For current ASCO meeting notes, click the heading “Kidney Cancer Information” at ACKC.
Steve’s Notes from the 2004 ASCO Meeting
Well there I was and it was Deja Vu all over again… the better part of four days inside a monstrous building with 25,000 oncologists – voluntarily. No it’s not a Stephen King story or an episode from the Twilight Zone. It’s ASCO! ASCO is the American Society of Clinical Oncology, and their annual meeting is the largest general cancer meeting in the world. Although it’s primarily for doctors and scientists, actually anyone who can get to the meeting, and pay for admission can go. Even me – and I was not the only patient there either. This was my third year in a row, funded by my grant from the Fischer Family Trust.
The Meeting Starts with a Bang! Targeting the VEGF Pathway in Kidney Cancer
Saturday morning, 7:45AM sharp, right at the start of the meeting, the most promising session on kidney cancer I have ever had the privilege to attend at any conference! Results of three phase II trials in kidney cancer, BAY 43-9006, SU11248, and Avastin + Tarceva presented, all with unusually excellent results (Abstracts 4500-4502). I have updated by BAY 43-9006, SU11248 and Avastin articles to reflect the detailed data. BAY 43-9006 and SU11248 weren’t a surprise because we had earlier data on BAY 43-9006 and because for SU11248 we had reports from patients on the KIDNEY-ONC E-Mail List on both their own results and their doctor’s information on the results overall (it was however very satisfying to see that early information we got on the list confirmed as accurate). The encouraging results with Avastin + Tarceva were a surprise – much better than the results with Avastin alone (although this could be a trick of the statistical light – see my Avastin Article.)
All of the abstracts and many of the presentations I reference are available on . The presentations include the audio and slides and are much more informative than the abstracts. Sadly, ASCO's webmasters are apparently incapable of maintaining a permanent address for their pages, so I don't dare link you directly to the appropriate abstracts and presentations, but if you go to their site you can find them using the abstract numbers I give.
What all these trials have in common is that they are targeted anti- angiogenic drugs which interfere with the Vascular Endothelial Growth Factor (VEGF) pathway which is highly activated in clear cell renal cancer. This is a breakthrough not only because of the good results, but every bit as much because this is an entirely new way of treating advanced kidney cancer.
All of these trials also had similar results – an unusually high rate patients with some degree tumor shrinkage and a prolongation of the median time to progression to 8 to 12 months compared to the 2 or 3 months you’d expect. The rate of actual partial responses (roughly 50% shrinkage or better) was 15-33% in these trials, but many other patients in all of these trials had shrinkages that weren’t enough to qualify as an official partial response. In fact, there was a continuum of shrinkages. Also common to these trials was that there were no complete responses at all.
So what’s going on here? I don’t think anyone knows, but my guess is that interfering with VEGF causes destruction of newly formed blood vessels which are not yet fully matured and may be more vulnerable to lack of stimulation by VEGF. Thus you get a lot of minor shrinkages and partial responses and a delay in growth of the tumors – but no complete responses.
So how good are these treatments, really? First, the answer is clearly better than the other options after IL-2 (or Interferon) fail. Because there aren’t complete responses it doesn’t look likely that anyone will be cured, but at the same time there is no upper limit to the length of time a tumor shrinkage or stability can last, and the data make it likely that these drugs extend life by a meaningful amount.
And the Future? Breathing deep, and gazing into my crystal ball… first, BAY 43-9006 and SU11248 are racing to approval and I predict both will be approved, I would guess in 1 to 3 years or so (Avastin is already approved for colon cancer, though Tarceva is still experimental), After these drugs are approved, many, if not most patients are going to be offered them as first line therapy even though they will be approved for second line therapy. It looks to me like they are far more “egalitarian” treatments than IL-2 – probably benefiting a much larger proportion of the kidney cancer patients, but probably with less extravagant benefits than obtained by those blessed with the occasional dramatic cure from Interleukin-2 immunotherapy. These drugs are also a hell of a lot easier to take than IL-2 in the short term, although, unlike IL-2, they apparently have to be taken continuously long term. Whether to try IL-2 or anti-angiogenic therapy first will be a choice for informed patients with no one right answer. Your answer will depend on personal preferences and circumstances. As usual, for many patients it will be up to them to realize they have a choice.
Because this breakthrough in anti-angiogenic therapies is so recent, there is still great room for further improvements in therapy with combination treatments, and newer even more effective drugs. I expect a flood of interest from the biotech and research communities. This should trigger an increase in research interest in kidney cancer which seems to be especially vulnerable to anti-angiogenic therapies compared to most other cancers. I also think that preventing blood vessel growth might make for a very effective adjuvant therapy to prevent recurrence after surgery for apparently localized kidney cancer. Finally, the sooner these drugs are approved the easier it will be for creative physicians and scientists to figure out better ways to use them and the sooner we will reap the benefits. Huge randomized trials like the BAY 43-9006 phase III randomized placebo trial are not the way to go and it’s not just the ethics.
Gene Expression Profiling from Paraffin Embedded Formaldehyde Fixed Tissue
Yum! I don’t usually like to spend much time in the commercial exhibit hall as big and glitzy as it is (the scientific program is far more interesting) but at this meeting I ventured into the exhibits in search of information on gene expression profiling. This technology will very likely become important in the future and I cover it in my article Put Your Tumor on Ice, which I also updated based on what I learned.
I learned two main things:
- Gene Expression Profiling is Now Commercially Available for Breast Cancer: Several companies have assays to predict prognosis in breast cancer patients. Clinical validation of this kind of assay is a problem because of the interaction of treatment and other prognostic factors with the outcome. So the approved assays are for very, very specifically defined clinical situations. The validation methodology means the results of such tests would be unclear in other situations. I imagine there will be a problem keeping assays useful as treatment changes. I think conceptual advances in the interpretation of such assays or increased tracking of results in central databases will be needed, but it’s very encouraging to see that this technology starting to move into the clinic.
- Gene Expression Profiling Doesn’t Necessarily Require Frozen Tissue: One of the assays I looked at uses paraffin blocks which are produced as part of any standard pathology exam on a resected tumor using a technique called RT- PCR. These blocks last indefinitely and are often kept by your hospital for years or forever. So the good news is that maybe when this kind of diagnostic is available for kidney cancer, you won’t need to have frozen your tumor. It’s still true that it’s possible to get a better profile from frozen tissue so I still think it’s still worth freezing your tumor, if practical.
The drug that saved me was Interleukin-2, but there is a whole extended family of Interleukins, which are all signaling molecules of the immune system. There were two presentations on phase I trials of Interleukin 18. Both showed the drug was tolerable and there was just a little sign of response – not enough to call it promising yet. What I got out of it that was really interesting was in discussion with one of the researchers who told me that in mice, IL-18 by itself has a modest effect, but that when combined with IL-2 or IL-12 (another interleukin, which like IL-18, is an experimental drug) there is dramatic synergy. I’ll be keeping my eye out for combination trials, although I fear because FDA will require more single agent trials first it may be quite a while before we see if men are like mice. We can only hope.
Quality of Community Pathology Reports
This little study (Abstract 4548) compared pathology readings from one expert kidney cancer pathologist to the reading that had been done by the patient’s ordinal local pathologist. The good news was great agreement when the local pathologist said it was clear cell. There was less agreement when rare subtypes or characteristics were mentioned and a surprising number of local pathology reports failed to even give the grade or subtype. While I don’t think this means everyone needs to run out and have their pathology re-read, if treatment decisions are being made on the basis of non-clear cell histology it makes sense to get a second expert pathology opinion. I made a small update to my article on Subtypes based on this study.
Carbonic Anhydrase IX Prognostic Marker for Predicting Response to IL-2
This marker, also known as CAIX, CA9, MN, and G250, is a protein expressed on the surface of most clear cell renal cell cancers as a result of the loss of VHL gene function (which seems to be the characteristic mutation in clear cell RCC). Efforts are underway to use this as a prognostic marker as well as a target for immunotherapy.
Abstract 4512 reported on use of this marker to predict response to immunotherapy. When this marker was combined with detailed information on subtype and associated features from the pathology they were able to do a pretty good job of predicting who had a chance of responding to IL-2 based therapy. The model would need to be prospectively validated, and in addition the quality and consistency of pathology reporting (as I reported above) could be a major difficulty in applying this approach widely. I also think given the lack of options for treating kidney cancer, a model has to do a very good job of predicting non-response before it makes sense to decide not to use IL-2 based on it. The bar should be high when you’re tossing one of the few known possibly curative options.
Gemzar + Xeloda (Gemcitabine + Capecitabine): Too Toxic!
Kidney cancer has been notoriously unresponsive to cytotoxic chemotherapy and generally these therapies are toxic and useless in kidney cancer. Gemzar, plus an old chemo standard called 5-FU, is a chemotherapy which a fair number of patients get as a palliative treatment. It has a noticeable response rate, but unfortunately the responses really don’t last. Maybe it can buy a little time for a few patients. I’ve never been enthusiastic about this therapy, but sometimes there really aren’t many options available.
Xeloda is a newer oral drug related to 5-FU. An enzyme which is more prevalent in cancer cells converts Xeloda to 5-FU. Xeloda then should be more specific and less toxic than 5-FU and maybe more powerful too. So it makes a lot of sense to see if Gemzar + Xeloda would be an improvement on Gemzar + 5-FU, and in fact on the KIDNEY-ONC E-Mail List we have heard of patients getting Gemzar + Xeloda.
At this year’s ASCO Dr. Walter Stadler reported on a phase II clinical trial of Gemzar + Xeloda (Abstract 4515), and unfortunately although they reported a partial response rate for this therapy of 12% (which is similar to that for Gemzar + 5-FU), along with a suggestion of improvement in time to progression (5.4 months median, compared to expected 2-3 months), more than half the patients discontinued therapy. 36% were taken off study by their doctors due to specific side effects, and 21% refused further therapy presumably because it was so miserable. Most of the side effects were pretty standard for chemo treatments, but I think this very high discontinuation rate is the best indicator. It is possible that dose reduction could make this more acceptable but that might reduce the already not too stunning partial response rate. It is a bit surprising that this combination appears to be more toxic and no better than Gemzar + 5-FU. I have no idea why.
ECOG 2898: Miserable Failure
This randomized trial compared low dose Interferon to low dose Interferon plus Thalidomide as first therapy for metastatic kidney cancer. I had advised against this trial because I didn’t think there was any good evidence to suggest either arm was the best first treatment. Well we got the results at this meeting (abstract 4516) and it turns out both arms did equally badly. As one prominent doctor commented, “It’s a bust!” For more, see my review of ECOG 2898 in KidneyCancerTrials.org. This exemplifies my belief that 1. Some clinical trials are more promising than others and 2. Sometimes you can tell in advance.
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: June 23, 2004, Last Updated: June 23, 2004