|Year : 2018 | Volume
| Issue : 3 | Page : 120-128
Practical updates in medical therapy for advanced and metastatic renal cell carcinoma
Ning Yi Yap1, Wan Thien Khoo1, Komathi Perumal1, Kar Aik Ng1, Retnagowri Rajandram1, Adlinda Alip2, Marniza Saad2, Teng Aik Ong1
1 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
2 Clinical Oncology Unit, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
|Date of Web Publication||27-Jun-2018|
Teng Aik Ong
Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur
Source of Support: None, Conflict of Interest: None
The evolution of therapy for advanced or metastatic renal cell carcinoma (RCC) progressed over the past decade from using cytokine immunotherapy to targeted therapy which predominantly inhibits angiogenesis via the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. Currently, there are several approved agents in the first-line (e.g. sunitinib, pazopanib, ipilimumab/nivolumab, bevacizumab/IFN-α combination and temsirolimus) and second-line settings (e.g. everolimus, axitinib, sorafenib, cabozantinib, nivolumab and lenvatinib/everolimus combination). These agents are used in sequence upon progression due to drug resistance or intolerable toxicities. The European Association of Urology (EAU), European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines recommend the use of these agents based on evidence from clinical trials and expert committee consensus. The recent approval of immune checkpoint inhibitors due to the encouraging results from clinical trials has expanded the treatment options for patients with advanced or metastatic RCC. This will hopefully improve the treatment outcomes, reduce toxicities and ameliorate quality of life for these patients.
Keywords: Metastatic, renal cell carcinoma, targeted therapy
|How to cite this article:|
Yap NY, Khoo WT, Perumal K, Ng KA, Rajandram R, Alip A, Saad M, Ong TA. Practical updates in medical therapy for advanced and metastatic renal cell carcinoma. Urol Sci 2018;29:120-8
|How to cite this URL:|
Yap NY, Khoo WT, Perumal K, Ng KA, Rajandram R, Alip A, Saad M, Ong TA. Practical updates in medical therapy for advanced and metastatic renal cell carcinoma. Urol Sci [serial online] 2018 [cited 2021 Jun 19];29:120-8. Available from: https://www.e-urol-sci.com/text.asp?2018/29/3/120/235383
| Introduction|| |
Renal cell carcinoma (RCC) represents 2%–3% of all cancers, with the highest incidence in Western countries. The peak incidence of RCC occurs between 60 and 70 years of age, with a 3:2 ratio of men to women. With the advancement in diagnostic imaging technologies including ultrasound and computed tomography, the number of incidentally diagnosed RCCs has increased in recent years. Prognosis worsens with increasing stage and histopathological grade. Approximately 30% of patients will have advanced or metastatic RCC at diagnosis and up to 40% develop metastasis after surgical removal of primary tumor.,
Clear cell RCC (ccRCC) encompasses 80%–90% of all RCC cases. The hallmark of ccRCC is an increase in angiogenesis contributed by an enhanced vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling or mammalian target of rapamycin (mTOR) activity. Hypoxia-inducible factor accumulation due to von Hippel–Lindau (VHL) mutation and VHL protein inactivation results in the overexpression of VEGF and platelet-derived growth factor (PDGF), promoting angiogenesis. The emergence of antiangiogenic drugs and tyrosine-kinase inhibitors (TKIs)-targeted therapy drugs for metastatic RCC (mRCC) in 2005 has changed the treatment paradigm for the disease. Before that, the standard treatment for mRCC was with cytokine immunotherapy such as interferon-alpha (IFN-α) and interleukin-2 (IL-2). Several agents targeting the VEGF pathway or the mTOR pathway have progressively been approved as the first-line or later-lines for the treatment of advanced or mRCC [Figure 1].
|Figure 1: Timeline of therapies that received FDA approval for the treatment of advanced or metastatic renal cell carcinoma|
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There are now several approved agents in the first-line (e.g., sunitinib, pazopanib, ipilimumab/nivolumab, cabozantinib, bevacizumab/IFN-α combination, and temsirolimus) and second-line settings (e.g., everolimus, axitinib, sorafenib, cabozantinib, nivolumab, and lenvatinib/everolimus combination). However, one of the major challenges remains to be the development of resistance to treatment. These agents are used in sequence upon progression. In addition, most published trials are concentrated on ccRCC subtypes, thus there is no strong evidence-based recommendations given for non-ccRCC subtypes. The year 2016 saw a major breakthrough with the approval of the first immune checkpoint inhibitor drug nivolumab which adds to the treatment armamentarium for mRCC.
In this review, the United States Food and Drug Administration (FDA) approved drugs for first and subsequent-line therapies for advanced or mRCC, as recommended by the latest (2016–2018) European Association of Urology (EAU), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) guidelines are discussed and summarized. A section with emphasis on immune checkpoint inhibitors, the latest targeted immunotherapy, is included in the final section of the review.
| First-Line Therapy for Advanced or Metastatic Clear Cell Renal Cell Carcinoma|| |
Several FDA approved drugs are recommended based on the evidence from clinical trials in the first-line setting in the EAU, ESMO, and NCCN guidelines [Table 1]a. There are some similarities in the sequence of preferred choices listed in all three guidelines, with additional options in the NCCN guidelines. [Table 1] summarizes the recommendations from all three guidelines.,, The summary of level of evidence can be found in [Supplementary Table 1].,,
|Table 1: Comparison of the EAU, ESMO and NCCN guidelines for patients with advanced or metastatic ccRCC|
Click here to view
| Tyrosine Kinase Inhibitors|| |
TKIs are commonly recommended as the first-line therapy for patients with good/intermediate performance status but are also treatment options for patients with poor risk.
| Sunitinib|| |
Sunitinib inhibits VEGFR and other tyrosine kinases, including the PDGF. Patients treated with sunitinib as first-line monotherapy demonstrated significantly longer progression-free survival (PFS) compared to IFN-α. Overall survival (OS) was improved in patients treated with sunitinib (26.4 months) versus IFN-α (21.8 months). Since the approval by FDA in 2006, sunitinib has rapidly replaced IFN-α as the choice of first-line therapy for mRCC.
| Pazopanib|| |
Pazopanib is an oral angiogenesis inhibitor. In the COMPARZ trial, pazopanib had comparable PFS and OS with sunitinib. However, the two drugs had different toxicity profiles and quality of life (QOL) was better with pazopanib. In a patient-preference study (PISCES), patients preferred pazopanib to sunitinib (70% vs. 22%) due to less symptomatic toxicities.
The EAU, ESMO, and NCCN guidelines have listed sunitinib and pazopanib as the preferred standard first-line treatments for patients with advanced or mRCC. Therefore, these two TKIs are the most commonly used treatments at present.
| Cabozantinib|| |
Cabozantinib is a multitarget inhibitor of VEGFR, tyrosine-protein kinase Met (MET), and tyrosine-protein kinase receptor UFO (AXL). Cabozantinib received FDA approval based on the results of CABOSUN phase II trial which compared cabozantinib and sunitinib in the first-line treatment of intermediate or poor-risk patients with mRCC. Cabozantinib had favorable PFS (8.2 vs. 5.6 months) and objective response rate (ORR) (46% vs. 18%) over sunitinib in these patients. Treatment-related grade 3 or 4 adverse events were similar between cabozantinib and sunitinib. The EAU and NCCN guidelines recommend cabozantinib as a first-line option for intermediate-/poor-risk mRCC patients.
| Sorafenib|| |
ESMO guidelines recommend sorafenib as an alternative option for the first-line treatment. A phase II trial which compared sorafenib and IFN-α found that PFS was similar in both treatments, but a better QOL was reported for sorafenib. Nonetheless, sorafenib is more popular as a second-line treatment choice.
| Axitinib|| |
The NCCN panel includes axitinib as a first-line treatment option. This is based on the results of a phase III trial which showed a better but nonsignificant PFS in patients treated with axitinib compared to those treated with sorafenib (10.1 vs. 6.5 months). Like sorafenib, axitinib is more popular as a second-line treatment option.
| Monoclonal Antibody Against Vegf|| |
Bevacizumab and interferon-alpha
The ESMO and NCCN guidelines recommend bevacizumab and IFN-α combination as an option for the first-line treatment. A phase III trial (AVOREN) comparing bevacizumab plus IFN-α combination and IFN-α monotherapy in mRCC reported superior overall response and PFS in good-/intermediate-risk patients treated with the combination therapy. The CALGB 90206 trial, evaluating the same drug combinations reported PFS and ORR in favor of patients given bevacizumab and IFN-α, but overall toxicity was higher for this group of patients.
| Mammalian Target of Rapamycin Inhibitor|| |
Temsirolimus is a specific inhibitor of mTOR which showed efficacy in high-risk/poor-prognosis mRCC patients. In a phase III trial, patients with poor-prognosis mRCC received first-line temsirolimus or IFN-α alone or a combination of both. Patients who received temsirolimus alone had significantly improved OS and PFS than patients on IFN-α only. No difference was seen in OS for the combination group compared to IFN-α alone. Based on this evidence, the ESMO and NCCN guidelines recommend temsirolimus as a first-line therapy for poor-risk mRCC patients.
| Cytokine|| |
IL-2 immunotherapy is reported to attain long-lasting complete or partial remissions in a small subset of patients. In mRCC patients treated with IFN-α or IL-2, ORR of 5% to 27% have been shown. However, high-dose IL-2 has been associated with significant toxicity, hence it should only be an option for selected patients with excellent/good performance status. This regime is a treatment option listed for first-line therapy in the ESMO and NCCN guidelines and also a second-/subsequent-line alternative in the NCCN guidelines.
Second-line therapy for advanced or metastatic clear cell renal cell carcinoma
Second-line treatment is implemented on failure of the first therapy either due to disease progression because of drug resistance or intolerable toxicities. The type of drug used in the first-line therapy, efficacy, and tolerability are considerations which affect the choice of second-line treatment.
| Tyrosine Kinase Inhibitors|| |
Axitinib is an oral, second-generation TKI inhibitor, which selectively inhibits VEGFR. In the AXIS trial, patients who progressed after first-line therapy were given axitinib or sorafenib. A significantly improved PFS and ORR were observed in the axitinib-treated group. Axitinib is recommended as a second-line treatment for advanced or mRCC in EAU, ESMO, and NCCN guidelines.
Sorafenib is also recommended as a standard second-line treatment for advanced or mRCC in ESMO and NCCN guidelines. Sorafenib, the first TKI approved by the FDA for mRCC treatment, showed improved PFS compared to placebo in patients previously treated with cytokines. Hence, sorafenib is a recommendation in the ESMO guidelines for patients who progressed after cytokine immunotherapy.
Pazopanib is recommended as the second line-therapy by ESMO and NCCN based on phase II/III trials and a retrospective analysis which reported acceptable PFS, OS, or response rate in mRCC patients who had prior therapies. Pazopanib is an option for the second-line therapy postcytokine as a phase III trial of pazopanib in cytokine-pretreated mRCC patients versus placebo found a significant improvement in PFS (7.4 vs. 4.2 months). Pazopanib as a subsequent therapy after a noncytokine targeted therapy in patients with mRCC has not been thoroughly evaluated. Consequently, pazopanib as a second-line therapy for mRCC after treatment with a targeted agent may be a viable option when other recommended drugs are less suitable for a number of reasons, such as the patient's inability to tolerate treatment.
There has been a recent shift in the guideline recommendations of second-line therapy for mRCC patients since the FDA approval of nivolumab, a checkpoint inhibitor, and cabozantinib. A phase III trial (METEOR) comparison of cabozantinib and everolimus in VEGF-refractory mRCC patients demonstrated a superior PFS (7.4 vs. 3.8 months), ORR (21 vs. 5%), and OS (21.4 vs. 16.5 months) for cabozantinib with manageable treatment-related toxicities. The promising results led to the inclusion of cabozantinib as a standard second-line treatment in the EAU, ESMO, and NCCN guidelines. According to the EAU and ESMO guidelines, if cabozantinib and nivolumab are available, either one can be recommended after a failed TKI., If both are unavailable, either axitinib, everolimus, or lenvatinib plus everolimus can be prescribed., Nivolumab will be further described in the checkpoint inhibitor section.
| Mammalian Target of Rapamycin Inhibitor|| |
The oral agent mTOR inhibitor, everolimus, was the first drug to be approved for the second-line therapy in patients with VEGF-refractory mRCC. Everolimus demonstrated improved PFS (4.9 vs. 1.9 months) over placebo for the treatment of mRCC in patients who progressed after sunitinib or sorafenib treatment. However, everolimus has been outperformed in terms of PFS or OS by newer therapies, cabozantinib and nivolumab.
| Combination Therapy|| |
Lenvatinib and everolimus
The combination of lenvatinib (a multitargeted TKI) with everolimus has been lately permitted by the FDA as a second-line therapy for mRCC. A phase II trial comparing lenvatinib plus everolimus and lenvatinib or everolimus monotherapy found a PFS benefit for the combination therapy versus everolimus (14.6 vs. 5.5 months). The ORR was highest for the lenvatinib plus everolimus combination (43%) followed by lenvatinib alone (27%) and everolimus only (6%). The median OS was also significantly increased in the combination arm compared to lenvatinib alone and everolimus alone (25.5 vs. 19.1 vs. 15.4 months).
The lenvatinib and everolimus combination is recommended as a succeeding second-line therapy combination in the NCCN guidelines. In the EAU and ESMO guidelines, it is mentioned as an option based on expert opinion but not an official recommendation as the study was a phase II trial with only 153 patients.,
| Other Therapies|| |
Bevacizumab, sunitinib, and temsirolimus are listed as second-line treatments in the NCCN guidelines based on phase II trials which demonstrated acceptable outcomes after initial cytokine therapy.,,, Sunitinib is listed as an option postcytokine in the ESMO guidelines.
| Third-Line Therapy for Advanced or Metastatic Clear Cell Renal Cell Carcinoma|| |
Due to the encouraging performances of cabozantinib and nivolumab, the EAU and ESMO guidelines both recommend either drugs for subsequent therapy after failure of second-line therapy. Other third-line recommendations are listed in [Table 1]a.
| Targeted Therapy for Advanced or Metastatic Nonclear Cell Renal Cell Carcinoma Subtypes|| |
At the moment, there is no solid evidence from phase III trials to warrant a strong recommendation of treatment strategy for advanced or metastatic non-ccRCC patients. The EAU, ESMO, and NCCN guidelines stated that the best strategy for these patients is the enrolment into clinical trials specifically for non-ccRCC subtypes., Sunitinib is listed in all three guidelines for these patients [Table 2]. A few phase II trials have reported acceptable efficacy in patients with advanced or metastatic non-ccRCC. Sunitinib also showed longer PFS in two trials, ASPEN and ESPN, compared to everolimus., A subset analysis of the ARCC phase trial III which compared temsirolimus with IFN-α favored temsirolimus in terms of OS in patients with poor-risk ccRCC and non-ccRCC. Everolimus, pazopanib, axitinib, and erlotinib (epidermal growth factor receptor TKI) evaluated in phase II trials or retrospective analyses for patients with non-ccRCC suggested that these patients may benefit from the therapies., RCC patients with sarcomatoid transformation have an aggressive disease with poor prognosis. The NCCN guidelines suggested treatment with gemcitabine in combination with doxorubicin or sunitinib for ccRCC and non-ccRCC patients with sarcomatoid features based on phase II trials which demonstrated efficacy.,,
|Table 2: Comparison of the EAU, ESMO and NCCN guidelines for patients with advanced or metastatic non-ccRCC|
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| Immune Checkpoint Inhibitors in Renal Cell Carcinoma|| |
For a decade since the introduction of targeted therapy, TKI or mTOR inhibitors have been the staple of prescribed treatments for advanced or mRCC patients. Immune checkpoints are the latest targets for treatment of various cancers, including advanced or mRCC. The emergence of several promising phase III trials evaluating checkpoint inhibitors for these patients indicates that the entrance of checkpoint inhibitors in the treatment settings of mRCC is inevitable [Table 3]. Nivolumab was the first checkpoint inhibitor which was approved by FDA for the treatment of patients with advanced or mRCC, followed by the approval of nivolumab and ipilimumab combination therapy.
|Table 3: Immune checkpoint inhibitor phase III trials in advanced or mRCC patients|
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| Mechanisms of Immune Checkpoints in Cancer|| |
Immune checkpoints are important in regulating the amplitude of immune response such as T-cell activation to limit the damage to peripheral cells and tissue. Among the well-studied immune checkpoint pathways in cancer therapy are the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) controlled responses.
The PD-1 receptors are expressed on the surface of B-cells, T-cells, and myeloid cells while the ligands, PD-L1 and PD-L2 are found on the surface of dendritic cells and macrophages., PD-L1 and PD-L2 have also been found on various tumor cells including RCC., The binding of PD-L1 or PD-L2 to the PD-1 receptor attenuates the T-cell activation, reducing T-cell proliferation, and cytokine production. Cancer cells can evade destruction by the immune system by presenting the PD-L1/2 on the cell surface. A meta-analysis of PD-L1 in metastatic RCC showed that the PD-L1 expression in primary tumors is associated with an unfavorable survival outcome. Higher PD-1 expression in tumor-infiltrating immune cells is also associated with clinically aggressive features and poorer survival in mRCC patients.
CTLA-4 is a receptor found on the surface of activated T-cells. Binding of CTLA-4 to CD80 (B7-1) or CD86 (B7-2) on the surface of antigen presenting cells inhibits further activation of T-cell responses. Studies have reported that higher expressions of CTLA-4 in breast cancer, esophageal carcinoma, and melanoma patients predict a poorer prognosis.,, Inhibition of these checkpoints by immune checkpoint inhibitors reinvigorates the immune system, so antitumor responses are mounted toward tumor cells resulting in cell death. Ipilimumab was the first checkpoint inhibitor approved for cancer therapy (metastatic melanoma) by the FDA in 2011.
| Nivolumab and Ipilimumab|| |
Nivolumab plus ipilimumab was approved for the first-line treatment of patients with advanced or mRCC based on encouraging results from the CheckMate 214 trial. This phase III clinical trial demonstrated significant benefit for nivolumab plus ipilimumab compared to sunitinib in intermediate- or poor-risk patients with treatment naïve mRCC. The 18-month OS rate was 75% for nivolumab plus ipilimumab compared to 60% for sunitinib-treated groups, and the median PFS was also better in the combination arm (11.6 months vs. 8.4 months). In addition, the ORR (42% vs. 27%) and complete response rate (9% vs. 1%) were higher for nivolumab plus ipilimumab compared to sunitinib. Grade 3/4 AE occurred in 46% of patients in the combination group, whereas 63% of patients in the sunitinib group had grades 3-5 AE, which amounted to a better health-related QOL in the combination group. However, in patients with favorable risk, sunitinib outperformed the combination therapy in terms of ORR and PFS. Therefore, the EAU and NCCN guidelines recommend nivolumab plus ipilimumab as a treatment option for intermediate- or poor-risk patients with mRCC.
Nivolumab was approved for the second-line treatment of advanced RCC based on results from a Phase III study, Checkmate 025. The study compared nivolumab with everolimus in patients with VEGF-refractory advanced RCC patients. The median OS was improved in patients treated with nivolumab compared to everolimus (25 vs. 19.6 months). The median OS was better in nivolumab for all Memorial Sloan Kettering Cancer Center (MSKCC) risk groups but was more significant in patients with poor risk. In addition, the ORR of nivolumab was significantly higher compared to everolimus (25% vs. 5%). However, there was no significant difference in the PFS between nivolumab and everolimus (4.6 vs. 4.4 months). There could have been a delayed benefit for nivolumab based on the late separation of PFS curves. The PD-L1 expression status did not affect the treatment benefit in this cohort of RCC patients. Grade 3 or 4 adverse events (AE) were reported in 19% of the patients compared to 37% in patients treated with everolimus. This was translated to a better improvement in health-related QOL in patients treated with nivolumab, which in turn, was correlated with a better OS.
Nivolumab and cabozantinib were both approved as they outperformed everolimus in phase III trials. Although there is no head-to-head comparison for nivolumab and cabozantinib in a clinical trial at the moment, Wiecek and Karcher have performed a comparison of OS for both drugs based on the results of the two separate phase III trials. They found that cabozantinib showed better OS outcome in the first few months of treatment (5–10 months) while nivolumab performed better afterward, leading them to suggest that patients with poor prognosis benefit more from cabozantinib and nivolumab benefitting patients with better prognosis. However, this comparison did not take into account the ORR, PFS, AEs, and QOL of patients, hence a direct comparison in a clinical trial would give a more accurate outcome.
With the positive results of checkpoint inhibitors, nivolumab/ipilimumab/cabozantinib combination therapy is being evaluated as a first-line treatment for advanced or mRCC in a phase III trial, Checkmate 9ER. Checkmate 9ER investigates the combination of nivolumab with cabozantinib or nivolumab and ipilimumab combined with cabozantinib compared to sunitinib as a first-line treatment in patient with advanced or mRCC. A phase I study of cabozantinib plus nivolumab with or without ipilimumab in patients with metastatic genitourinary tumors who have failed at least one standard therapy showed that the drug combinations had tolerable toxicities and an ORR of 32%. Hence, the results of Checkmate 9ER would be exciting as it is combining a potent VEGF TKI cabozantinib with nivolumab and ipilimumab in the first-line setting.
| Other Ongoing Phase Iii Trials for Immune Checkpoint Inhibitors|| |
In an ongoing phase III trial (IMmotion 151), atezolizumab plus bevacizumab is compared to sunitinib in previously untreated advanced or mRCC. The outcome from a phase II trial (IMmotion 150) testing a similar drug combination was promising as patients who expressed PD-L1 treated with atezolizumab plus bevacizumab had a 36% reduction in risk of the disease worsening or death compared to people treated with sunitinib alone. Other ongoing phase III trials for first-line therapy are the JAVELIN Renal 101, Keynote 426 and NCT02811861 trials [Table 3]. Results for these phase III trials are still pending, but if checkpoint inhibitors outperform sunitinib in these trials, it could change the future landscape of the first-line treatment in patients with mRCC.
| Immune Checkpoint Inhibitors in Nonclear Cell Renal Cell Carcinoma Patients|| |
Despite the major breakthrough of immune checkpoint inhibitor in the treatment of advanced or mRCC, this is mostly limited to ccRCC. Similar to other targeted therapies, there is still a lack of evidence in patients with non-ccRCC as most of the phase III trials involve patients with ccRCC. Checkmate 374, a phase 3b/4 trial evaluating the safety data of nivolumab in patients with mRCC includes patients with non-ccRCC as well, but the results have not been published. A phase II trial evaluating the ORR, PFS, and AE of atezolizumab and bevacizumab in patients with advanced non-ccRCC is also currently ongoing (ClinicalTrials Identifier NCT02724878). An assessment of PD-L1 expression in non-ccRCC tumors (papillary, chromophobe, Xp11.2 translocation, and collecting duct RCC) showed that patients with PD-L1 positive expression in the tumor-infiltrating mononuclear cells (TIMCs) had a shorter OS while patients with PD-L1 positivity in both tumor and TIMC had a shorter time to recurrence. These patients with nonclear cell mRCC could possibly benefit from checkpoint inhibition therapy and other novel agents.
| Conclusion|| |
The treatment of advanced or mRCC has evolved from the cytokine era to the current angiogenesis inhibition targeted therapy era. The recommendations of EAU, ESMO, and NCCN guidelines have also changed over the years according to evidence from expanding the clinical trials. New clinical trials on immune checkpoint inhibitors have further increased the treatment options for these patients. This will hopefully improve the treatment outcomes, reduce toxicities, and improve QOL for patients with advanced or mRCC.
Financial support and sponsorship
This article was partially supported by University Malaya PPP grant PG140-2015B.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]