Barbara Fletcher

James J. Hsieh, MD, PhD, on the Frontline Treatment of Kidney Cancer

Hsieh is a medical oncologist at Memorial Sloan-Kettering Cancer Center.

The development of drugs that target angiogenesis and signal transduction pathways in the treatment of metastatic renal cell carcinoma (RCC) has led to improved survival rates for patients. Although these drugs are more effective and better tolerated than the older cytokine therapies, they are still associated with considerable toxicity that can severely affect patient quality of life. Effective management of treatment-related side effects is therefore paramount to effective disease management and patient quality of life.

There are eight FDA-approved drugs for metastatic RCC, with most of them being approved in the last five to seven years, noted Brian I. Rini, MD, Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute in Ohio. &ldquo;Kidney cancer is a rare disease,&rdquo; he said, &ldquo;so the average practitioner doesn&rsquo;t see that many patients per year. Therefore, he or she most likely doesn&rsquo;t have the opportunity to get to know all of the drugs really well from a risk-benefit ratio and how to best give them. So, one of the important principles in patient management is to gain expertise with a particular drug and become comfortable using it, know how to dose it, when to hold dose, when to reduce dose, how to monitor/recognize side effects, and supportive care strategies to reduce toxicity.&rdquo;

The COMPARZ phase III noninferiority trial, recently published in

, is a case in point. In this trial, sunitinib and pazopanib, two tyrosine kinase inhibitors (TKIs), were compared as a treatment in 1110 previously untreated patients with metastatic RCC. Both treatments were shown to have similar efficacy.

Patients in the sunitinib treatment group versus those in the pazopanib arm had a higher incidence of fatigue (63% vs 55%), hand-foot syndrome (50% vs 29%), and thrombocytopenia (78% vs 41%). Patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60% vs 43% with sunitinib).

&ldquo;Each drug has a somewhat unique toxicity profile" said Rini. This factor, among others, has important consequences for treatment. &ldquo;For example, panzopanib would not be a treatment choice for patients with liver dysfunction. But pazopanib is a good choice when more common sunitinib toxicities such as fatigue and hand-foot syndrome would be particularly troubling to an individual patient,&rdquo; he said.

Dosing Strategies: Intermittent and Alternate Schedules

This is why, Rini said, it&rsquo;s better to become completely familiar with a given therapy and be reassured that efficacy is similar. Overall, there is probably more to be gained by developing a greater expertise with a smaller number of drugs rather than knowing a little bit about each of them. Patients are better served that way because none of the current drugs are considered curative, he said. Rini believes that in the long run, it is likely more optimal for a patient to receive two or three drugs that are given for the maximal duration rather than to get five or six drugs, where none of them is optimized.

Avoiding unnecessary side effects is an important part of any treatment strategy. This makes managing a toxicity profile and side effects a major objective because treatment therapies are continuous. However, emerging data are challenging traditional dosing strategies, and offering new possibilities. These new strategies appear to maintain both dose intensity and patient quality of life.

&ldquo;We have reported a retrospective experience demonstrating that extended treatment breaks are feasible without a reduction in efficacy. We also recently presented data at the 2013 ASCO meeting on a phase III prospective study of intermittent sunitinib. This was a trial that enrolled 36 treatment-na&iuml;ve patients with metastatic RCC to look at longer break periods. Patients with 10% or greater reduction in tumor burden following 4 cycles had sunitinib held, with CT scans approximately every 10 weeks. Sunitinib was re-started for 2 cycles in those patients who had an increase in tumor burden of 10% or greater and again held if a 10% or greater tumor burden reduction was achieved. The results of the trial showed that sunitinib dosing with periodic extended time off drug is feasible and also associated with resolution of toxicity during the off periods. For some study patients, that amounted to as much as 12 months off treatment. So, for a select group of patients, some time off drug is possible. We are still trying to understand for which patients this might be the right approach,&rdquo; said Rini.

Decision to Switch Therapies: Progression

There are also emerging data suggesting that an alternate strategy for sunitinib is possible. &ldquo;There are data from MD Anderson, from Sunnybrook in Toronto, and from our center,&rdquo; Rini said. &ldquo;The data suggest that the standard 4 weeks on/ 2 weeks off schedule may not suit all patients. It might be reasonable to explore other dosing schemasfor instance, 2 weeks on/1 week off to maintain dose intensity and preserve quality of life. Of course, these are all retrospective data. A prospective study of the alternative schedule of sunitinib is in the works for the near future and should help resolve this.&rdquo;

Treatment for RCC is maintained with a given drug for as long as it works. &ldquo;Some patients will have some response to a drug; the tumors will get smaller after they start taking it, sometimes by a little, sometimes by a lot. Often patients experience reductions in their tumor burden for a while, and then the burden slowly starts to increase. Often, a patient may meet the defined threshold for progression before we think the benefit of the drug has been exhausted, or a radiology report indicates that there&rsquo;s progression,&rdquo; Rini said.

But, in all actuality, Rini noted, it is not that much worse, not in an absolute sense. &ldquo;It&rsquo;s hard to define it in words, exactly what that looks likebut there&rsquo;s progression and then there&rsquo;s

. There&rsquo;s a little bit worse and then there&rsquo;s something that&rsquo;s obviously a red flag: new organ sites of disease, a new disease-related problem or symptom. That&rsquo;s the indication that the patient very likely needs a change in therapy.&rdquo;

Familiarity with the disease and how it changes over time is imperative, Rini said. &ldquo;Looking at your own scans can be really helpful.&rdquo; The bottom line is to know the drug well enough in order to get the most out of it as opposed to a &ldquo;rapid fire&rdquo; trial of five different drugs. &ldquo;This is where knowledge about the drug, where understanding of nuance and detail, comes into its own.&rdquo;

Articles

The development of drugs that target angiogenesis and signal transduction pathways in the treatment of metastatic renal cell carcinoma (RCC) has led to improved survival rates for patients.

Patient-Centered Management of Metastatic Renal Cell Carcinoma

The treatment of advanced renal cell carcinoma (RCC) remains a major challenge for clinicians. However, according Daniel J. George, MD, director of Genitourinary Oncology, Duke Cancer Institute, the progress being made in understanding RCC tumor biology is already helping us to discover better, more effective treatments.

Using Current Treatments More Effectively

&ldquo;We now know that RCC is not one single entity, but a complex set of heterogeneous tumors, each defined by distinct genetic abnormalities, histopathological characteristics, and natural histories. Even within clear cell RCC, the most common type of kidney cancer, we&rsquo;re recognizing through genomic studies and protein analyses that we&rsquo;re really dealing with distinct subgroups.&rdquo; The fact that these subgroups have different molecular features has direct implications for treatment.

Better understanding of the molecular pathways involved in the development of RCC has led to the selection of important therapeutic targets such as the vascular endothelial growth factor (VEGF), and the mTOR (mammalian target of rapamycin) pathways.

George notes that the VEGF receptor tyrosine kinase inhibitors (TKIs) pazopanib, axitinib, sunitinib, sorafenib, and bevacizumab have well-established therapeutic effects in patients that extend from shrinking tumors, to delaying progression, to improving survival in the context of that delayed progression. &ldquo;In our latest studies looking at frontline TKIs, the median survival for patients has improved from 20 months to about 30 months due in part to the benefits of sequential treatments.&rdquo;

provided evidence for using pazopanib in the frontline setting, thus adding to the physician&rsquo;s therapeutic armamentarium. In the COMPARZ trial, pazopanib was compared with sunitinib, the current standard treatment for RCC in a population of 1110 treatment-na&iuml;ve patients with clear-cell, metastatic RCC. The trial showed that these two drugs had similar efficacy but that their side-effect profiles were different. Overall, the trial suggests that both drugs are safe and effective first-line therapies. &ldquo;This study offers the best perspective to date of how these therapies differ from one another with regards to side effects,&rdquo; said George.

There is growing evidence that using more than one line of VEGF/TKI is advantageous, and that speaks to the benefit of sequential uses of these drugs, George said. &ldquo;We have lots of examples where patients respond even better in the second-line setting than they did upfront. Importantly, the point is that these drugs are not identical; they&rsquo;re not simply &lsquo;me, too&rsquo; drugs. They have different pharmacokinetics, clearance, metabolism; they have different degrees of side effects that are shared across this class of agents, and in all likelihood they have differences in the effectiveness or efficacy in patients due to the differences in the drugs themselves.&rdquo;

Another therapeutic point sometimes missed, notes George, is that there is a second class of agents that has activity in this disease, the mTOR inhibitors temsirolimus and everolimus. &ldquo;The mTOR inhibitors work by a different mechanism; they inhibit a critical intracellular protein within the tumor cell that slows the growth or progression of the disease,&rdquo; George said. &ldquo;Temsirolimus is very specific in its function. It doesn&rsquo;t block any other protein in the body. When we use temsirolimus upfront as a single agent in a population of untreated patients with really aggressive metastatic disease, we see a dramatic improvement in overall survival. On average, these patients from the time of diagnosis have an expected survival of about 7 months. However, temsirolimus extends that survival to almost 11 months.&rdquo; In addition, George said, temsirolimus has a different side-effect profile than the VEGF/TKIs, and has been tolerated at near full dose, even in a symptomatic population of patients. &ldquo;Temsirolimus is a well-tolerated drug with a real clinical benefit, and community physicians should not fear using it to treat patients with aggressive disease.&rdquo;

Jeffrey A. Sosman, MD on Immune Response in RCC

Sosman is the director of the Melanoma and Tumor Immunotherapy Program at Vanderbilt University School of Medicine.

The other drug in this class, everolimus, an oral mTOR inhibitor, also has clinical benefit. &ldquo;Everolimus delays progression in patients who have relapsed on one or more of the VEGF receptor TKIs. This is in many respects a complementary strategy to the VEGF receptor TKIs, and for these more rapidly-growing tumors, we can see a real clinical benefit from this class of agents,&rdquo; George said.

Ongoing clinical trials are studying immunotherapeutic agents for advanced RCC, some of which have very disparate mechanisms. &ldquo;We&rsquo;ve known for decades that RCC is particularly sensitive to reactivation of the immune system. Tolerance is when the immune system no longer recognizes the cancer as dangerous and is an important part of kidney cancer progression. When our immune systems overcome that tolerance and re-engage in fighting the cancer, we can see some dramatic effects. Historically, that&rsquo;s using high doses of a natural compound, interleukin-2, in order to passively activate the immune system. Now, there are more active ways of re-engaging the immune system. We can, for example, create a tumor vaccine from patients who are undergoing a nephrectomy. There&rsquo;s one important pivotal studythe Autologous Dendritic Cell Immunotherapy (AGS-003) Plus Standard Treatment of Advanced Renal Cell Carcinoma (RCC) or ADAPT&mdash;currently in phase III, where patients are randomized to either receive sunitinib or sunitinib plus the tumor vaccine (AGS-003). This may result in a significant change in the progression of this disease. That&rsquo;s what the study is hoping to show,&rdquo; said George.

A second important immunotherapy study, notes George, is the study of nivolumab, now in phase III development. &ldquo;Nivolumab is the most advanced agent of PD-1-targeting cancer immunotherapies,&rdquo; George said. &ldquo;The drug works by blocking the protein PD-1, which is a receptor on the surface of the T-cell, the immune cells that fight and kill cancer. PD-1, when it&rsquo;s activated, shuts off the T-cell. It&rsquo;s the &lsquo;snooze button&rsquo; for T-cells. Tumors can activate that snooze button by expressing the PD-1 ligand. This antibody prevents that from happening and allows those T-cells to re-engage, to &lsquo;wake up,&rsquo; if you will. This is associated with a fairly dramatic and durable treatment response in about one-third of patients. This agent is being studied now in an advanced population of patients who have failed a VEGF receptor TKI and are going on that agent or everolimus, the mTOR inhibitor. This is a really important study that&rsquo;s going on right now.&rdquo;

The treatment of advanced renal cell carcinoma (RCC) remains a major challenge for clinicians. However, according Daniel J. George, MD, the progress being made in understanding RCC tumor biology is already helping us to discover better, more effective treatments.

Barbara Fletcher | Authors

Articles

Patient-Centered Management of Metastatic Renal Cell Carcinoma

Treatment of Advanced Renal Cell Carcinoma