Emerging tyrosine kinase inhibitors for the treatment of metastatic colorectal cancer

ABSTRACT

Introduction: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Over the last decade, the addition of antibodies that block the epidermal growth factor receptor (EGFR) or angiogenesis to the classic chemotherapy backbone has improved overall survival in metastatic colorectal cancer (mCRC). However, the role of the other major targeted therapy, the tyrosine kinase inhibitors (TKIs), is not yet fully clarified.

Areas covered: This review discusses key published and ongoing studies with TKIs in mCRC, the mechanisms of resistance to standard treatments that are potentially targetable with these small molecules, along with the role of biomarkers in therapeutic decision-making process.

Expert opinion: The current effectiveness of TKIs is limited by two principal reasons, firstly the use of combination chemotherapy necessitates lower dose-density to manage the toxicity profile and secondly, development of these drugs has mainly been performed in molecularly unselected populations. mCRC is a heterogeneous and dynamic disease, and clinical trials with TKIs must be designed on the basis of specific molecular alterations targeted by these drugs. Success with this approach relies on identifying mutations at the time of progression, raising the importance of minimally-invasive monitoring tools. Liquid biopsies are a promising option, although this technique remains to be validated. Overall, this approach contributes to the move towards personalized and precision therapeutic strategies.

KEYWORDS:

• Metastatic colorectal cancer
• targeted therapies
• biomarkers
• emerging resistance
• tyrosine kinase inhibitors
• molecular subtypes

Declaration of interest

J Tabernero has been a consultant/on the advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai Pharmaceuticals, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho Pharmaceutical and Takeda. E Elez has been a consultant/on the advisory boards for Amgen, Bayer, Merck Serono, Roche and Sanofi. 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. Writing assistance was utilized in the production of this manuscript, it was funded by the authors and carried out by Sara Mackenzie.

Additional information

Funding

This paper was not funded