Recent pharmacological approaches for the treatment of renal cell carcinoma

ABSTRACT

Introduction

Therapies combining either two immune check-point inhibitors (ICIs) or an ICI and a tyrosine kinase inhibitor (TKI) have been shown to improve overall survival (OS), progression-free survival (PFS) and objective response rates (ORR) in metastatic renal cell carcinoma (mRCC); moreover, unprecedented rates of complete remission (CR) have been reported.

Areas covered

Among six randomized trials of ICI combinations, four have outperformed the TKI sunitinib in terms of OS. The CheckMate 214 trial investigated the combination of nivolumab (a programmed cell death protein 1 [PD-1] inhibitor) and ipilimumab (a cytotoxic T-lymphocyte antigen-4 [CTLA-4)] inhibitor). Three other trials evaluated combinations of an ICI and a TKI. These combinations are: 1) pembrolizumab (PD-1 inhibitor) plus axitinib, 2) nivolumab plus cabozantinib, and 3) pembrolizumab plus lenvatinib. This short review addresses the findings of these trials, comparing outcomes and discussing the challenges of decision-making in clinical practice.

Expert opinion

Not all patients benefit from ICI combinations. Predictive biomarkers and new therapeutic approaches are urgently needed to overcome treatment failures. A growing understanding of immune escape mechanisms and the interplay between the immune response and the gut microbiota may offer additional rescue strategies beyond ICIs and TKIs.

KEYWORDS:

• Renal cell carcinoma
• immune check point inhibitors
• tyrosine kinase inhibitors

Article highlights

• ICI combinations have led to unprecedented objective response rates, including complete responses, and the longest progression-free survival and overall survival yet reported in patients with mRCC

• Four ICI combinations are currently approved and recommended as first-line treatment, but there are no head-to-head trials comparing these strategies

• Treatment decisions are currently based on patient- and disease-related factors as there are no validated predictive biomarkers

• Biomarker research is ongoing, and the current findings have increased our understanding of the complexity of this disease

• Crucial next steps to improve outcomes in mRCC include identifying the most effective treatment for each individual patient together with greater understanding of how to overcome treatment failures.

Disclosure statement

M Schmidinger has received honoraria for lectures of advisory boards from Ibsen, Exelixis, Pfizer, Eusa, Eisai, BMS, MSD, Merck, Janssen, and Alkermes. S Shariat has received honoraria from Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, Sanofi, Takeda, and UroGen; had/having consulting or advisory roles in Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, Sanofi, Takeda, and UroGen; is a member of speakers’ bureau in Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolfe, Roche, Sanochemia, Sanofi, Takeda, UroGen, and Movember Foundation; and has filed the following patents: method to determine prognosis after therapy for prostate cancer (granted 6 September 20220), methods to determine prognosis after therapy for bladder cancer (granted 19 June 2003), prognostic methods for patients with prostate disease (granted 5 August 2004), and soluble Fas urinary marker for the detection of bladder transitional cell carcinoma (granted 20 July 2010). The authors have no other 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 apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed participation in a scientific advisory committee for Merck; consulting fees from Amgen, Bristol Myers Squibb, Eisai, Exelixiz, Pfizer, Merck, and EMD Serono; honoraria from AiCME, Intellisphere and Research to Practice; and research funds to the institute from Bristol Myers Squibb, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.