GRACE :: Kidney Cancer

Kidney Cancer Awareness Month

It’s Kidney Cancer Awareness month, and I’m hoping that we’ll be able to use our dialogue over the coming month to address some key issues in kidney cancer therapy. I was recently at the Genitourinary Cancers Symposium in San Francisco, CA.  At this meeting, Dr. Primo Lara from UC Davis gave a phenomenal talk outlining developments in kidney cancer over the past decade.  He highlighted some of the key developments (such as VEGF and mTOR inhibitors), but also some of the shortcomings of our research (for example, biomarker work to predict who will/will not respond to therapy).  I’m curious to know about your perspective on where you would like to see kidney cancer research go.  Hope to hear from you soon!

New Treatments for Kidney Cancer: Can They Interact With Your Other Medications?

One of the frequent nuisances when visiting a doctor’s office is filling out that form that requires an update of medications. Well, in the setting of metastatic kidney cancer, filling out that form can really have a major impact on the effectiveness of therapy. This is a complex issue – many of the treatments that are available for metastatic kidney cancer can potentially interact with drugs that are given for other common conditions. In a very well written article by Dr. Thomas-Schoemann published in Critical Reviews in Oncology and Hematology earlier this year, there was an excellent outline of these potential interactions.

For instance, a seemingly benign drug such as omeprazole (given for acid reflux) may potentially reduce concentrations of the drug sorafenib by anywhere between 20% and 50%. Similarly, a drug such as felodipine can actually result in a decrease of sorafenib concentrations in the blood by more than 50%. Felodipine is one of several drugs given to control blood pressure. It is also possible that certain drugs may actually result in significant increases in various drug levels. For instance, with the agent temsirolimus, use of the common blood pressure medication diltiazem can actually result in a more than 50% increase in the blood levels of the anti-cancer drug.

With all of this in mind, it’s certainly worthwhile to fill out those forms. As time goes on, oncologists are going to be more and more reliant on dedicated oncology pharmacists to help guide knowledge of these multiple potential drug interactions. As the list of available drugs for kidney cancer becomes longer, so too will the list of potential drug interactions – making this issue all the more important!

The Role of Removing the Kidney in the Setting of Kidney Cancer

There has been a lot of debate in the kidney cancer community regarding the utility of a procedure known as cytoreductive nephrectomy. Cytoreductive nephrectomy refers to the removal of the kidney in a patient with distant spread of his or her kidney cancer. Data from the immunotherapy era, when patients received agents such as interferon and interleukin-2, seemed to suggest that there was a substantial benefit with this procedure. However, it’s unclear whether or not the same benefit may potentially exist in the era of targeted therapy.

We’ve done an analysis of a large database known as the Surveillance Epidemiology and End Results Database (SEER) and our data seems to suggest that there’s still a benefit with cytoreductive nephrectomy in the era of targeted drugs. Having said that, I would still concede that we would probably need to rely on clinical trials to decide whether or not there is really a benefit related to this procedure. One trial that may get at the root of this issue is the SURTIME trial. This is a trial that compares immediate surgery or surgery after therapy with the drug sunitinib in patients with metastatic kidney cancer. In this particular clinical trial, the investigators are looking at the primary endpoint of progression-free survival (essentially, delay in tumor growth). The study is estimated to enroll a total of 458 patients.

A second study that will help address the role of cytoreductive nephrectomy in the targeted therapy is the CARMENA trial. This trial is a bit different in its design – as opposed to comparing sunitinib prior to surgery to sunitinib after surgery, the CARMNEA trial evaluates whether there is a benefit to surgery altogether. In this particular clinical trial, patients are randomized to receive nephrectomy followed by therapy with sunitinib or sunitinib alone (without nephrectomy). This trial differs slightly in that it evaluates the primary endpoint of overall survival. This study is also larger, including a total of 576 patients.

The SURTIME and CARMENA trials, if completed, may ultimately provide a more definitive answer regarding the potential utility of cytoreductive nephrectomy in patients that are receiving VEGF-directed agents, like sunitinib. However, with multiple promising drugs emerging (like PD-1 inhibitors and MET inhibitors, I wonder whether we will again need to demonstrate the benefit of cytoreductive nephrectomy using these novel classes of agents.

When is Genetic Screening Necessary for Kidney Cancer?

I wanted to highlight an important study that outlines considerations for obtaining genetic testing in patients with renal cell carcinoma (RCC). It’s estimated that just under 10% of RCC is hereditary, passed down from one generation to the next. From day to day in the clinic, there are really no firm guidelines to ensure oncologists screen patients for any mutations. Of course, this has implications not just for the patient but for family members and generations to come.

Dr. Brian Shuch and other investigators at the National Cancer Institute performed an analysis of a very large database called the Surveillance Epidemiology and End Results Database (SEER). Using this database, they performed a detailed analysis of age distribution and RCC. They also used a large dataset that has been accumulated at the National Cancer Institute from families with hereditary kidney cancer. Ultimately, Dr. Shuch and his colleagues found that an early age of onset might be a sign of hereditary kidney cancer. Amongst a cohort of 608 patients with hereditary kidney cancer, the median age at presentation was 37 years.  Using a cutoff at age 46, they found that they captured approximately 70% of cases of hereditary kidney cancer. On this basis, Dr. Shuch and his colleagues have suggested that perhaps it would be reasonable to use an age of onset of 46 years or less to prompt consideration of genetic counseling in patients with renal cell carcinoma.

This truly informs our day to day practice for this disease. Although an oncologist’s instinct is always to suspect a hereditary disorder when a patient is diagnosed with RCC at a very young age, Dr. Shuch’s report offers a potential guide we can follow to implement genetic testing and screening.

The RECORD-3 Trial: What Can We Learn From It?

For the past year, several pivotal trials have emerged that truly are giving us in the RCC community a better sense how to appropriately sequence therapies. One trial that I’d like to focus on is the so called RECORD-3 trial. The RECORD-3 trial asks a fundamentally important question — whether or not the sequence of a VEGF-TKI followed by a MTOR inhibitor is better than the sequence of an MTOR inhibitor followed by a VEGF-TKI. We are familiar with the treatment options for first and second line treatment of RCC in the metastatic setting. The RECORD-3 trial evaluates the sequence of sunitinib followed by everolimus, the standard, and compares it to everolimus followed by sunitinib in a one to one fashion. Patients cross over to the second treatment when their treatment progresses or worsens. The primary endpoint of this trial (i.e. the principal focus) was to determine whether or not everolimus or sunitinib led to a greater delay in tumor growth in the first-line setting. However, the trial also explored multiple secondary endpoints such as the combined delay in growth from the sequence of therapies. In addition to that, the study looked at response rate and overall survival.

In this trial, patients could have clear cell or non-clear cell histology. I will focus on that a bit later because I think there’s some important information that can be gleaned from the subpopulation of patients that did not have clear cell disease. In addition to this, patients in this clinical trial may or may not have had prior nephrectomy. Ultimately sunitinib resulted in a greater delay in tumor growth as compared to everolimus (10.7 months versus 7.8 months) in the first-line setting. I actually think one of the most interesting observations from the RECORD-3 trial has to do with what was seen in the breakdown based on clear cell and non clear cell histology. It’s always tricky for us to know what to do for patients with non-clear cell metastatic kidney cancer. We typically apply the treatments that have been developed for clear cell disease. In this trial, it seemed as though patients did a bit better with sunitinib, with median delay in tumor growth of 7.2 months versus 5.1 months with everolimus. The numbers here were very small — just over 60 patients within the subset of patients with non-clear cell disease — so it’s hard to make any definitive conclusions. However, this trial offers some suggestion and seems to indicate that patients may potentially do better with VEGF-TKI in the upfront setting whether or not they have clear cell disease or non-clear cell disease.

If we look at combined progression free survival, this data seems to suggest that there may be benefit with the sequence of sunitinib followed by everolimus as compared to everolimus followed by sunitinib. The total delay in tumor growth for sunitinib followed by everolimus was 25.8 months as compared to 21.1 for everolimus followed by sunitinib. One encouraging note from this study was the overall survival data. If we go back to the interferon era when we were quoting a median survival closer to just 1 year, we see that the results from RECORD-3 trial suggest a ray of hope. Specifically with a sequence of sunitinib followed by everolimus a median overall survival of 32 months was observed. Notably, this overall survival was substantially higher than with a sequence of everolimus followed by sunitinib. With that particular sequence, overall survival was 22 months.

Interesting Findings on Kidney Cancer Incidence

I was struck by a recent article published in the Journal of Urology by Dr. King and colleagues from the National Center for Chronic Disease Prevention and Health Promotion and from Emory University. This study looked at a SEER database analysis. SEER is a registry that has information for nearly 28% of the US population, and therefore there is immense power tied into the database. They assessed trends in the diagnosis of renal cell carcinoma over the course of the past decade specifically from 2001-2010. Over that period in time there were a total of 342,501 cases of RCC diagnosed. What they found was that the incidence of RCC rose from 10.6 per 100,000 in 2001 to 12.4 per 100,000 in 2010. Furthermore, it seemed as though the incidence of RCC increased based on age up until about the age of 70-74. Notably it was found that kidney cancer incidence was about twice as common in men as compared to women.

Although many of us chalk up the increased rate of RCC to better detection or catching kidney cancers earlier, what this report actually suggested was that the highest annual percent change in the diagnosis of kidney cancer occurred within grade 3 tumors. These are more aggressive tumors and therefore, despite the fact that we may be catching more cases of kidney cancer, it may not be that we’re simply catching very slow growing indolent disease; rather, we may be catching more aggressive tumors as well. I feel this data truly underscores the need for us to continue scientific advancements at the breakneck pace with which they have been preceding over the past several years.

Older adults and sunitinib: A formal evaluation

With many cancer therapies, we always wonder about the potential impact and relevance in an elderly population. Dr. Hutson and colleagues recently published a report in the British Journal of Cancer in January of 2014 formally assessing this in the context of patients with metastatic renal cell carcinoma. In their study, they pooled data from 1059 patients that were treated across six clinical trials that utilized the agent sunitinib. Ultimately, what Dr. Hutson and his colleagues demonstrated is that the delay in tumor growth, known as progression free survival, seemed to be pretty comparable between younger and older patients. Specifically amongst younger patients median progression free survival was 9.9 months versus 11 months in older patients.  In addition to this, there were no significant differences in terms of median overall survival when patients received first line therapy with sunitinib. Notably, there were several toxicities that seemed to be more common in older adults as compared to younger adults. These toxicities included fatigue, cough, edema or swelling, as well as anemia, a low blood count, decreased appetite, and low platelet counts. Interestingly, the study found that hand-foot syndrome was more common in younger patients. These study results really seem to indicate that we shouldn’t be ageist in prescribing drugs for renal cell carcinoma, such as sunitinib. I would suggest that similar studies are warranted across other targeted agents that are currently in use for the disease.

Kidney cancer risk: A new method of detection?

Some really interesting data has been coming out of the prostate, lung, colorectal and ovarian in (PLCO) cancer screening clinical trial, a massive effort to optimize screening practices for these diseases. Some of this data is also quite relevant to renal cell carcinoma, believe it or not. Dr. Hoffman and his colleagues at the National Cancer Institute looked at a specific type of DNA, called mitochondrial DNA. The mitochondria are the energy powerhouse of the cell and DNA from the mitochondria are particularly vulnerable to mutations. What they found was that a high copy number of mitochondrial DNA was associated with an increased risk of kidney cancer. So far there have not been very many definitive studies to suggest biological factors that can contribute to the development of kidney cancer outside of inherited genetic traits. This study is hopefully the first of many to emerge from large trials (like the PLCO) that will elucidate such factors.

PD-1 Inhibitors for Kidney Cancer

I wanted to update the audience at Cancer GRACE with some really interesting developments at the American Society of Clinical Oncology meeting this year. Dr Charles Drake, from Johns Hopkins University, presented data related to the agent nivolumab, a so-called PD-1 inhibitor. I’m quite sure that PD-1 inhibitors are going to be drugs you’ll be hearing a lot about in coming years, along with PD-L1 inhibitors. These are drugs that work at the interface between immune-based cells called T-cells as well the cancer cell. Essentially, what they do is they stimulate the body’s own immune response to fight cancer.

There’s been a lot of talk related to some data from a Phase I clinical trial of nivolumab that encompasses a number of cancer types, including lung cancer and melanoma, as well as patients with kidney cancer. I wanted to mention specifically the data related to kidney cancer that has been presented to date. Specifically, Dr. Drake reported results from a total of 34 patients that were treated one of two doses of nivolumab, either 1 mg/kg or 10 mg/kg. In this total cohort of 34 patients, it was noted that 29% of patients had responses. The median delay in cancer progression, also known as progression-free survival, was 7.3 months. Now this in and of itself might not seem shocking, but what I will say is that patients in this trial were very heavily pre-treated. About half of patients in this study had 3 or more prior therapies. In my experience, it is relatively rare to see patients who have had this extent of prior therapy respond so well. What might be even more impressive than the response data or the delay in cancer progression is the survival data. That, so far, indicates that about 70% of patients on the trial lived to 1 year, and about half of patients are still alive at 2 years and beyond.

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Tivozanib: A Closer Look at the Data

It’s been a while since I’ve posted to the Cancer Grace website, but that’s not for a lack of very exciting studies in the area of metastatic kidney cancer. We’ve seen a number of small studies this year reported for promising targeted drugs, such as the PD-1 inhibitors and the agents targeting MET. However, I wanted to discuss on this post data related to the agent tivozanib. Tivozanib is a drug that has a mechanism of action that is very similar to sunitinib or pazopanib, but it differs in that it binds more tightly to the same receptors that sunitinib or pazpnanib does. Presumably, this may actually make tivozanib a clinically more effective agent and that was the rationale behind the large Tivo-1 trial. This was a phase III study in which tivozanib was compared to sorafenib. Patients that were enrolled in this study had to have clear cell disease and in addition, they had to have prior nephrectomy or removal of their kidney. Patients may have received up to one prior therapy, but many patients in this trial have received no prior treatments. Tivozanib was given in an oral formulation three weeks on and one week off, while sorafenib was given at the standard schedule, which is a total of 400 mg twice daily. If patients were randomized to sorafenib they had the option to receive tivozanib if their disease worsened.

We saw some data presented at the American Society of Clinical Oncology meeting this year that clarified the delay in cancer growth in both the overall study and specifically in those patients that had received no prior treatment. What we saw is that in the overall study population there is a pretty modest difference in terms of progression-free survival or delay in cancer growth. Specifically, progression-free survival was 11.9 months with tivozanib versus 9.1 months with sorafenib, and this was a significant difference by the statistical methods used in this analysis. In the population of patients that had received no prior therapy, we saw a slightly more pronounced difference in terms of median progression-free survival, 9.1 months versus 12.7 months. One thing that I will point out is that all this data was called into question on the basis of the overall survival that was determined in this study. Specifically with tivozanib, the overall survival noted was 28.8 months versus 29.3 months with sorafenib. Now, this is a very slight difference, but nonetheless this change in favor of sorafenib really did cause some concern when this data was reviewed by the Oncology Drug Advisory Committee to the Food and Drug Administration.

Now, there are a number of reasons that account for the finding of sorafenib having a longer survival than tivozanib. First and foremost, a lot of patients in this trial were accrued in central and eastern Europe where treatment options are very limited. Here in the United States we have the benefit of having multiple lines of therapy available to us so if a patient progresses on tivozanib or sorafenib, they may have one of a number of different agents available to them, for instance axitinib, everolimus, and so on. However, in many countries there may not be such availability. As such, only about 10% of patients who receive tivozanib in the first-line setting went on to get another VEGF-directed therapy. In contrast, about 70% of patients went on to receive tivozanib or another VEGF-directed therapy amongst those who got sorafenib upfront. This may certainly account for the difference of survival that was seen in the study, but the Oncology Drug Advisory Committee nonetheless did not recommend tivozanib for approval in spite of this caveat.

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