SU11248 is a new “targeted” drug in clinical trials (and not otherwise available). SU11248 interferes with several cellular signaling pathways, including the VEGF pathway which is particularly relevant to kidney cancer. SU11248 an oral medication with significant side effects. There is some very promising data for this drug in kidney cancer!
A Little History
SU11248 was first developed by a small biotech company called SUGEN. SUGEN no longer exists as such but they are the “SU” in SU11248. SUGEN was acquired by Pharmacia, a big pharma company, and shortly thereafter Pharmacia was acquired by Pfizer, a giant.
SUGEN, as is typical for small biotechs looking to attract investors, had great information on SU11248’s mechanism of action on its website. In contrast, Pfizer, as is typical for large well funded pharmaceutical companies, has virtually no information on drugs in development such as SU11248. To Pfizer’s great credit however, they seem to be offering ethical trials in which patients who’ve already tried the standard treatment are guaranteed to actually get the drug.
How SU11248 Works
This treatment is a convergence of two “hot” trends in cancer medicine, targeted therapies and antiangiogenesis, and also directly relates to a specific defect in most clear cell renal cell cancers.
SU11248 is a member of a new class of drugs which are specifically engineered to bind with a certain class of receptor called a Protein Tyrosine Kinase (PTK) in a way which interferes with their normal function. Briefly, these receptors sit in the cell membrane with part projecting into the interior of the cell. When the appropriate substance binds to the receptor, it causes a signal to be transmitted into the cell which then responds according to what kind of receptor was triggered. This process is called “Signal Transduction”
There are many different receptors in this class and SU11248 is designed to bind with a few of them, in particular: VEGF Receptor, PDGF Receptors alpha and ك, Flt3, and C-KIT tyrosine kinase [Mendel 2003]. Gleevec, another PTK inhibitor which is now approved treatment of two rare cancers, targets PDGF and C-KIT. Unfortunately, Gleevec wasn’t effective in clear cell renal cell cancer. However, the VEGF receptor is very relevant to renal cell cancer and this makes SU11248 of particular interest.
Anti-Angiogenesis, VEGF and Clear Cell Renal Cell Cancer
In most clear cell renal cell carcinomas the function of a specific gene called VHL has been lost (VHL stands for Von Hippel-Lindau, a hereditary syndrome which includes renal cell cancer as one of it’s manifestations.). The protein produced by the VHL gene is involved with sensing that the cell is adequately oxygenated. When VHL function is lost, the cell “thinks” it is low on oxygen and reacts by trying to signal blood vessel growth (which would bring oxygen). The signal is VEGF (Vascular Endothelial Growth Factor) which binds to receptors of cells in nearby blood vessels and stimulates new blood vessel growth. This causes typical kidney cancer tumors to be highly vascular. The hope is that by specifically targeting the receptor the process of angiogenesis can be shut down.
I would expect this to merely halt growth rather than cause tumors to shrink. Apparently SUGEN did too, according to this archived Press Release (Note: It’s a Microsoft Word Document, not a web page) which describes early Phase I results. It’s not clear why this is causing tumor shrinkage and it’s possible that SU11248’s ability to inhibit other receptors is responsible for tumor shrinkages. It is also possible that new blood vessels will die if their VEGF receptors are blocked and this causes tumor shrinkage.
While this is relevant and promising, you should realize that angiogenesis is a complex process which involves multiple, possibly redundant, signaling pathways and there is no guarantee that just blocking VEGF is enough. Recent results from a trial in RCC of a drug called Avastin, which is a monoclonal antibody which binds VEGF itself and takes it out of circulation, showed a delay in time to progression but eventually everyone’s tumors started to grow again. The tumor-blood vessel system may have been able to evolve an angiogenic response using other pathways. For more details, see my article on Avastin.
The Results So Far
The best data for this were reported at the 2004 ASCO Meeting (The biggest annual oncology meeting) [Motzer 2004] and the results were very encouraging. The study involved 63 patients who had already tried IL-2 or Interferon without success and 33% had a partial response. This is a remarkably high response rate compared to other drugs for RCC and is very exciting. Moreover, of the 21 responses, 14 were still ongoing (with continued treatment) with follow up more of 5 to 12 months. We don’t know how long these responses might last but there is certainly every reason for hope that they can last for several years. There were no complete responses and so despite these encouraging results there is no reason to think this is curing anyone, but again nothing here limits how long this treatment could help you and no limit to hope with this treatment. Time will tell.
In addition to the partial responses, 37% of patients had stable disease for at least 3 months. Now “stable disease” doesn’t mean stays exactly the same. It can include shrinkage less than a partial response or a little growth. One of Dr. Motzer’s slides showed that most patients who didn’t have a partial response had some shrinkage rather than growth as a best response. Furthermore the median time until there was significant tumor growth (median Time To Progression) was 8.3 months – and this is substantially greater (even with 95% confidence intervals) than the 2-4 month median time to progression seen without treatment. I believe this treatment really is giving many patients additional time.
Side effects were generally moderate. The most common side effect is significant fatigue in about a third of patients which I understand can be cumulative with time (and is why the treatment schedule includes time off from treatment). Some patients also had nausea, diarrhea, indigestion, or mouth sores. About 1/3 of patients had their dose reduced at some point during their treatment, mostly for asymptomatic changes in lab tests, especially relating to pancreatic function. No patients had to actually stop treatment. Patients on the KIDNEY-ONC E-Mail List have generally found the treatment pretty easy to take.
Last but not least, this is an oral drug given on an outpatient basis. The treatment schedule is 50mg per day for four weeks and then two weeks off. Patients receive treatment until there is significant tumor growth.
Results in GIST
GIST (GastroIntestinal Stromal Tumor) is a rare cancer which responds to this drug. A phase I study in GIST which had stopped responding to other treatment had encouraging results [Demetri 2003]. I understand Pfizer is pursuing further trials to lead to FDA approval for GIST as well. This both provides additional evidence the drug is active against cancer. This, however, may be via a different mechanism than the activity in RCC. GIST is specifically driven by mutations in KIT – and the activity in RCC may be due to inhibition of the VEGF or PDGF receptors which drive angiogenesis. Clinical development of SU11248 in GIST may also provide another route for the drug to be approved (after which it could legally be used to treat RCC).
Clinial Trials Resources
This treatment is only available in trials, so to get it you need to enroll in a trial. The Renal Cell Cancer Evaluated Trials Database (another of my projects) will keep track of worthy trials I am aware of but you might also want to check Cancer.gov and ClinicalTrials.gov
Demetri GD, George S, Heinrich MC, Fletcher JA, Fletcher CM, Desai J, Cohen DP, Scigalla P, Cherrington JM, Van Den Abbeele AD.
Clinical activity and tolerability of the multi-targeted tyrosine kinase inhibitor SU11248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2003 22 : Abstract 3273 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: This trial isn't for RCC but results were very encouraging. Side effects and final dose seem are consistent with phase II RCC study [Motzer 2004].
Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM.
In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet- derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.
Clin Cancer Res. 2003 Jan;9(1):327-37. [PubMed Abstract (will open in new window)]
Comment: This is a highly technical pre-clinical (mouse) study.
Motzer RJ, Rini BI, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Zhu J, Kim ST, Baum C
SU011248, a novel tyrosine kinase inhibitor, shows antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma: Results of a phase 2 trial.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2004 23 : Abstract 4500 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: This is the bulk of the clinical evidence for SU11248 in RCC. Note that in addition to the abstract, Dr. Motzer's complete presentation, including his slides, is available on ASCO's site.