Fruquintinib as new treatment option in metastatic colorectal cancer patients: is there an optimal sequence?

ABSTRACT

Introduction

Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC).

Areas covered

Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Expert opinion

Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRAS^G12C or HER2 amplification) and in non-oncogenic driven patients.

KEYWORDS:

• Metastatic colorectal cancer
• chemorefractory
• fruquintinib
• VEGFR 1-2-3
• angiogenesis

Article highlights

• In the last decade the number of patients with mCRC that undergo at least three lines of therapy is increasing. So, it becomes imperative to establish a new strategic approach in order to expand the continuum of care for pretreated mCRC.

• Fruquintinib is a tyrosine kinase inhibitor, with a high selective action on VEGFR-1, 2 and 3, and weak one on RET, FGFR-1, and c-kit kinases.

• Fruquintinib showed efficacy and a good safety profile in phase III clinical trials (FRESCO and FRESCO 2).

• An optimal treatment sequence for the late lines of therapy in mCRC has yet to be determined.

• Fruquintinib and new combinations of treatments in both molecularly selected and in all-comers patients represent a potential option for heavily pretreated mCRC patients.

Declaration of interest

A Santoro reports honoraria and advisory board consultancy from BMS (Bristol Myers Squibb), Servier, Gilead, Pfizer, Eisai, Bayer, and MSD (Merck Sharp and Dohme); speaker honoraria from Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD (all outside the submitted work). The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

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 receiving research funding from HutchMed, Enterome, Guardant Health, Natera, Eisai; and being on the Advisory Board of HutchMed, Takeda, Illumina, Personalis. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.