Investigational MET inhibitors to treat Renal cell carcinoma

ABSTRACT

Introduction: Renal cell carcinoma (RCC) consists of distinct clinical and biologic entities, with an urgent need for novel therapies targeting histology-specific molecular drivers of cancer growth. The MET pathway is now being targeted by multiple novel agents in clinical development. This review highlights the upcoming role of MET inhibition in the treatment of RCC.

Areas covered: The HGF-MET axis is now recognized as playing a vital role in the growth of papillary histology and in driving VEGF inhibitor resistance. The heterogeneity of MET alterations influences sensitivity to MET inhibition and we need predictive biomarkers for improving patient selection. In this review, we highlight the role of the MET pathway in both clear cell and non-clear cell RCC and  provide a comprehensive review of preclinical and early clinical data on multiple drugs targeting the MET pathway.

Expert opinion: MET alterations can act as primary or secondary drivers of tumor growth in RCC and represents a viable therapeutic target. Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance. Addition of checkpoint inhibitors to MET inhibition has also demonstrated promising signs of early efficacy.

KEYWORDS:

• Renal cell carcinoma
• MET inhibitors
• non-clear cell RCC
• MET pathway

Article highlights

• The recognition of the biologic diversity of RCC and efforts like the cancer genome project have helped identify distinct oncogenic drivers of RCC subtypes.

• Alterations in the HGF-MET pathway play a crucial role in a majority of pRCC type 1 and some of the pRCC type 2 subtypes, described as ‘MET-driven’.

• A diverse range of MET alterations including MET amplifications, mutations, and chromosome 7 duplication have been described which could all lead to a ‘MET-driven’ phenotype.

• Responses differ across MET alterations with better responses in mutations than in amplifications or chromosome 7 duplication and better biomarkers are needed to predict response and guide patient selection.

• MET-targeted approaches have thus far yielded improved response rates compared to currently available therapies in MET-driven pRCC.

• Both selective and nonselective MET inhibitors are currently under development. Biomarker – driven trials using the presence of MET alterations to guide patient selection are currently underway.

• Combination of MET and VEGF inhibition could overcome one of the mechanisms of VEGF resistance in RCC. Combining MET inhibitors and checkpoint inhibitors can overcome the immune inhibitory effects of the MET pathway.

This box summarizes key points contained in the article.

Declaration of interest

G Sonpavde is a Consultant for Bayer, Sanofi, Pfizer, Novartis, Exelixis, Eisai, Janssen, Amgen, Astrazeneca, Merck, Genentech, EMD Serono, Astellas, receives research support to his institution from Sanofi, Bayer, Boehringer-Ingelheim, Merck, Astrazeneca, BMS, Pfizer, is on the steering committee of trials sponsored by Astrazeneca, BMS, Bavarian-Nordic, Astellas and receives speaker fees from Clinical Care Options, Physicians Education Resource (PER), Research to Practice (RTP), and Onclive.

N Agarwal is a Consult to Astellas, Astra Zeneca, Argos, BMS, Bayer, Clovis, Eisai, Exelixis, EMD Serono, Ely Lilly, Foundation One, Genentech, Janssen, Merck, Medivation, Novartis, Nektar, Pfizer and Pharmacyclics, receives research funding to his institution from Astra Zeneca, Bavarian Nordic, Bristol Myers Squibb, Calithera, Celldex, Eisai, Exelixis, Genetech, GSK (glaxosmithkline), Immunomedics, Janssen, Medivation, Merck, New link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Sanofi, Takeda, Tracon, Bayer, Clovis, EMD Serono, Ely Lilly, Janssen, and Nektar.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded