Investigational multitargeted kinase inhibitors in development for head and neck neoplasms

ABSTRACT

Introduction: Despite advances in treatment, head and neck squamous cell carcinoma (HNSCC) survival rates remain stagnant. Current treatment is associated with significant toxicities and includes chemotherapy, radiation, surgery, and few targeted treatments. Targeted treatments, epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, and immune checkpoint inhibitors, pembrolizumab and nivolumab, show improved toxicity profiles and modestly improved survival in select patients. An urgent need remains to identify novel targeted treatments for single-agent or combined therapy use.

Areas covered: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy.

Expert opinion: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance.

KEYWORDS:

• Head and neck cancer
• immunotherapy
• multitargeted kinase inhibitors
• squamous cell carcinoma
• tyrosine-kinase inhibitors

Article highlights

• Due to an incomplete understanding of treatment resistance and the heterogeneity of HNSCC tumors, current targeted therapies, such as the EGFR targeting monoclonal antibody, cetuximab, have not significantly improved treatment outcomes of HNSCC.

• Multi-targeted kinase inhibitors have been approved for use in various hematologic and other solid tumors, either as monotherapy or in combination with other therapies.

• Various multi-targeted tyrosine kinase inhibitors are in the early stages of development for HNSCC and include EGFR targeting agents, potential radiosensitizers which target PDGFR and VEGFR, BCR-ABL targeting agents, and potent anti-angiogenesis agents.

• While single agent m-TKIs have not been shown to improve clinical outcomes in HNSCC to date, m-TKIs with the most promising clinical results are being tested in combination with current FDA-approved therapies and/or in mutation-defined patient subgroups.

• Future work in this field requires the identification of predictive biomarkers to increase clinical responses to m-TKIs alone or in combination with standard of care including immune modulating agents.

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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 relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.