The clinical application of fruquintinib on colorectal cancer

ABSTRACT

Introduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect.

Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed.

Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.

KEYWORDS:

• Fruquintinib
• EGFR
• VEGF
• VEGFR
• CRC

Article Highlights

• Chemical name:

• HMPL-013, chemical name is 6-(6,7-dimethoxyquinazolin-4-yloxy)-N,2-dimethyl benzofuran-3-carboxamide

• Mechanism of action: a highly selective long-term inhibitor of VEGFR (VEGFR1,2, and 3)

• Pharmacokinetics: Cmax is 2 h, bioavailability is about 100% with tissue distribution mainly in the gastrointestinal tract, liver, kidney, adrenal and adipose, T1/2 is 33.4 h.

• Indication: CRC, NCSLC, gastric cancer

• Route of administration: oral

• Dose: 5 mg/day on a 3-week-on/1-week-off treatment cycle

• Most frequent AEs: hypertension, skin reactions in the hands and feet, proteinuria, and diarrhea

• Clinical trials (detail in Table 1)：

  1. Phase 1: NCT01645215 (tumor), NCT02689752 (health), NCT01955304 (health), NCT03251378 (advanced solid tumor);

  2. Phase 1 and 2: NCT01975077 (CRC), NCT02415023 (Gastric cancer);

  3. Phase 2: NCT02196688 (CRC), NCT03684967 (lung cancer), NCT02976116 (NCSLC), NCT02590965 (NCSLC)

  4. Phase 3: NCT02314819 (CRC), NCT02691299 (NCSLC), NCT03223376 (advanced gastric cancer)

Acknowledgments

Thanks, Dr. Kelly Ann Koral (Department of Pathology, School of Medicine, University of Pittsburgh) for her careful revision on the writing of the manuscript.

Declaration of interest

The authors have no 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. Hutchison China MediTech Limited provided a scientific accuracy review at the request of the journal editor.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.