Investigational drugs for head and neck cancer

ABSTRACT

Introduction: In the treatment of advanced/metastatic head and neck cancer (HNC), resistance to chemotherapy and to anti-EGFR agents remains a major issue, and new molecular drugs are eagerly awaited. Over the last decade, knowledge of the genetic landscape of HNC has rapidly grown. However, no tailored therapeutic intervention targeting HNC molecular abnormalities is currently available outside from clinical trials.

Areas covered: In this review, the authors analyze new drugs in the HNC setting which have been investigated in recently published trials or are currently being investigated. The article excludes strategies directed towards the EGFR pathway and antivascular agents.

Expert opinion: Agents acting on the PI3K axis have a strong biological rationale and show the preliminary signs of activity, in particular when combined with other agents. There is limited clinical data of the other discussed pathways; the CMET/HGF pathway as a possible modulator of anti-EGFR drug sensitivity and agents directed towards MEK, WEE-1, NOTCH represent new interesting approaches to HNC. It is of the utmost importance to try and incorporate the molecular dissection of the tumor profiles in clinical trials with such agents. Moreover, the mutational status of other cross-talking pathways should be assessed, since potential resistance mechanisms can be recognized and possibly overcome by a careful selection of patients and combination regimens. Immunotherapy represents a growing field in HNC and its wider application will impact on future therapeutic strategies, including the association with chemotherapy, targeted agents and radiation.

KEYWORDS:

• HDAC
• head and neck cancer
• HGF/CMET
• immunotherapy
• MEK
• NOTCH
• PI3K/AKT/mTOR/PTEN pathway
• proteasome
• WEE1 inhibitors

Article highlights

• In the era of targeted therapies, cetuximab (an anti-EGFR agent) remains the only biological agent approved by the regulatory agencies for the treatment of head and neck cancer (HNC). Nevertheless, a comprehensive understanding of cetuximab-resistance mechanisms is a major issue significantly impacting on the HNC patients’ outcome.

• The main genome-wide sequencing studies have identified the genetic hallmark of HNC showing them as difficultly druggable tumors due to a very high mutations’ rate in tumor suppressor genes (TSGs). Restoring a loss of function in TSGs is much more difficult than inhibiting the increased activity resulting from a gain-of-function in oncogenes’ mutations. Despite this, all well-known pathways and molecular mechanisms of HNC might be new potential therapeutic targets.

• All reported investigational drugs (ID) have currently showed a limited activity in HNC, possibly due also to their frequent use in heavily pretreated advanced patients and their use in molecularly unselected diseases. A new chance to maximize IDs efficacy may be to study these drugs in earlier settings, as suggested by most promising results of window trials described, and/or in combination with other therapies, with attention to possible synergic toxicities.

• PI3K inhibitors have a strong biological rationale showing also preliminary signs of activity, in particular when combined with other agents. A careful selection of patients, molecular profile, and combination regimens could offer the best therapeutic approach.

• Only few clinical data exist about other pathways: drugs interacting with the CMET/HGF pathway as possible modulator of anti-EGFR drug sensitivity and agents directed toward MEK, WEE-1, NOTCH are the most intriguing therapies. Immunotherapy will be more broadly used, alone or in combination with other therapeutic strategies, both in the curative and in recurrent/metastatic setting.

This box summarizes key points contained in the article.

Acknowledgments

Editorial assistance was provided by Luca Giacomelli, of the Fondazione IRCCS Istituto Nazionale Tumori.

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.