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Systemic Therapy of Metastatic Renal Cell Carcinoma in the Senior Cancer Patient

Chapter 19 - Renal Cell Cancer

Targeted Agents

Until recently, treatment options were limited for patients with RCC. Options for the medical management of metastatic RCC (mRCC) have been radically improved through the introduction of agents targeting tumour Angiogenesis or intracellular pathways mediating cell growth and proliferation. Recommendations are needed on how to integrate specific management strategies into clinical practice to optimise the use of these targeted agents in the elderly. The goal is to maximise the clinical benefit through strategies focused on patient selection, assessment of quality of life, management of adverse events, and appropriate dose modification.

The main targeted agents used to manage mRCC are the small-molecule inhibitors sorafenib, sunitinib, pazopanib, axitinib, everolimus, temsirolimus, and the Monoclonal antibody bevacizumab.

  • Sorafenib, sunitinib, pazopanib and axitinib are orally bioavailable, small-molecule tyrosine kinase inhibitors (TKIs). They have a broad range of targets, among which they both inhibit vascular endothelial growth factor (VEGF) and Platelet-derived growth factor (PDGF) receptor Tyrosine kinases. Similarly, cabozantinib, an agent targeting VEGF, AXL, and MET, has shown improved clinical outcomes in patients with mRCC (METEOR trial).
  • Temsirolimus and everolimus differ from these agents in targeting the mammalian target of rapamycin (mTOR), a kinase that is active in a cell growth and proliferation pathway frequently activated in advanced RCC.
  • The monoclonal antibody bevacizumab has Antiangiogenic activity by targeting different Isoforms of VEGF.

All of these targeted agents have been shown to add significant clinical benefit when compared with placebo or interferon (IFN) therapy in the treatment of mRCC (Table below). Although at the present time it does not seem that targeted agents will offer a complete cure for mRCC, with careful management, they may offer the potential to transform it into a chronically treatable disease. Indeed, the median OS for patients with mRCC has increased from around 13 months in the IFN immunotherapy era to around 24 to 30 months in recent years and it is expected to improve further with the incorporation of new immunotherapies that target immune checkpoints.

Randomised controlled trials (RCTs) have shown that six targeted agents - sorafenib, sunitinib, pazopanib, temsirolimus, bevacizumab, and everolimus - improve outcome in advanced RCC.

Clinical experience suggests sorafenib, sunitinib, pazopanib, and bevacizumab-INF are all associated with different toxicities, and it may be helpful to take this into account in the case of individual patients (such as those who have cardiac risk factors or are elderly). Given the data available from randomised trials, sunitinib and pazopanib (along with bevacizumab plus INF) should be considered the preferred first-line therapy in patients in favourable and intermediate-risk categories, although sorafenib (despite the lack of supporting data from randomized trials) might be indicated in selected populations at risk, such as elderly patients The COMPARZ trial was the first trial which aimed to show non-inferiority of sunitinib versus pazopanib with respect to progression-free survival (PFS) in patients with mRCC. Both drugs demonstrated similar efficacy in this trial, however, pazopanib had a more favourable toxicity profile than sunitinib. These findings may be helpful when choosing treatments for elderly patients, although no trial has specifically tested pazopanib in the elderly population.

Everolimus is approved in the European Union and in the United States for the treatment of advanced RCC that has progressed on or after treatment with VEGF-targeted therapy.

Summary of Phase III Clinical Trials with Approved Targeted Agents

Trial designsLine of treatment/patient characteristicBenefit from novel agent
Sorafenib vs. placeboSecond line/ECOG PS 0-1

Median PFS 5.5 vs. 2.8 mo

Better OS (censoring data for crossover)

Sunitinib vs. IFNFirst line/ECOG PS 0-1

Median PFS 11 vs. 5mo

Median OS 26 vs. 22 moa

Pazopanib vs placeboFirst-line

Median PFS 9.2 vs. 4.2 mo

Median OS 22.9 mo vs.20.5 mo

Bevacizumab plus IFN vs. placebo plus IFNFirst lineMedian PFS 10.2 vs. 5.4 mo
Bevacizumab plus IFN vs. IFNFirst lineMedian PFS 8.5 vs. 5.2 mo
Temsirolimus vs. IFNFirst line (poor risk)Median OS 11 vs. 7 mob
Everolimus vs. placeboSecond line post TKIMedian PFS 4.0 vs. 1.9 mo
Sunitinib vs. PazopanibcFirst lineMedian OS 26.9 vs. 26.1 mo
Axitinib vs. SorafenibSecond LineMedian PFS 8.3 vs. 5.7 mo

aSignificant when patients crossing over from IFN to sunitinib are excluded.
bComparison is temsirolimus versus IFN; median OS in the temsirolimus plus IFN arm was eight months.
cNon-Inferiority trial
Abbreviations: IFN, interferon; PFS, progression-free survival; PS, performance status; TKI, tyrosine kinase inhibitor; OS, overall survival; mo, months; ECOG, Eastern Cooperative Oncology Group.

Reprinted from Bellmunt J, Négrier S, Escudier B, et al. Crit Rev Oncol Hematol 2009; 69:64–72, with permission from Elsevier.

None of the phase III trials listed in Table 1 had an upper age limit to recruitment. This itself is of interest since a maximum age would generally have been stipulated in similar studies carried out a decade ago. The average age of patients across these studies and their treatment arms was remarkably similar (the lowest median being 58 years in the sorafenib arm of the placebo-controlled phase III trial, and the highest a median of 62 years in the sunitinib arm of the study versus IFN). These trials were also very consistent in the range of ages included (typically, the youngest patients entered were 25–35 years old, and the oldest were 80–86 years old). Along the same lines, recent pivotal trials in mRCC are notable for the fact that they have not restricted eligibility by age. All included some patients over the age of 80 years, and around a third of those accrued were aged over 65.

This offers the opportunity for subgroup analyses to assess the relationship between age and treatment benefit. Since such analyses have been undertaken retrospectively they should be regarded as hypothesis-generating and certainly not as definitive. Nevertheless, they provide grounds for further investigation. All the recent randomised phase III trials report the proportion of patients aged 65 years or over: 36% in the sunitinib study, 30% in the sorafenib study, 30% in the study involving temsirolimus, and 37% in the bevacizumab trial. This proportion (roughly one-third) certainly under-represents the proportion of patients aged 65 years or over in the general population of patients with mRCC. However, due to the large size of these trials there was a sufficiently high number of elderly patients involved to allow at least some assessment of the relationship between age and the efficacy and tolerability of treatment.

While these trials were similar in age characteristics, they differ somewhat in the apparent effect of age on the benefits of treatment.

  • The sunitinib and bevacizumab studies suggest that there is little (if any) influence of age on the effect of these targeted agents.
  • However, in the sorafenib study, it seems that the benefit of this TKI relative to placebo is greater in more elderly patients than in younger patients.

In the COMPARZ study there is a non-statistically significant trend favouring sunitinib in patients ≥ 65 years. 

  • Hazard ratios from the subset analysis of the temsirolimus study suggest a trend toward the reverse effect, but confidence intervals around these estimates are wide and no definite conclusion can be drawn on this point without a prospective study (Fig. below).
  • Recently, a randomised phase III clinical trial showed a significant improvement in PFS with cabozantinib compared to everolimus in patients with mRCC previously treated with VEGF targeted therapy (7.4 vs. 3.8 months, respectively). However, further analyses are needed to define the impact of this agent in the older population.

Progression-free survival benefit of targeted therapies in elderly and younger patients enrolled in phase III clinical trials.

 

Sorafenib versus placebo; temsirolimus, sunitinib, and bevacizumab plus IFN versus IFN.
Abbreviations: IFN, interferon; PFS, progression-free survival.

Immunotherapy

The concept that the immune system has an important role in the development and progression of malignancies has been postulated for over a century. For decades immunotherapeutic strategies, such as IFN and high dose interleukin 2 (IL-2), were the only treatment for advanced RCC, with their use limited in elderly patients due to toxicity and modest clinical benefit.

Recently, immune checkpoints have been described as key regulators of the T cell immune response that are able to inactivate or activate the immune system. This knowledge has led to the development of monoclonal antibodies that block the interaction between immune checkpoint proteins and their receptors, leading to promising and durable responses in patients with advanced RCC.

A phase II study of nivolumab, an inhibitor of programmed cell death protein 1 (PD-1), in previously treated patients with mRCC showed an overall response rate of 20% and median OS ranging from 18.2 to 25.5 months, depending on the dose received. An acceptable toxicity profile, and one which differs from that observed with VEGF-targeted therapies, was reported. Positive results from a pivotal phase III trial comparing nivolumab with everolimus in previously treated patients with metastatic clear cell RCC, have been recently reported. The final analysis showed an improvement in OS (25 vs. 19.5 months, respectively), including an elderly population. Similarly, early phase studies evaluating the role of the combination of immune checkpoint inhibitors have reported encouraging preliminary results (NCT01472081). However, the toxicity profile of the combination may limit their use in the elderly population.

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