Developments in the use of tyrosine kinase inhibitors in the treatment of renal cell carcinoma

ABSTRACT

Introduction: Renal cell carcinoma (RCC) is among the most commonly diagnosed solid malignancies, but until recently there were few systemic treatment options for advanced disease. Since 2005, the treatment landscape has been transformed by the development of several novel systemic therapies. In particular, tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) pathway have been instrumental in improving outcomes in patients with metastatic disease.

Areas covered: The armamentarium of TKIs available for the treatment of RCC has expanded in recent years. The most active area of research at this time is the development of treatment regimens combining newer-generation TKIs and immune checkpoint inhibitors. Emerging data point to a role for combination therapy in the frontline management of advanced RCC. Other ongoing areas of research include the use of TKIs in the adjuvant setting and the role of cytoreductive nephrectomy within a changing treatment landscape.

Expert opinion: Although TKIs and immune checkpoint inhibitors have incrementally improved outcomes for patients with advanced RCC, long-term survival remains poor. The development of regimens combining these agents represents the next step in the evolution of the field. For the clinician, this will offer exciting possibilities and novel challenges.

Trial registration: ClinicalTrials.gov identifier: NCT02493751.

Trial registration: ClinicalTrials.gov identifier: NCT02133742.

Trial registration: ClinicalTrials.gov identifier: NCT02501096.

Trial registration: ClinicalTrials.gov identifier: NCT02496208.

Trial registration: ClinicalTrials.gov identifier: NCT02684006.

Trial registration: ClinicalTrials.gov identifier: NCT02853331.

Trial registration: ClinicalTrials.gov identifier: NCT02811861.

Trial registration: ClinicalTrials.gov identifier: NCT03141177.

KEYWORDS:

• Kidney cancer
• renal cell carcinoma
• tyrosine kinase inhibitors
• immunotherapy
• immuno-oncology

Article highlights

• The development of newer-generation TKIs along with other targeted agents has led to incremental improvements in the survival of patients with advanced RCC.

• Early-phase trials of several novel combinations of TKIs and PD-1/PD-L1 inhibitors have identified regimens with high response rates and acceptable toxicity profiles.

• Preliminary data from the JAVELIN Renal 101 trial shows that the combination of axitinib and avelumab is superior to sunitinib in terms of PFS and ORR, independent of PD-L1 expression status and across all risk groups.

• Several phase 3 trials of TKI-immunotherapy combinations for the treatment of mRCC are ongoing, with results anticipated in the near future. This may lead to regulatory approval for multiple regimens in this class.

• The role of adjuvant TKI therapy following complete resection of localized RCC is a subject of debate. Based on results from the S-TRAC trial, sunitinib is FDA-approved for use in patients at high risk of recurrence, but further refinement of risk models is needed.

• In patients with advanced RCC, cytoreductive nephrectomy remains an important tool in carefully selected patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.