Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation

ABSTRACT

Introduction

RAS-RAF-MEK-ERK signaling is implicated in tumor development by promoting cell proliferation and other cancer hallmarks. MEK1/2 kinases are up-regulated in the majority of human cancers due to activation of tyrosine kinase receptors, RAS proteins, BRAF kinase, or some other members of the MAPK pathway. Targeting of MEK1/2 kinases may counterbalance cancer progression.

Areas covered

The authors analyze the scientific publications relevant to selumetinib (AZD6244, ARRY-142886) systematically and provide their expert opinion.

Expert opinion

Selumetinib is an oral selective allosteric inhibitor of MEK1 and MEK2 kinases. Single-agent selumetinib is usually administered in hydrogen sulfate capsules 75 mg twice a day; combination with other therapeutic compounds may or may not require reduced dosing of this drug. The established dose for pediatric patients is 25 mg per square meter twice a day. Selumetinib was extensively evaluated in non-small cell lung cancer (NSCLC) patients. Studies utilizing this drug as a monotherapy did not confirm its efficacy toward NSCLC. A phase II trial showed that the addition of selumetinib to docetaxel improved response rates and progression-free survival (PFS) in chemotherapy-pretreated KRAS-mutated NSCLC patients; however, a subsequent phase III study did not confirm these findings. There are several highly successful non-NSCLC selumetinib trials involving, e.g., patients with neurofibromatosis type 1 related tumors and children with low-grade BRAF-driven gliomas.

KEYWORDS:

• Selumetinib
• AZD6244
• lung cancer
• BRAF
• KRAS
• MEK
• neurofibromatosis
• glioma

Article highlights

• RAS-RAF-MEK-ERK pathway plays a key role in cancer development.

• Down-regulation of MEK1/2 kinase may lead to cessation of tumor growth in preclinical experiments and the clinical setting.

• Selumetinib (AZD6244, ARRY-142886) is an oral selective allosteric inhibitor of MEK1 and MEK2 kinases.

• The established dose of single-agent selumetinib is 75 mg twice a day for adult patients and 25 mg per square meter twice a day for children.

• Selumetinib monotherapy showed limited efficacy in non-small cell lung cancer (NSCLC) patients.

• A phase II trial demonstrated that the addition of selumetinib to docetaxel in the second-line treatment of KRAS-mutated NSCLC improves response rates and progression-free survival (PFS).

• A subsequent phase III trial did not confirm these results.

• Some clinical data indicate that the addition of selumetinib to the standard first-line NSCLC chemotherapy may improve tumor response rates.

• There are highly successful clinical trials on selumetinib in pediatric patients.

• Selumetinib demonstrates high clinical efficacy in neurofibromatosis type 1 associated plexiform neurofibromas and low-grade gliomas.

• Selumetinib renders significant benefit to pediatric patients with BRAF-driven low-grade gliomas.

Box 1. Drug summary box

Acknowledgments

We thank Dr A Whitehead of The University of Illinois College of Medicine for the critical reading of this 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

One referee declares having participated in the phase 3 trial of selumetinib + docetaxel as well as in ongoing trials with trametinib. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work has been supported by the Russian Science Foundation [grant 17-75-30027].