AstraZeneca’s selumetinib sparks oncologist reservations on Phase III efficacy given challenges targeting KRAS mutant NSCLC

14 Apr 2016

AstraZeneca’s (LON:AZN) AZD6244 (selumetinib) has oncologists reserved about Phase III efficacy predictions in KRAS-mutant non-small-cell lung cancer (NSCLC) due to past failures in this patient population.

Whilst Phase II results appeared promising, other experts questioned the magnitude of benefit, noting that it was relatively modest. However, all experts agreed there is mechanistic rationale for targeting this population with selumetinib.

Selumetinib is under investigation in a Phase III trial (NCT01933932) in combination with docetaxel in 500 patients with KRAS-mutant NSCLC, according to The primary completion date is estimated to be June 2016.

Selumetinib is an oral small-molecule MEK inhibitor; MEK is a key protein kinase in the RAS/RAF/MEK/ERK pathway, which regulates several key cellular activities. Inappropriate activation of this pathway has been shown to occur in many cancers, in particular through mutations in BRAF, KRAS and NRAS genes, according to company information. Selumetinib was discovered by Array Biopharma (NASDAQ:ARRY) before being licensed to AstraZeneca.

KRAS mutations are found in approximately one quarter of patients with NSCLC adenocarcinoma histology, said Dr Pasi Janne, director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, and principal investigator in the Phase II selumetinib trial. Unlike EGFR- and ALK-mutant NSCLC patients, KRAS has not seen the development of a successful targeted therapy, he explained.

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