What Is Next in Second- and Later-Line Treatment of Metastatic Renal Cell Carcinoma?

Review of the Recent Literature

Keiichiro Mori; Manuela Schmidinger; Fahad Quhal; Shin Egawa; Shahrokh F. Shariat; Viktor Grünwald


Curr Opin Urol. 2021;31(3):276-284. 

In This Article

Abstract and Introduction


Purpose of Review: The current treatment landscape of metastatic renal cell carcinoma has changed dramatically from the dominance of single-agent tyrosine kinase inhibitor (TKI) therapy to immune-checkpoint inhibitor (ICI)-based combinations in recent years. However, the optimal subsequent therapy remains ill-defined owing to the novelty of this approach.

Recent Findings: Treatment with TKIs after failure of single or dual ICI therapies may result in robust clinical efficacy. Nonetheless, there is a trend toward lower efficacy of TKIs after previous ICI–TKI combination therapy. Currently, tivozanib is the only drug whose third- and later-line use after failure of TKI and ICI is supported by evidence, with significantly longer progression-free survival and higher objective response rates than sorafenib. Data from retrospective studies highlight the safety and clinical activity of ICI rechallenge.

Summary: Overall, the level of evidence remains low. Treatment after failure of dual ICI therapy is not well defined and may consist of any available TKI. Although first-line use of TKI is less common, strong evidence suggests cabozantinib or nivolumab as standard options in that setting. The recommendations after first-line TKI–ICI therapy failure mirror this recommendation, although the data are less robust.


Renal cell carcinoma (RCC) is among the top 10 most frequently diagnosed cancers worldwide.[1] Approximately 25% of patients with RCC present with metastatic disease at the time of initial diagnosis and require systemic treatment. Moreover, 20–50% of RCC patients with localized disease eventually develop metastatic RCC (mRCC).[1,2]

The advent of immune-checkpoint inhibitors (ICIs) has transformed the treatment landscape of mRCC.[3,4] In recent clinical trials, ICI-based combination therapies have markedly improved survival outcomes in mRCC patients compared with the previous standard of care (sunitinib) in first-line setting.[5–9]

In an era of targeted therapy with antiangiogenic tyrosine kinase inhibitors (TKIs) for mRCC, approximately 52% and 35% of patients reach second- and third-line treatment, respectively.[10] With the introduction of ICI combination therapy, the proportion of patients reaching later lines of treatment is expected to further increase, given the prolonged survival currently obtained.[11]

Physicians are faced with the challenge of choosing an optimal treatment for the individual patient, especially in second and later lines of treatment. The choice of second and subsequent-line TKI or mammalian target of rapamycin (mTOR) inhibitor therapy is a subject of current debate, and data following prior ICI-based therapy is limited. Therefore, this review aims to summarize recent clinical evidence regarding second- and later-line treatment of mRCC.