Jan 11, 2011 Speaker: Dr Janice Dutcher
Dr. Janice Dutcher, Attending Physician at Roosevelt Hospital in Manhattan, gave a talk before ACKC’s New York Support Group on the current status of therapies for kidney cancer. She adapted her presentation to answer questions from the audience and spoke first about scanning options. Both CT Scans and MRIs are superior to x-rays in that they allow the radiologist to see abnormalities in the body’s internal organs. However, they both use dyes that can be deleterious to your health. CT Scans use an iodine type dye that can cause an allergic reaction or can damage a poorly functioning kidney. MRIs use gladolinium, which, in rare cases and usually in patients with renal failure, can cause a serious skin disease called nephrogenic systemic fibrosis. When taking either test, it is best to be well hydrated since the dyes are cleared by the kidney. For the lungs, a CT Scan without contrast is sufficient, but if one is looking at lymph nodes or lesions in the mediastinal area, then a CT Scan with dye is preferable. An MRI can’t be used for inspection of the lungs as the lengthy processing would be affected by movement of the lungs during breathing. Radiologists have recently been reluctant to do contrast for those with above-normal creatinine levels, the normal amount varying by blood center. For a patient who has been NED for several years, Dr. Dutcher would dispense with the dye for CT Scans. A final note: Dr. Dutcher, in response to a question, said that the most efficient way she can view scans is if her patients utilized the radiology center belonging to the Continuum Cancer Centers from which she would obtain a disc or be able to view directly from the local computer.
A question came up with respect to biomarkers. Dr. Dutcher sits on the NIH’s Biomarker Study Group and stated that there are no biomarkers that can be used in a screening test for the existence of kidney cancer. For example, David McDermott recently reported on the “Select” trial (see below), which tested whether the presence of a high degree of carbonic anhydrase IX (CA-9) staining in clear cell patients would predict for a positive response to Interleukin-2. The results were that CA-9 staining was not a predictor at all, which contradicted two earlier but retrospective studies of this marker in predicting outcome of IL2 treatment.
Dr. Dutcher next spoke about the current FDA-approved drugs used to fight kidney cancer (tyrosine kinase inhibitors (TKIs): Nexavar, Sutent, Votrient; mTOR inhibitors: Torisel, Afinitor; and the antibody Avastin. The targeted therapies, everything but Interleukin-2, are most effective on lesions in the lung and in soft tissue. The jury is still out on bone mets, for which zometa and radiation are effective. A severe side effect of Zometa is osteonecrosis of the jaw. Dental procedures should be avoided when the patient is on Zometa. With respect to Torisel and Afinitor, which are mTOR inhibitors, mTOR is a protein that activates cell growth and survival and potentially enhances angiogenesis. It is now surmised that two complex proteins that contain mTOR, TORC1 and TORC2, must be inhibited in order to stem cancer cell growth, however, Torisel and Afinitor only block TORC1 and not TORC2. Therefore, dual TORC inhibitors must be developed to effectively suppress the mTOR pathway. Further “upstream” of mTOR are two other proteins, Akt and PKI3, that could also be inhibited in order to control cancer growth.
The targeted therapies stop working after a while but the patient can then be switched to another targeted therapy , and, after a break in therapy, even to the same one again, which can have some efficacy though usually not as much as the original dosage. Sutent at 50 mg is often difficult to tolerate on a 4 week on/2 week off cycle so Dr. Dutcher often starts at a lower dosage and builds up.
For papillary cases, Torisel has shown some efficacy, but for chromophobe there is no specific treatment and given its rare occurrence, there are no research projects for metastatic chromophobe disease.
Combination of drugs is difficult due to toxicity. Avastin has been used successfully in combination with mTOR inhibitors. Dr. Dutcher expects two newTKIs to be approved, within the coming year, for therapy for kidney cancer: axitinib and tivozanib.
Another targeted therapy in testing now is XL-184, which is a Met and VEGFR2 inhibitor. It’s being tested with Avandia (to gauge drug interaction) in a Phase I trial for renal cell and thyroid cancers. The renal cell patient population is being restricted to clear cell only even though mutations of the c-Met gene are know to cause papillary renal cell cancer. The theory behind XL-184’s activity is that when VEGFR2, an angiogenic agent, is suppressed, Met is up-regulated and enables the tumor cells to migrate to cells with unrestricted blood supply and thereby proliferate. Exelixis, the creator of XL-184, has no plans at this time to test it in papillary patients.
SIR-spheres can be useful for liver mets. They are resins that are bonded to a radioactive isotope, yttrium-90, which is delivered into the liver via the hepatic artery and which then become lodged in the tumor vasculature. It is often a palliative rather than a curative treatment.
As for immunotherapies, CTLA-4 is a negative regulator of the immune system, i.e. it puts on the brakes when the immune system becomes overactive and could start damaging healthy cells. Specifically, CTLA-4 suppresses T-cell activity, which, for renal cell, fight the cancer. Ipilimumab is an antibody that inhibits CTLA-4 activity thus freeing up T-cells to go after the tumor. It is being studied mostly in melanoma but also in a Phase I kidney cancer for young patients. A number of years ago, James Yang of the NCI studied ipilimumab in renal cell patients and had mixed success, with high toxicity – causing colitis. Investigators have since been able to more effectively control the toxicities of the drug. Dr. Dutcher is trying to get a trial for ipilimumab for adults with renal cell cancer.
MDX-1106, an anti-PD-1 drug, is being tested in renal cell as well as melanoma and other cancers. PD-1 is part of the CTLA-4 family, and as such, suppresses T-cell activity. In a report at ASCO last summer, MDX-1106, in a Phase I trial, showed good results for kidney cancer as well as for melanoma. Dr. Dutcher is meeting with Bristol Myers Squibb people to gain access to this drug for kidney cancer patients.
Finally, still around is Interleukin-2. Dr. Dutcher said that she will be re-establishing an IL-2 treatment center in Roosevelt Hospital in February. A report at the ASCO General Meeting in 2010 by David McDermott on the “Select” trial, of which Dr. Dutcher is an investigator, showed a 30% response rate among clear cell patients to High Dose IL-2 treatment, including patients with poor risk. This response rate was more than double the historical rate, probably due to better patient selection (none of the five non-clear cell patients responded). More importantly, 14% of the patients were durable responders, i.e. 6 months to 41 months, and counting. In response to a question from the floor about treatment with IL-2 after Sutent, Dr. Dutcher said that the Boston group found cardiac toxicity in patients who were treated with IL-2 shortly after Sutent therapy. She believes that the threat of cardiac toxicity is minimalized if IL-2 is not administered until after the remnants of Sutent leave the body. In other words, it’s a timing problem.
Some new studies in the pipeline are:
- A SWOG (Southwest Oncology Group) study of ARQ197 (a c-Met inhibitor) either alone or in combination with erlotininb (Tarceva), which is an EGFR (epidermal growth factor) inhibitor. EGFR promotes cell division.
- A number of drugs in Genentech’s pipeline, including GDC-0941, a PI3K inhibitor, and GDC-0980, a dual PI3K and mTOR inhibitor) – the PI3K-Akt-mTOR pathway regulates cell growth and cell survival. Genentech and Roche are cooperatively developing RG7321, another PI3K inhibitor. Genentech is also working with ABT-869, aka RG3635), which is a tyrosine kinase inhibitor.
- There is also a Roche drug, RG1507, which is a monoclonal antibody that is an inhibitor of the receptor IGF-1R, which, if activated, can result in cell growth (proliferation) and resistance to cell death (apoptosis).
- There is GDC 0449, a “Hedgehog anatagonist” developed by Genentech and Roche, which has been used by Genentech in a variety of cancers but not kidney cancer. The Hedgehog pathway, if gone awry, can lead to uncontrolled cell proliferation. Note that the name hedgehog is derived from the hedgehog gene in fruit flies, which if mutated, can give rise to short and stubby, haired embryos, that resemble hedgehogs.
- Novartis is working on TK-1258, which targets FGFR3 (fibroblast growth factor receptor 3), whose over-expression has been noted in bladder cancer and melanoma. These receptors play a role in cell growth and division, formation of blood vessels, etc.
- Finally, through support of the NCI, there are researchers looking into TORC1/TORC2 inhibitors.
Note that the above agents are still in the pipeline of drug companies and most are not yet involved in kidney cancer trials.
On another front, Memorial Sloan-Kettering Hospital is putting together a consortium of institutions in New York including NYU Hospital, Mt. Sinai Hospital, the Beth Israel Consortium, and Montefiore Hospital to purchase and install a proton beam therapy center in Manhattan. The advantage of proton beam therapy over standard radiation therapy is the minimal damage caused to adjacent organs in proton beam therapy. So, for example, it is often used in treating children with cancer. It has not yet been used in kidney cancer, but Dr. Ken Youner, ACKC’s Medical Director, was scheduled to have been treated with proton beam therapy at MD Anderson in Houston. The cost of the new proton beam center is $200 million, it will be located somewhere in Manhattan, and is projected to be operational in two years.