Oncology Renal Cell Carcinoma


Table 3: Comparison of Reported Adverse Event Profiles of Tyrosine Kinase Inhibitors Adverse Event


Hypertension


Mucositis/stomatitis Hand–foot syndrome Rash


Fatigue Diarrhoea


Dose reduction Dose interruption


NA = not applicable.


The role for cytokine therapy in mRCC is evolving and currently is unclear. EAU (and NCCN) guidelines no longer recommend IFN-α or interleukin-2 (IL-2) monotherapy as first-line treatment for mRCC,18,19 except in selected patients such as those with clear-cell histology and good performance status, who may benefit from high-dose IL-2 therapy.36


Targeted therapies are now established as first- and second-line treatments in mRCC. In treatment-naïve and favourable- and intermediate-risk patients, sunitinib is more effective than IFN-α monotherapy, as is bevacizumab + IFN combination therapy. Pazopanib is effective in both treatment-naïve mRCC patients and those who have progressed on cytokine therapy. Based on the evidence, the first-line agents recommended by the EAU for favourable- and intermediate-risk patients are therefore sunitinib, bevacizumab + IFN and pazopanib.19 The mTOR inhibitor temsirolimus is recommended as first-line therapy for advanced mRCC in poor-risk patients.19


Sorafenib is efficacious in


cytokine-refractory patients, thus sorafenib or pazopanib is recommended as second-line therapy for patients who have progressed on cytokine treatment.19


Everolimus is recommended as the second-line


agent in patients previously treated with VEGF TKIs. Except for temsirolimus, most clinical trials of targeted therapies enrolled patients with clear-cell RCC exclusively. The EAU guidelines are summarised in Table 2.


Unmet Needs with Current Targeted Therapies The introduction of targeted treatments has greatly improved the prognosis for mRCC patients. However, durable complete responses are rare using targeted therapy in mRCC and the eventual development of refractory disease is inevitable. Furthermore, treatment with the first-generation TKIs often results in a wide range of adverse events that can negatively affect patient quality of life. Therefore, further improvements in the efficacy and safety of first- and second-line treatment strategies in mRCC are essential. Current research efforts are focused on optimising the use of available approved agents and the development of next-generation therapies.


A number of studies have addressed the matter of whether improved outcomes are best achieved by the sequential or combined use of currently approved targeted agents. Targeting different pathways through combination or sequential therapy could offer benefits in terms of overcoming resistance to individual agents. The RECORD-1 trial highlighted the benefit from mTOR inhibitors following failure of anti-VEGF therapy37


and suggested that the development of cross- resistance between inhibitors of VEGF and mTOR pathways may be minimal. However, there is less clarity on whether switching from one VEGF-targeted therapy to another could be advantageous. Results


34


from prospective studies suggest that sorafenib has modest efficacy at best in patients who experience treatment failure with first-line sunitinib.38,39


Sunitinib14 24 (8) 45 (3) 20 (5) 19 (2) 51 (7) 53 (5) 32 38


(n=375)


Sorafenib22 16 (4) NA


30 (6) 40 (1) 37 (5) 43 (2) 13 21


(n=451)


All Grades, % (Grade 3 or 4) Pazopanib25


40 (4) NA NA NA


19 (2) 52 (4) NA 14


(n=290)


Axitinib49 58 (15) 17 (2) NA


12 (0) 52 (8)


60 (10) 29


NA (n=52)


Tivozanib47 50 (9) 4 (<1) 4 (<1) 6 (1) 8 (2)


12 (2) 10 4


(n=272)


Furthermore, significant toxicities were observed, with 58% of patients experiencing a grade 3 adverse event in one study.39 These studies highlight the potential concerns of cross-resistance and overlapping toxicities between these agents, emphasising the need for further prospective clinical trials investigating the sequencing of sunitinib and sorafenib.


Combination regimens targeting complementary pathways are the mainstay of treatment for most solid tumours. This approach is being actively studied in mRCC with the hope of additionally increasing the efficacy of targeted therapies. However, such a strategy may also increase the likelihood of greater toxicity. Whether complete inhibition of the VEGF pathway by combining anti-VEGF therapy and VEGFR TKIs will improve clinical outcomes, or indeed whether combinations of inhibitors of multiple signalling pathways will result in greater anticancer efficacy, remains to be determined. The combination of sunitinib and bevacizumab was shown to cause unacceptable levels of hypertension as well as vascular and haematological toxicities in patients with mRCC, raising doubts about this regimen in this setting.40


The combination of


everolimus and bevacizumab has demonstrated efficacy and tolerability in both untreated mRCC patients and those previously treated with sorafenib in a phase II study,41 bevacizumab,42


sunitinib43 or sorafenib44


but temsirolimus in combination with was associated with significant


toxicity. Additional larger studies are needed to fully elucidate the efficacy and safety of combination regimens of VEGF-targeted agents and mTOR kinase inhibitors in mRCC.


In addition to optimising the use of available agents, a better understanding of the pathogenesis of RCC will hopefully enable the development of a next generation of targeted agents that provide more durable responses with lower toxicity. Novel agents are continuously being identified within the oncology therapeutic pipeline and are currently in clinical development for mRCC. The majority of these agents can be categorised as second-generation VEGFR TKIs and include tivozanib, axitinib, regorafenib and linifanib.


Tivozanib and axitinib are of particular interest as these are agents with a higher affinity and greater specificity for VEGF receptors compared with currently available multikinase inhibitors with proven efficacy in mRCC management, such as sorafenib or sunitinib. Currently available first-generation TKIs inhibit multiple pathways and the VEGF pathway is not their principal molecular target. Inhibition of non-VEGF receptor targets is not thought to contribute to the clinical benefits observed with multikinase inhibitors in mRCC, yet the promiscuity of these agents results in a wide range of often


EUROPEAN UROLOGICAL REVIEW


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