Selumetinib for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seem to remain ‘undruggable’, with any effective targeted therapy approved at the moment. The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supportive of KRAS testing in clinical practice of NSCLC therapy.

Areas covered: A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone. Disappointing data emerged from the next phase III trial in which the addition of selumetinib to docetaxel in patients with advanced KRAS mutant lung cancer did not improve survival or show clinical benefit.

Expert opinion: Promising strategies against this common mutation are under evaluation in clinical trials. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents, by simultaneous inhibition of the RAS–RAF–MEK–MAPK pathway. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors.

KEYWORDS:

• KRAS
• MEK-inhibitors
• non-small cell lung cancer
• selumetinib
• targeted therapy

Article highlights

• KRAS-mutant lung cancer is the largest genomically defined subset of lung cancer where no affective targeted therapy is available.

• The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supporting the KRAS testing in clinical practice of NSCLC therapy.

• A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone.

• In a phase III trial the addition of selumetinib to docetaxel in KRAS-mutant NSCLC did not provide a clinical benefit in terms of improving PFS or OS.

• Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumour agents by simultaneous inhibition of the RAS–RAF–MEK–MAPK pathway.

This box summarizes key points contained in the article.

Declaration of interest

C Gridelli has received honoraria as speaker bureau and advisory board member for Bristol Myers Squibb, MSD, Pfizer, Roche, Novartis, Astra Zeneca, Eli Lilly and Celgene. 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.

Additional information

Funding

This paper was not funded.