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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

FDA-approved (i.e., indicated for use in advanced kidney cancer)

Immunotherapy

Targeted agents

 

VEGF inhibitors

mTOR inhibitors

 

 

Interferon-alfa

Axitinib

Everolimus

 

Interleukin-2 (IL-2)

Bevacizumab

Temsirolimus

 

 

Pazopanib

 

 

Sorafenib

 

Sunitinib

 

Selected investigational agents*

Checkpoint inhibitors:

  • Pembrolizumab (MK-3475)
  • MPDL-3280a
  • Nivolumab (BMS- 936558)
  • Ipilimumab
  • MEDI-4736

Cabozatanib (also inhibits C-MET)

mTORC2 inhibitors

Endoglin & ALK1 inhibitors: Dalantercept

TRC-105

 

Not currently in development for RCC: Tivozanib

Dovitinib

Note: “mTOR” may refer to mTOR complex 1 mTORC1.

mTORC2 = mTOR complex 2)

Angiopoetin 1 & 2 (Ang-1 & Ang-2) inhibitor:

AMG-386

 

 

 

Vaccines:

ARGOS dendritic cell vaccine

 

 

*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

Trial

Treatment arms

OS results

Comment

SWITCH20

Sunitinib followed by sorafenib

Sorafenib followed by sunitinib

Similar in both arms

PFS and frequency of major response also similar in both arms

COMPARZ19,[30],[31]

Sunitinib

Pazopanib

Similar in both arms

Final median OS were reported with a split by risk group; no significant differences in terms of which drug to use first

  • Favorable risk: 42.5 months for sunitinib vs. 43.6 months for pazopanib
  • Intermediate risk: 26.9 vs. 26.1 months
  • High risk: 9.9 vs. 7.7 months

PISCES[32]

Sunitinib followed by pazopanib

Pazopanib followed by sunitinib

Not reported

PFS similar in both arms. Quality-of-life assessments favored pazopanib

AXIS21

Sorafenib as 2nd-line treatment

Axitinib as 2nd-line treatment

Similar in both arms

PFS favored axitinib overall and in patients previously treated with immunotherapy, but not for patients previously treated with sunitinib

TIVO-123

Sorafenib

Tivozanib

Similar in both arms

PFS favored tivozanib. Most sorafenib patients crossed over to tivozanib; few tivozanib patients took 2nd-line treatment. Tivozanib was not approved

GOLD22

Sorafenib as 2nd-line treatment

Dovitinib as 2nd-line treatment

Similar in both arms

PFS similar in both arms

RECORD-318

Sunitinib followed by everolimus

Everolimus followed by sunitinib

Preliminary results favored sunitinib first

PFS also favored sunitinib first. OS results favored sunitinib but were still preliminary at time of report

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

 

 

Table 3. Online resources for clinical trial information

Website

URL

Comments

National Cancer Institute

www.cancer.gov/clinicaltrials

 

Searchable database of more than 12,000 open clinical trials across various cancer types

ClinicalTrials.gov

www.clinicaltrials.gov

 

Lists more than 170,000 trials (not limited to cancer) in 50 states and 187 countries

Kidney Cancer Association (KCA) Clinical Trial Matching and Referral Service

http://emergingmed.com/partners/kca/

Free, confidential matching service offered by KCA in partnership with EmergingMed

World Health Organization (WHO) International Clinical Trials Registry Platform

http://apps.who.int/trialsearch/Default.aspx

Search portal provides access to central database containing trial registration data sets provided by clinical trial registries around the world

 

 

 

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