Advances and New Research in the Treatment of Kidney Cancer

Michael B. Atkins, MD

CancerNetwork speaks with Dr. Michael Atkins, leader of the kidney cancer program at the Dana-Farber Harvard Cancer Center and professor of medicine at the Beth Israel Deaconess Medical Center and Harvard School of Medicine. Dr. Atkins, who has extensive clinical experience in kidney cancer and development of various new treatments, is presenting this weekend during the renal cancer translational science session at the American Society of Clinical Oncology 2012 Genitourinary Cancers Symposium.

-Interviewed by Anna Azvolinsky, PhD

CancerNetwork: As a researcher that is involved in the development of new therapies and in the treatment of patients with kidney cancer, what are some of the recent important successes in either the detection or treatment of kidney cancer?

Dr. Atkins: There are a number of recent advances in the treatment of kidney cancer. One category would be more potent and selective inhibitors of the VEGF pathway with the recent-I think as of today-approval of axitinib (Inlyta), which is one of the more potent VEGF inhibitors as a second-line treatment for patients who progressed after a prior VEGF pathway inhibitor or a cytokine; and the announcement within the last month of the preliminary results of the trial of Aveo’s drug, tivozanib, in patients who are treatment nave relative to sorafenib, suggesting that there are ways of, potentially, more potently inhibit the VEGF pathway that could lead to better outcomes.

A second area of improvement is identifying novel targets for kidney cancer treatment and those include PI3 kinase, TORC1, TORC2 inhibitors, in particular the knowledge that by inhibiting both TORC1 and TORC2, you might be able to inhibit HIF-2α, which is the dominant oncogene in kidney cancer (as opposed to many other cancers). We’re going to see, now that these molecules are around, clinical trials with those combinations-TORC1, TORC2, and possibly PI3 kinase inhibitors-compared to TOR inhibitors and other agents over the next year or so. And then the third most important development is the reemergence of immunotherapies as a treatment approach for patients with kidney cancer with targeted immunotherapy targeting molecules that suppress the immune system such as the PD-L1, PD-1 complex, or potentially CTLA4.

CancerNetwork: So going back to axitinib for a minute, could you maybe compare that to bevacizumab (Avastin), comparing the small-molecule inhibitor vs the monoclonal antibody? Is there any difference in the types of outcomes?

Dr. Atkins: From a strategy standpoint, axitinib and tivozanib are more like oral Avastin’s because they more selectively inhibit the VEGF pathway and they have less off-target effects than sunitinib (Sutent), sorafenib (Nexavar), and pazopanib (Votrient), so you can get more intensive inhibition of the VEGF receptor, similar to a monoclonal antibody that just might be binding a ligand VEGF such as Avastin. But there is no ability to compare the clinical results of axitinib with those of bevacizumab. They’ve been studied in completely different studies. They have never been studied head to head, and you can’t really compare easily across different populations.

CancerNetwork: And in terms of some of the immunotherapies that you were discussing, there are quite a few novel immunotherapies that are being developed for kidney cancer. Is there something particular that makes kidney cancer amenable to immunotherapy? And maybe you could briefly describe some of these new immunotherapies for kidney cancer.

Dr. Atkins: Kidney cancer has always been one of the solid tumors that is most amenable to immunotherapy. Interferon was one of the early treatments for it and interleukin-2, which was the first pure immunotherapy that was approved for the treatment of cancer was approved first for kidney cancer. And that’s likely because kidney cancers are very vascular, they don’t have a lot of hypoxia so there is access to the immune system, to tumor antigens, and there is not a lot of ongoing immune suppression in the tumors that prevents any immunotherapy from working.

The trouble with immunotherapies such as interferon or interleukin-2 is that they have a lot of side effects and they helped only a small minority of patients, although they help those, particularly interleukin-2 (IL-2) , in a major way. The therapeutic index, the risk-benefit ratio was not that great in favor of those treatments and so many patients couldn’t tolerate them and many physicians were not predisposed to using them because it was a complicated, toxic therapy. So what has happened over the last few years is there is better understanding of the mechanism that prevent the immune system from eliminating tumors. These include expression of molecules such as CTLA4 on the surface of immune cells when they are activated that sort of shuts off an immune response, or expression of PD-1 on immune cells when they are activated that binds to PD-L1 on tumor cells that also shuts off an immune response, and this has been worked out in preclinical settings.

So if you have antibodies that block those particular interactions you can take the breaks off the immune system or restore immune function and when you do that you can see the unleashing of already existing immunity against tumors. Preliminary results with the PD-1 antibody in patients with kidney cancer as well as other solid tumors have been very encouraging with up to one-third of patients showing tumor shrinkage and toxicity profiles that are much more favorable than IL-2 and even interferon. So those results are preliminary but they raise the potential for a significant therapeutic benefit for a larger percentage of patients and a broader ability to administer these treatments. There are confirmatory phase II and hopefully phase III trials that will be going on shortly as well as these agents becoming combined with VEGF pathway inhibitors for potentially additive or synergistic effects.

CancerNetwork: That’s great. We will look forward to data on that in terms of kidney cancer. And my final question is, as a principle investigator of the National Cancer Institute Specialized Program of Research Excellence-or SPORE as it is called-that began in 2009 and aims to improve detection, diagnosis, treatment, and prevention of kidney cancer, could you give us a quick update of the type of research that is ongoing?

Dr. Atkins: Sure. So this is a kidney cancer SPORE so it doesn’t focus just on renal cell cancer. One of our projects is focusing on a novel genetic abnormality that was detected in about 30% of Wilms tumors, and trying to identify whether it has prognostic significance and whether the downstream effects of that particular abnormality can serve as therapeutic targets. That research is going very well, the work of Dan Haber and Miguel Rivera from the Mass General Hospital.

A second project, which is led by Bill Kaelin, Sabina Signoretti, and Toni K. Choueiri from Dana-Farber Cancer Institute and Brigham and Women's, is focused on trying to target HIF-2α as a specific dominant oncogene in patients with kidney cancer.

A third project that I am involved in, along with Dr. James Meyer and a group at Beth Israel Deaconess as well as a number of other investigators, is trying to understand the mechanisms of resistance to VEGF-targeted therapy and to potentially develop drugs that block those or delay those resistance mechanisms. Through that project we have identified that antiangiogenic escape is the primary mechanism of resistance-identified several proteins or pathways that are involved in that escape-and are involved in starting clinical trials targeting those pathways. Some of that work will be presented at AACR and the full ASCO meeting, although not too much at ASCO GU.

A fourth project is looking at trying to inhibit PI3 kinase, TORC1, TORC2 in kidney tumors. That work is led by Dan Cherrin, James Meyer, and David McDermott, and is progressing well and was the basis of a clinical trial of a combined TORC1, TORC2, PI3 kinase inhibitor from Genentech that has recently been launched.

And the final project is focusing on vaccines and novel immunotherapies with work focusing on a PD-1 antibody initially by itself, and then in combination with a dendritic cell tumor fusion vaccine. The SPORE also supports a lot of developmental research projects, pilot projects, which will form the basis of new projects as well as career development awards helping young investigators launch their career focused on kidney cancer.

CancerNetwork: That sounds great, a lot of different programs that look at all different aspects of kidney cancer. Thank you so much Dr. Atkins for speaking with us. I appreciate it.

Dr. Atkins: You’re very welcome.