Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments?

ABSTRACT

Introduction

Pharmacological combinations using immune checkpoint inhibition (ICI), tyrosine kinase inhibition (TKIs), and mammalian target of rapamycin inhibitors (mTOR) have improved survival in metastatic clear cell renal cell cancer (mccRCC). Despite improvements in survival, complete durable responses are rare.

Areas covered

Molecular pathways involved in mccRCC and drugs targets are highlighted. The background and rationale for combination therapy are covered. Results from combination trials are reviewed and potential approaches with biomarker-stratified treatment and novel experimental agents are examined. PubMed Central and ClinicalTrials.gov were searched. Search terms used to identify clinical trials were ‘(metastatic renal cell cancer OR renal cell carcinoma OR mccRCC OR mRCC OR RCC OR kidney cancer) AND (combination OR combined).’

Expert opinion

First-line standard of care has moved to combination therapy with ICI-ICI and TKI-ICI combinations; VEGF-mTORi is available in subsequent lines. Combining targeted treatments without validated biomarkers is imprecise, and combinations may lead to overtreatment of a subset of patients, exposing them to unnecessary toxicity. The aim of combinations must be clear: improvement in overall survival (OS) and complete response (CR). Recent data suggest a role for novel biomarker stratification rather traditional risk groups. Further combination approaches with triplets and quadruplets should be biomarker directed.

KEYWORDS:

• Combination trials
• metastatic renal cell cancer
• mccRCC
• mRCC
• immunotherapy
• VEGF-IO combination

Article highlights

• The most common histological type of renal cancer is clear cell carcinoma, also called conventional RCC.

• Single-agent chemotherapy and polychemotherapy combinations have been investigated in early-phase clinical trials with disappointing results because of multiple chemotherapy resistance mechanisms.

• The crosstalk between pathways is key in terms of resistance and an understanding of this is crucial for designing combination therapies.

• Characterization of the tumor microenvironment (TME) and the tumor itself is likely to enable better targeting of treatment. There is sound scientific rationale for VEGF-IO and IO-IO combination therapy; extensive phase 3 data have proven its efficacy.

• With immunotherapy, VEGF-directed therapy, mTOR inhibition, and HIF blockade, further combinations with triplets and quadruplets are being trialled, which may further change treatment options.

• Future approaches will hone combinations based on detailed biomarker stratification to an era of true precision medicine thus improving the chances of durable response and cure.

This box summarizes key points contained in the article.

Declaration of interest

T Eisen is employed by Roche, holds stock in Roche and Astra Zeneca, and has received research support from AstraZeneca, Bayer and Pfizer. 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. 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.