Combination of immune checkpoint inhibitors and tyrosine kinase inhibitors for the treatment of renal cell carcinoma

ABSTRACT

Introduction

We have experienced several paradigm shifts and substantial changes in the treatment of metastatic renal cell carcinoma (mRCC) over the last two decades. Combination therapy with immune checkpoint inhibitors (ICI) as a dual combination (ICI-ICI) or with VEGFR-tyrosine kinase inhibitors (VEGF-TKI) has shown remarkable efficacy in mRCC patients and has become the standard of care in first-line therapy.

Areas covered

In this review, we will discuss the background as well as the benefits of combining ICI with TKI compared to ICI-ICI combination therapy for mRCC treatment and will also briefly highlight biomarkers for patient selection on therapies to improve patient outcomes and limit toxicities.

Expert opinion

Due to the mediated additional anti-tumor effects, there is a strong rationale to combine ICIs and TKIs for mRCC therapy. When comparing first-line therapy options, the exceptionally higher ORR and PFS for the ICI-TKI combinations should be highlighted, whereas, nevertheless, the complete response rate is slightly higher for the ICI-ICI combination. In terms of an individualized therapeutic approach, biomarkers predicting the success or failure of an anti-VEGF-based regimen or ICI therapy as a corresponding mono – or combination therapy are lacking so far, however, gene expression signatures can be a landmark in this field.

KEYWORDS:

• Biomarker
• combination therapy
• gene signature
• immune checkpoint inhibition
• individualized treatment
• renal cell carcinoma
• tyrosine kinase inhibitor

Article highlights

• For first-line treatment of mRCC, the ICI-TKI combination with axitinib plus pembrolizumab or avelumab and cabozantinib plus nivolumab, regardless of IMDC risk profile and histological entity, and the ICI-ICI combination of nivolumab plus ipilimumab in patients with IMCD intermediate and poor risk profile are new standards.

• Antiangiogenic drugs can suppress MDSCs and decrease the amount of regulatory T cells, upregulate MHC class I expression, induce immunosuppressive tumor-associated macrophages, and increase T cell traffic in the tumor.

• Due to the mediated additional and potential synergistic antitumor effects, there is a strong rationale for combining ICIs and TKIs for mRCC therapy.

• The exceptionally high ORR, the low rate of primary progressing patients and the improved PFS for the ICI-TKI combinations should be highlighted, whereas complete response rate is higher for ICI-ICI combination.

• There are more ICI-TKI combinations to come, meaning that the end of new combination therapies has not yet been reached.

• In terms of an individualized therapeutic approach, biomarkers predicting the success or failure of an anti-VEGF-based regimen or ICI therapy as a corresponding mono- or combination are lacking so far, however, gene expression signatures can be a landmark in this field.

This box summarizes key points contained in the article.

Declaration of interest

J Bedke reports Consultancies and Speaker ́s Bureau: BMS; Eisai, EUSA, Ipsen, Novartis, MSD, Pfizer, Roche and study participation with institutional funding: Bayer, BMS; Eisai, Exelixis, Ipsen, Novartis, MSD, Pfizer, Roche. A Stenzl reports Consultancies and Speaker ́s Bureau: Ipsen, Roche, Janssen, BMS, Alere, Stebabiotech, Synergo, Ferring, Astellas, Amgen, Sanofi Aventis, CureVac and study participation or research grants with institutional funding: Johnson & Johnson, Roche, Cepheid, Amgen, Bayer, CureVac, GemeDx biotechnologies GmbH, Novartis, Karl Storz, immatics biotechnologies GmbH. 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

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

Additional information

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.