Clinicians Must Tailor Treatment for Metastatic RCC

Neeraj Agarwal, MD

The 2017 American Society of Clinical Oncology (ASCO) Annual Meeting is taking place June 2–6 in Chicago. As part of this year’s coverage, we are speaking with Neeraj Agarwal, MD, associate professor of medicine and director of the genitourinary oncology program at the University of Utah Huntsman Cancer Institute. At this year’s meeting, he will be speaking during an Education Session about decision making in the treatment of renal cell carcinoma (RCC).

-Interviewed by Leah Lawrence

Cancer Network: Thank you for speaking with us today. First, as an update, where does treatment of RCC stand today compared with 10 years ago?

Dr. Agarwal: There has been a revolution as far as the advent of targeted therapy in metastatic RCC. As you know, there was literally nothing to treat these patients with other than first-generation immunotherapy, such as high-dose interleukin-2 and interferon-like drugs, which were marginally effective and only benefited a small fraction of patients. In the last 10 years, we have seen approvals of more than 10 targeted therapies, which benefit the majority of patients in the metastatic RCC setting. We have seen a shift in the paradigm as far as treatment of kidney cancer is concerned in the last 10 years and it continues to evolve very rapidly.

Cancer Network: I believe it is standard of care for a targeted treatment to be used as a first-line drug, but how do clinicians decide on which drug to use? Can you discuss some of the options available?

Dr. Agarwal: First, I will talk about the first-line therapy setting-meaning those patients who have never seen any systemic therapy and have newly diagnosed metastatic RCC. In this setting, there are three different kinds of drugs: one is a VEGF-targeted treatment, or a treatment that targets the vascular endothelial growth factor pathway. These can be antibodies such as bevacizumab or tyrosine kinase inhibitors such as sunitinib or pazopanib, or many others.

Second, there are mTOR inhibitors, or mechanistic target of rapamycin inhibitors, including temsirolimus, which is used in a small minority of patients who are considered to have poor prognosis disease.

The third drug is high-dose interleukin-2, which is the only drug so far that has consistently been shown to induce durable complete responses in approximately 10% of patients with metastatic RCC. Hence, this drug continues to be endorsed by National Comprehensive Cancer Network guidelines and is a treatment option offered to healthier patients with intact organ function and who have good performance status.

What to choose amongst these is a good question. In my view, high-dose interleukin-2 is an option for those patients who have good performance status and have adequate organ function, meaning they have good heart function, kidney function, and lung function. These patients ought to be offered high-dose interleukin-2 because this is the only drug that has the potential to produce long-term responses-which last for up to 10 years if they have complete response, which no other drug has shown yet in a consistent fashion. Only a minority of patients will be candidates for high-dose interleukin-2.

To the rest of patients, I offer VEGF tyrosine kinase inhibitors. The most commonly used drugs for the vast majority are sunitinib and pazopanib. These drugs are associated with a progression-free survival of approximately 9 to 10 months. There are also some reports of long-term responses obtained with these drugs; however, you have to keep taking these drugs on a continuous basis to sustain these long-term responses. Having said that, these are the most commonly used drugs in my practice because of the consistency of responses and progression-free survival in the vast majority of patients.

For a small number of patients who belong to the poor prognosis category, I offer them the mTOR inhibitor temsirolimus, which is associated with marginal progression-free survival benefits.

However, in the first-line therapy setting for these patients, my preferred option is enrollment in clinical trials. We know that many combinations of novel therapies are being used in the first-line setting through clinical trials and we expect them to be a lot more efficacious than the current standard. Given that, my preferred choice of intervention in the first-line setting is a clinical trial.

Cancer Network: As patients require second-line therapy, what are some of the therapies available and what should clinicians consider when selecting a drug?

Dr. Agarwal: That is a great question. We do not have any guidelines on which drug is going to work best for a given patient. We do not know how these drugs compare to each other because these drugs have not been compared in a randomized controlled trial. All drugs have been approved based on individual clinical trials. There is clearly a huge dilemma amongst clinicians and oncologists regarding which drug to use. However, if you look at the nuances of the efficacy data on these individual drugs or the trials, we do get some indications on which drug may be best for a given patient.

Two of the early drugs approved in the second-line setting were everolimus and axitinib. Three more drugs were approved in the last 1.5 years. The first is nivolumab, which is a programmed death 1 (PD-1) checkpoint inhibitor. The second is cabozantinib, which is a multikinase tyrosine kinase inhibitor, with a novel mechanism of action with new targets that have not been exploited by pre-existing drugs when the drug was approved. The third drug is lenvatinib in combination with everolimus. This combination has new targets, including fibroblastic growth factor in addition to VEGF.

These three treatments-nivolumab, cabozantinib, and lenvatinib/everolimus-have not been compared with axitinib in randomized controlled trials. The comparison was everolimus alone. So, as of now, these are the drugs I have for my patients who are progressing on first-line therapy.

The most important thing to consider is that almost half of patients will not be treated with second-line therapy. Only half of second-line therapy patients will ever see a third-line therapy drug in their lifetime. This is based on a European Urology paper published by the International Metastatic Renal Cell Carcinoma Database Consortium.

It is important to realize that we need to select the most optimal agent for a given patient at a given time point. If you look at the clinical data or efficacy data from these clinical trials, we can look at the nuances. That has the potential to help physicians in selecting a drug. For example, in the METEOR trial in patients with bone-predominant metastasis, the progression-free survival associated with cabozantinib was 7.4 months compared with 2.7 months with everolimus, with a hazard ratio of 0.51. This clearly shows that in patients with bone-predominant metastases, cabozantinib would be an ideal drug.

Another example is a patient who has high-volume, rapidly progressing disease, and we estimate his progression-free survival to be less than 3 months. In this patient, I would be hesitant to use nivolumab, which is not associated with progression-free survival benefit compared with everolimus. I would be more inclined to use cabozantinib, or the combination of lenvatinib with everolimus, which was associated with impressive progression-free survival benefits.

On the other hand, nivolumab is one of the most well-tolerated drugs in terms of side effects such as hand-foot syndrome or hypertension, which have the real potential to affect quality of life. If I see a patient with relatively indolent disease, I am more likely to offer nivolumab to that patient, which would allow him to maintain a good quality of life and not worry about rapidly progressive disease.

Cancer Network: Is it possible to re-challenge a patient with RCC with a therapy that was already used in the first line?

Dr. Agarwal: We used to talk about re-challenge quite a bit when we didn’t have many options. There have been small studies on re-challenge, but there has not been a randomized controlled trial. There is no Level 1 evidence supporting re-challenge with these drugs. When we have options, in terms of these novel drugs, I do not see a real role for re-challenge with a first-line drug currently.

Cancer Network:You mentioned that there are no biomarkers to help clinicians predict which drugs will work best. How should this be researched in the future?

Dr. Agarwal: Yes, unfortunately, we don’t have biomarkers in the clinic to help select patients for these individual drugs. We need biomarkers. There is a lot of effort in various cancer centers, including ours, to look for biomarkers.

Having biomarkers is also going to make agents more effective not only in terms of side effects-because you get more benefit out of the drug, improving the benefit/side effect ratio-but also more cost-effective because you are not going to be wasting time with a drug that is not going to be effective in a given patient.

Cancer Network: Thank you so much for taking the time to speak with us today about this important topic.

Dr. Agarwal: It was my pleasure. Thank you for having me.