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Navigating the Treatment Landscape for Advanced-stage Kidney Cancer

Mayer N. Fishman, MD, PhD

For the patient with advanced-stage kidney cancer, deciding on a course of treatment presents diverse choices. The physician must weigh how quickly the cancer is spreading, the pattern of that spread, and relative risks from other medical conditions against the patient’s individual treatment goals and medical needs. In many cases of patients with advanced disease, there are therapies that can realistically be used to meet the goals of longer survival, longer time to disease progression, and tumor shrinkage. While choosing a kidney cancer treatment can be a complex process, it is one in which the patient can and should participate. Patient input may impact the disease in real and significant ways.

Once the patient and physician decide to start medical therapy, there is an array of options. As shown in Table 1, such options include FDA-approved agents as well as investigational drugs, and can generally be divided into a just a few general categories:

1. Immunotherapy such as interleukin-2 (IL-2) and interferon-alfa, which are cytokines
2. Immunotherapy with checkpoint inhibitors, which are newer agents still only available in trials; examples are the drugs that are PD-1 inhibitors[1]^,[2],[3]
3. Targeted therapies such as medicines that inhibit the vascular endothelial growth factor (VEGF) pathway; most of these agents are commonly known as VEGF receptor-tyrosine kinase inhibitors (VEGFR-TKI)[4]
4. Targeted therapies that block proteins of the mammalian target of rapamycin (mTOR) pathway[5]

For some patients, treatments could include several investigational agents, for example, vaccines or endoglin/ALK1 pathway inhibitors. The medicines in this endoglin/ALK1 group block another target on blood vessels within a tumor and are being tested in combination with VEGF inhibitors.[6]

Which Drug to Start With?

Criteria for selecting one drug over another are not always well defined by detailed, specific data. In general, the decision of whether to choose immunotherapy or a targeted agent as initial therapy depends on a number of patient- and cancer-related factors.[7] The answer will not be the same for every patient.

VEGFR-TKIs

Overall, the VEGF inhibitors are the most-used medical treatment for advanced kidney cancer. Reasons for this include the potential for inducing visible tumor shrinkage, availability for administration in the outpatient setting (which is important for patients motivated to avoid hospitalizations), and the convenience of oral dosing. Sunitinib and pazopanib are the most commonly used VEGF inhibitors for initial therapy in advanced kidney cancer patients, although sorafenib, bevacizumab and axitinib may be used in certain cases, based on physician judgment.[8]^,[9],[10] There are side effects among patients treated with VEGFR-TKIs. These include high blood pressure, thyroid problems, mouth pain, diarrhea, rashes and blisters on the hands and feet, but usually can be managed with other medications such as anti-diarrheal agents, or thyroid supplements, or dose changes.[11]^,[12],[13]

IL-2

For many patients, IL-2 is an attractive therapy because of its potential to induce complete and durable responses, where all of the metastatic cancer regresses and stays gone. Treatment with IL-2 is generally appropriate to consider for patients with clear-cell kidney cancers with metastases that are not that big, and who lack high-risk features such as an unresectable primary tumor (a kidney tumor that cannot be removed surgically), cancer-related anemia, and high levels of calcium in the blood. However, IL-2 is impractical for many patients because it is administered at a high dose on an intense schedule, and good heart, lung and liver function in the patient are required. Additionally, the experience with a low chance of a complete response to IL-2, coupled with required hospital stays, may motivate patients to choose targeted therapy instead. When a patient does choose to receive IL-2, it is important to manage the known side effects, and to administer the highest dose that is practical and tolerable.[14] Response rates to targeted therapies when used after IL-2 appear to be similar to those reported with initial targeted therapy, but this comparison has not been specifically tested in a prospective, large trial format.[15]

mTOR Inhibitors

Patients at higher risk, defined by the presence of risk factors such as anemia, spread of the cancer into the liver, or a diseased kidney with the tumor still in place, may benefit from blocking the mTOR pathway as the first medical treatment. Improved survival with weekly intravenous (IV) temsirolimus treatment has been observed in higher-risk patients, compared to that seen with interferon.[16] Alternatively, the mTOR inhibitors may be administered after VEGFR-TKI drugs in this setting. In the RECORD-1 trial, the oral mTOR inhibitor everolimus, administered after VEGFR-TKI therapy, was superior to placebo (no treatment).[17] Consequently, everolimus is often considered for patients whose kidney cancers had gotten worse while on anti-VEGF treatment. In the RECORD-3 trial, the sunitinib-then-everolimus sequence was superior to the reverse sequence in terms of median progression-free survival (PFS) and in the early assessment of overall survival.[18] Although treatment with an anti-mTOR therapy is not uncommon in patients with advanced kidney cancer, most often, it is not first-line treatment.

Specific Sequences of VEGFR-TKI therapy

Does it matter which VEGFR-TKI drug is used exactly first line? Exactly second? For many patients, the selection of follow-on therapy can be as important as choosing the initial therapy, especially if the first medicine works only for a short time. Some trials have addressed the sequence issue. However, as shown in Table 2, the prospective, randomized trials directly comparing different initial choices within the anti-VEGF group, or different sequences of anti-VEGFI therapies, do not show an overall survival advantage for one sequence over another.[19]^{,[20],[21],[22],[23]} It is possible that subsequent treatments, administered after the use of trial drug ended, had had more of an impact on overall survival, but such differences, if they exist, are very hard for these trials to detect. Similarly, testing of treatment selection strategies based on tumor features has not demonstrated a specific way to make a choice. For patients who have decided on starting treatment with VEGFR-TKI medications, but are faced with choosing from among the approved agents, there may not be a wrong answer, from this perspective.

When patients experience disease progression after IL-2 therapy, the usual second-line treatment is a VEGF inhibitor; often that is the first targeted drug to be used.[24] But when patients progress after anti-VEGF therapy, they face another choice between a second VEGF inhibitor or an mTOR inhibitor. This issue has been described as the “TKI then TKI then mTOR vs. TKI then mTOR then TKI” question. Practically, the choice may be influenced by factors such as how well -- and for how long -- the first anti-VEGF agent was tolerated. If there had been a poor tolerance or a shorter duration of tolerability with the first medicine, it may justify switching to an anti-mTOR drug sooner rather than later.

Future Directions in the Treatment of Advanced Kidney Cancer

When the anti-VEGF drugs were introduced about a decade ago, IL-2 and interferon-alfa had been in use for years. It did not take long for the VEGF inhibitors to capture a majority of initial prescriptions, even in patients exhibiting the general features that appeared to be conducive to IL-2 response. That is because the disease attributes that favor an IL-2 response are essentially the same as those that favor a positive initial response to VEGF inhibition. In a small, retrospective study, higher toxicity and low responses were seen with IL-2 when used as an immediate salvage therapy for patients experiencing disease progression while on anti-VEGF therapy.[25] Consequently, IL-2 was generally reserved for first-line use, and had been excluded from subsequent lines of therapy. However, opinions have evolved in recent years. While IL-2 is still used more often as initial therapy than after other treatments, some clinicians will consider prescribing IL-2 to patients who had been on targeted therapy, and who otherwise still meet the IL-2 patient criteria.[26]

The capacity for immunotherapies such as IL-2 and interferon to make kidney cancer regress has been known for years.[27] An evolving area of research focuses on another type of immunotherapy, checkpoint inhibitors. Blocking the programmed cell death protein 1 (PD-1) pathway, a checkpoint on white blood cells, is thought to make the immune system attack tumors that were previously being ignored.³ Such a treatment strategy holds promise for the treatment of many patients in addition to those with kidney cancer. The subset of patients who respond to the checkpoint inhibitors may be different from those who respond to cytokine therapy (e.g., IL-2, interferon).[28]^,[29] We may be hopeful that as these drugs are developed, an increasing proportion of patients with kidney cancer can be immunotherapy responders.

Deciding about Participation in a Clinical Trial

From one perspective, participation in a clinical trial, whether of a first-line therapy or for a later line, is a way of “paying it forward” to advance new drug development, but it can also be a chance to try a drug that is not yet commercially available. Table 1 lists only a few of many investigational drugs in testing; Table 3 provides links to various resources that provide clinical trial information.

Increasing numbers of clinical trials and investigational drugs, combined with a better understanding of the biology of cancer, present a widening range of on-trial treatment options for kidney cancer patients, even compared to a few years ago. Each type of trial has its own particular details about patient eligibility and expected responses. Eligible and motivated patients must review potential trials with their doctor and clinical trial staff members. While understanding medical terminology and choosing a kidney cancer therapy can be a daunting task, improved education and understanding helps a person to make critical decisions in partnership with their doctor. Understanding the treatment landscape can give patients an opportunity to have a sense of control about outcomes of their treatment and ultimately become better partners in their own care.

Table 1. Drug therapies for advanced kidney cancer

*In general, access to investigational agents is limited to clinical trial participants.

Table 2. Selected large, prospective, randomized, head-to-head trials of targeted drugs

(OS=overall survival; PFS = progression-free survival)

Table 3. Online resources for clinical trial information