfizer has inexplicably decided to discontinue AG-013736 trials in kidney cancer patients while embarking instead on breast, melanoma, thyroid, and lung cancer trials.

The AG-013736 trial results were presented by Brian Rini of UCSF, while those for Sutent were presented by Robert Motzer of Memorial Sloan-Kettering. Both drugs are multi-targeted tyrosine kinase receptor inhibitors, which means that they work on multiple targets within the renal cancer cell, thereby disrupting biochemical processes necessary for the cells to maintain themselves, to divide and reproduce, and to stimulate new blood vessel growth, which is necessary for the tumor's survival. The AG-013736 trial enrolled 52 patients with RCC who had previously failed cytokine therapy (Interleukin-2 or Interferon).

For the results of the trials, if a tumor shrank by at least 30% in its longest diameter, it was categorized as a "Partial Response", and if it grew by 20% or more in its longest diameter it was classified as "Progression". The range between 29% tumor shrinkage and 19% tumor growth is classified as "Stable Disease".

In the AG-013736 trial, 46% of subjects had a Partial Response, and another 40% had Stable Disease. It is worth noting that 20 of the 21 Stable Disease subjects in this trial did show some tumor shrinkage although not the 30% required for PR classification. Only 8% of subjects had Progression. (6% of the subjects were indeterminate.) After a year, 29 (56%) patients remain in the trial on AG-013736 with either continuing partial response or stable disease. The treatment also carried a relatively low rate of serious side effects, with only 15% of subjects experiencing hypertension and 8% experiencing diarrhea and fatigue. These side-effect rates are especially low when compared to cytokine therapy.

	AG-013736	Sutent Trial One	Sutent Trial Two
Partial Response	46%	40%	39%
Stable Disease	40%	28%	23%
Complete Response	0%	0%	1%
Progression	8%	25%	31%

As the above table shows, after this initial Phase 2 trial, AG-013736 appears very promising. AG-013736's relatively low toxicity may make it a better candidate for combination with other drug therapies, which, as reported at ASCO, is the direction in which kidney cancer treatment is currently heading. Given AG-013736's potential efficacy based on this early trial, kidney cancer specialists believe that the new drug has great potential in renal cell carcinoma treatment, and that its further development should be pursued.

Why, then, is Pfizer no longer testing it in kidney cancer patients?

Go to Take Action to write to Pfizer management asking them to continue testing AG-013736 for kidney cancer.

Update: In September 2005, anecdotal evidence indicates that another phase 2 trial may be initiated within the next few months for AG-013736. This is good news for kidney cancer patients, and updated results from the first phase 2 trial should be available by then as well.