Although the 5-year overall survival rate of patients with renal cell carcinoma is approximately 75%, the median survival of patients with refractory or relapsed disease is only 19 to 37 months, highlighting the need for effective later-line treatments.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 90% of all renal malignancies.1,2 The prognosis of RCC can vary depending on the tumor stage at diagnosis, the patient's age and overall health, and the mutation profiles of tumors.3 Refractory or relapsed disease is common in RCC, occurring in 20% to 30% of patients.4 Although the 5-year overall survival rate of patients with RCC is approximately 75%, the median survival of patients with refractory or relapsed disease is only 19 to 37 months,5-7 highlighting the need for effective later-line treatments.

First- and Second-Line Treatment Options for Advanced RCC

The management of advanced RCC is challenging and requires an understanding of the current expanding treatment landscape. Various vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, immune checkpoint inhibitors, and mTOR inhibitors have been approved for the treatment of advanced RCC (Figure 1).8

Figure 1. Overview of Treatments for Advanced RCC and Their Targets.

VEGF = vascular endothelial growth factor; TKI = tyrosine kinase inhibitor.

According to recent real-world data, most patients with newly diagnosed metastatic RCC are treated with dual immunotherapy (ipilimumab plus nivolumab) or a combination of an immuno-oncology agent and a VEGFR tyrosine kinase inhibitor.9 Upon relapse or disease progression, most patients are offered a tyrosine kinase inhibitor as monotherapy (cabozantinib), a tyrosine kinase inhibitor in combination with immunotherapy (cabozantinib plus ipilimumab or nivolumab), or dual immunotherapy (ipilimumab plus nivolumab).9

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors suppress tumorigenesis and are effective in patients with RCC.10,11 The VEGFR tyrosine kinase inhibitors axitinib, sunitinib, pazopanib, sorafenib, and cabozantinib are commonly used as first-line treatment for patients with advanced RCC,3,12 often in combination with immunotherapy.13,14 VEGFR tyrosine kinase inhibitors are also active in patients with disease progression after immunotherapy or antiangiogenic therapy (Table 1).15 For example, axitinib, which has been approved for the second-line treatment of advanced RCC, has been shown to improve progression-free survival in patients with metastatic RCC who showed disease progression on or after one prior systemic therapy including sunitinib, bevacizumab, temsirolimus, or cytokine-containing regimens.16 Cabozantinib (alone or in combination with nivolumab), lenvatinib (plus everolimus or pembrolizumab), sunitinib, pazopanib, and under certain circumstances, sorafenib, may also be useful in patients with RCC following disease progression on or after treatment with antiangiogenic therapy.3,17

Immunotherapy

Immune checkpoint inhibitors have been shown to improve progression-free survival in previously untreated patients with advanced RCC18,19 and are recommended for the first-line treatment of advanced RCC according to the Society for Immunotherapy of Cancer (SITC) and NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).17,20 The combination of nivolumab plus ipilimumab is superior to targeted therapy with sunitinib in improving overall and objective response rates in patients with advanced RCC and is often the first-line treatment of choice for this population.21-23

Immuno-oncology agents may also be effective in patients with disease progression after first-line antiangiogenic therapy. In this population, nivolumab is superior to everolimus in improving response rate and overall and progression-free survival (Table 1).24,25 Rechallenge immunotherapy (eg, nivolumab plus ipilimumab) could also be considered for patients with relapsed or refractory RCC who have been previously treated with immune checkpoint inhibitors.8,20,26

mTOR Inhibitors

The mTOR inhibitor everolimus combined with lenvatinib can improve progression-free survival and response rates in treatment-naive patients with advanced RCC.27 The SITC and NCCN Guidelines recommend the use of everolimus plus lenvatinib or temsirolimus (in case of poor-risk disease) in patients with advanced RCC who progress on or after treatment with ipilimumab/nivolumab or axitinib/pembrolizumab.17,20 However, there are limited data to support the efficacy of everolimus or other mTOR inhibitors in this setting.8

Table 1. Efficacy and Safety of TKIs and Immuno-Oncology Agents in Phase III Trials of Relapsed/Refractory Advanced Clear Cell RCC

ICI = immune checkpoint inhibitor; IFN = interferon; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TKI = tyrosine kinase inhibitor.

Later-Line Therapy for Relapsed or Refractory RCC

Even though tumor progression is common among patients with advanced RCC, recent real-world data suggest that only 12% and 4% of patients with advanced RCC receive third-line and fourth-line treatments, respectively.9 The underutilization of third-line treatments may create a missed opportunity for improving survival in patients who would benefit from additional treatment.28 In addition, the population of surviving patients with RCC who have received multiple lines of previous therapies has grown due to the recent expansion of first- and second-line treatments that prolong survival.29-31 However, the high toxicity of multitargeted tyrosine kinase inhibitors results in frequent dose reductions, interruptions, or treatment discontinuations, reducing the clinical benefit of treatment and discouraging continued or additional treatment.32-35 Less selective tyrosine kinase inhibitors tend to cause class-related off-target adverse events more frequently than selective VEGFR inhibitors,32 and adverse events may hinder the efficacy of treatment and contribute to poor patient outcomes.36 Therefore, there is a need for effective and tolerable later-line therapies suitable for long-term use in patients with highly refractory disease.

Tivozanib for Third- or Fourth-Line Treatment of RCC

The scarcity of clinical data on the efficacy and safety of later-line treatments for relapsed or refractory RCC3 may contribute to the underutilization of later-line treatments, variations in practice, and suboptimal management of patients with refractory disease. However, data from a phase III randomized controlled trial (TIVO-3; ClinicalTrials.gov identifier NCT02627963) investigating the use of a VEGFR tyrosine kinase inhibitor, tivozanib, in patients with refractory RCC support the use of tivozanib as third- or fourth-line therapy in patients with advanced RCC,10 leading to its approval in 2021.

Tivozanib is the first and currently the only agent approved by the FDA for use in adult patients with relapsed or refractory advanced RCC following two or more lines of systemic therapies.37 Tivozanib is a potent and selective oral VEGFR tyrosine kinase inhibitor that targets all three vascular endothelial growth factor receptors (ie, VEGF1, VEGF2, VEGF3).38,39 By inhibiting angiogenesis, tivozanib suppresses the supply of nutrients to the tumor and subsequent tumor growth.38,39 The high specificity of tivozanib and the fact that it inhibits all three VEGF receptors may lead to potent VEGF blockade and reduced off-target toxicity.40 In contrast to other VEGFR inhibitors that have a short half-life and require multiple doses per day (eg, axitinib),41 tivozanib has a long half-life; hence, administration of 1.5 mg once daily is sufficient to provide clinical activity.39 Such differences in pharmacokinetic profiles among VEGFR inhibitors may allow the use of antiangiogenic therapy in patients who do not tolerate certain tyrosine kinase inhibitors.

Efficacy

The efficacy of tivozanib as a third- or fourth-line treatment for RCC was studied in the TIVO-3 trial.10 The study involved 350 patients with relapsed or refractory RCC previously treated with two or more lines of systemic therapy, including at least one VEGFR tyrosine kinase inhibitor other than tivozanib or sorafenib. Patients were randomly assigned 1:1 to receive either tivozanib (1.5 mg once daily, 4-week cycles) or sorafenib (400 mg twice daily continuously) until progression or unacceptable toxicity.

The median progression-free survival, the primary endpoint of the study, was significantly longer in the tivozanib group than in the sorafenib group (5.6 vs 3.9 months; P = .02), yielding a hazard ratio for progression of 0.73 (95% confidence interval [CI] = 0.56–0.95) (Table 1). The 1-year progression-free survival rate was 28% (49 of 175) with tivozanib and 11% (19 of 175) with sorafenib. Exploratory analysis showed that tivozanib treatment provided benefit even in patients previously treated with a VEGFR tyrosine kinase inhibitor plus immunotherapy or a combination of VEGFR tyrosine kinase inhibitors.10

Long-term data are always intriguing, and overall survival remains the gold standard, although it is confounded by subsequent therapies. Progression-free survival, complete responses, and duration of response in partial responders can offer insight into the long-term activity of a regimen. Toni Choueiri, MD

“Long-term data are always intriguing, and overall survival remains the gold standard, although it is confounded by subsequent therapies. Progression-free survival, complete responses, and duration of response in partial responders can offer insight into the long-term activity of a regimen,” said Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology and co-leader of the Kidney Cancer Program at Dana-Farber Cancer Institute/Harvard Cancer Center.

Long-term follow-up of patients showed that tivozanib treatment provided a benefit for up to 4 years. The 4-year progression-free survival rate was 7.6% (95% CI = 4%–13%) in the tivozanib arm and 0% in the sorafenib arm.42 Tivozanib treatment also improved the objective response rate, duration of response, and overall survival. Clinically meaningful response was observed in 18% (95% CI = 12%–24%) of patients in the tivozanib group and 8% (95% CI = 4%–13%) in the sorafenib group.10 “There is a lack of positive randomized data in patients whose cancers have progressed after immune therapy. A positive overall survival signal is important to set a new standard,” noted Thomas Powles, MD, Professor of Genitourinary Oncology and Director of Barts Cancer Centre at St. Bartholomew's Hospital, United Kingdom.

Safety and Tolerability

The safety profile of tivozanib in patients with RCC treated with at least two prior treatment lines was acceptable and consistent with the established adverse event profile of tivozanib in patients with advanced solid tumors.10,39 Treatment-related adverse reactions occurring in more than 20% of patients who received tivozanib in the TIVO-3 study included hypertension, diarrhea, fatigue, decreased appetite, dysphonia, and asthenia.10 The frequency of serious treatment-related adverse events was similar between the two groups (11% in the tivozanib arm and 10% in the sorafenib arm; Table 1). No treatment-related deaths occurred. Seventy-nine percent of patients in the TIVO-3 study were able to continue tivozanib treatment, compared with 70% of patients in the sorafenib group.10 Dose reductions and treatment interruptions due to adverse events were less frequent with tivozanib than with sorafenib (24% vs 38%; 48% vs 63%).10

In the refractory setting, the goals of therapy remain to get patients to live longer and better. To that end, the toxicity profile and tolerability are critical if a drug is to be adopted in clinical practice. Toni Choueiri, MD

“In the refractory setting, the goals of therapy remain to get patients to live longer and better. To that end, the toxicity profile and tolerability are critical if a drug is to be adopted in clinical practice,” Dr. Choueiri noted. He added that with most tyrosine kinase inhibitors, dose reductions and interruptions are common, and engaging with the patient early in the process to find the highest tolerated effective dose is critical for long-term success. 

Emerging Third-Line Options

Other third- or later-line treatment options under investigation include nivolumab, belzutifan, and telaglenastat. Nivolumab is being investigated as second- or third-line treatment in a phase III study of patients with RCC who were previously treated with one or two VEGFR inhibitors. In this cohort, nivolumab was superior to everolimus in improving response rates, although its effect on progression-free survival was modest.25

“The HIF-2 alpha inhibitor belzutifan is an exciting new agent being tested as a single agent and in combination in patients with advanced RCC,” said Dr. Powles when asked about emerging third- or fourth-line treatments that show promise for patients with refractory or relapsed RCC. In two phase I/II trials, belzutifan alone or in combination with cabozantinib showed efficacy in patients with advanced RCC who received one or two prior therapies.43,44 A phase III study evaluating the efficacy of second- or third-line treatment with belzutifan is ongoing.45

Telaglenastat in combination with everolimus or cabozantinib is also being investigated as third- or fourth-line treatment in patients with RCC. Although data from phase III trials are awaited, the efficacy of later-line treatment with telaglenastat in two phase II studies are encouraging.46,47

Management Goals and Considerations in Treatment Sequencing

Delaying disease progression is an important goal of RCC management because it can help reduce the risk of complications, alleviate pain, and improve physical functioning and quality of life.48 Additional priorities for the management of relapse or refractory RCC include reducing tumor burden and minimizing adverse events. The treatment plan for patients with relapsed or refractory RCC should be individualized based on the risk score, tumor stage, prior treatment history, the type of RCC, the patient's overall health, and patient preference.3 “In the end, new later-line drugs will need to be moved into an earlier line setting to maximize their benefit. Ideally, we would move away from a one-size-fits-all approach and start using molecular biomarkers in renal cancer,” Dr. Powles explained.

In the end, new later-line drugs will need to be moved into an earlier line setting to maximize their benefit. Ideally, we would move away from a one-size-fits-all approach and start using molecular biomarkers in renal cancer. Thomas Powles, MD

Bradley McGregor, MD, Director of Clinical Research for the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute, agreed that priorities in the later-line setting may vary from patient to patient. “If a patient has a single progressing lesion, surgery or radiation to the site of progression and continued systemic therapy may be the best option. In patients with rapid progression, choosing a regimen with the best chance for quick response will be critical, and each decision involves a discussion with the patient on what is important to them and how we can work together to reach those goals,” he explained.

Many patients with advanced RCC may not be considered good candidates for subsequent-line therapy or may decline treatment.28 The frequent use of immunotherapy in the first-line setting and the scarcity of phase III data on the efficacy of later-line treatment after progression on immunotherapy create uncertainty on how best to treat patients with relapsed or refractory RCC.3,9,28,49 “Combination treatments in first-line therapy have made historical second- and third-line trials difficult to interpret,” Dr. Powles said. The approval of tivozanib based on recent clinical data on its efficacy in the third-line setting has led to the recommendation of tivozanib for patients with relapsed or stage IV RCC following two or more lines of prior systemic therapies by the NCCN Guidelines.17 The availability and quality of clinical evidence regarding treatment efficacy and tolerability in different settings should be considered in clinical decision-making.3

Each [treatment] decision involves a discussion with the patient on what is important to them and how we can work together to reach those goals. Bradley McGregor, MD

Treatment sequencing is another key consideration in treatment planning for patients with relapsed or refractory RCC, and optimal sequencing could potentially delay resistance and help mitigate toxicities.50 Dr. McGregor said that how the patient was treated in the front-line setting is the most important consideration when choosing second- or third-line treatment. “For a patient whose disease progressed on nivolumab/ipilimumab or non–cabozantinib-containing doublet, we would often pursue cabozantinib. For patients whose disease progresses on nivolumab/cabozantinib, lenvatinib/everolimus followed by tivozanib is an intriguing option,” he explained. Duration of response with previous treatment, availability of clinical data, and overlapping class effects should be considered (Figure 2).30,50

However, there are no data from clinical trials to inform best-practice guidelines on optimal treatment sequencing. “It’s not clear how much benefit different treatment sequences give. We need new targets and biomarkers to help determine the next steps in the management of the disease,” Dr. Powles noted.

Figure 2. Potential Sequences for Second- and Third-Line Treatment of Advanced RCC

Adapted from Mitsogiannis et al.54

Conclusion

The therapeutic landscape of advanced RCC is evolving rapidly, and clinical decision-making is particularly challenging for patients with highly refractory disease. With the availability of new clinical data in the third- or fourth-line setting, it is crucial to select treatments with the best efficacy and safety profiles in a cohort that resembles the current population of patients with relapsed/refractory RCC (ie, prior treatment with a combination of immunotherapy and VEGFR inhibitors). Tolerability and target selectivity should also be considered when choosing VEGFR tyrosine kinase inhibitors as later-line treatment for relapsed or refractory RCC. Addressing the underuse or suboptimal use of later-line treatments is critical as it may help improve outcomes in patients with disease progression after multiple lines of treatment.

Disclosure

Dr. Choueiri has disclosed that he or his institution has received paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, AVEO, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi Aventis, Surface Oncology, Takeda, and Tempest.

Dr. Powles has received honoraria for advisory boards and lectures from Bristol Myers Squibb, Astellas Pharma, Roche, Pfizer, Merck & Co., Exelixis, Eisai Co., Bayer AG, Merck & Co., and Serono.

Dr. McGregor has served as consultant for Bristol Myers Squibb, Exelixis, Eisai Co., Pfizer, Seagen, and Astellas; and has received research funding from Bristol Myers Squibb, Exelixis, Seagen, and Gilead Sciences.

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