AstraZeneca announced results from the phase III SELECT-1 trial of the MEK 1/2 inhibitor, selumetinib, in combination with docetaxel chemotherapy as 2nd-line treatment in patients with KRAS mutation-positive (KRASm) locally-advanced or metastatic non-small cell lung cancer (NSCLC).

The results showed that the trial did not meet its primary endpoint of progression-free survival (PFS), and selumetinib did not have a significant effect on overall survival (OS). The adverse event profiles for selumetinib and docetaxel were consistent with those seen previously.

Sean Bohen, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said, “A randomised phase II trial showed promising activity of selumetinib in combination with docetaxel in patients with KRAS mutation-positive lung cancer. It is disappointing for patients that these results have not been confirmed in phase III. We expect to present data at a forthcoming medical meeting. We remain committed to further developing treatments in the lung cancer setting, such as our immunotherapy combinations and targeted EGFR treatments.”

SELECT-1 is an international trial with 510 randomised patients in over 200 centres. Patients received either selumetinib (75mg, orally, twice daily) or placebo in combination with docetaxel (intravenously, 75mg/m2, on day one of every 21-day cycle).

Selumetinib is being explored as a treatment option in registration-enabling studies in patients with differentiated thyroid cancer where the treatment received Orphan Drug designation, and patients with neurofibromatosis type 1, a genetic disorder that causes tumours to grow along nerve tissue.

KRAS is one of the most common genetic mutations in NSCLC, and is found in 30% of patients. Adenocarcinomas make up the majority of cases with KRAS mutations, which are less common in squamous cell NSCLC.2,3

KRAS mutations are associated with activation of the RAS-ERK signalling pathway, which drives tumour growth.

Selumetinib is an oral, potent and highly selective MEK 1/2 inhibitor. MEK 1/2 are critical components of the RAS-ERK pathway, activation of which is implicated in driving cancer growth and progression, including in patients with KRASm NSCLC.

AstraZeneca acquired exclusive worldwide rights to selumetinib from Array BioPharma Inc. in 2003.

In May 2016, selumetinib was granted Orphan Drug designation by the US Food and Drug Administration (FDA) for adjuvant treatment of patients with stage III or IV differentiated thyroid cancer (DTC), and AstraZeneca is committed to exploring its full potential, including in phase III trials in patients with DTC and in a US National Cancer Institute-sponsored phase II registration trial in patients with paediatric neurofibromatosis type 1.

SELECT-1 (NCT01933932) is a phase III, double-blind, randomised, placebo-controlled trial. It is designed to assess the efficacy and safety of selumetinib (75 mg twice daily, given orally on a continuous schedule) in combination with docetaxel (75 mg/m2 intravenously on day 1 of every 21-day cycle), compared with matched placebo in combination with docetaxel (same schedule) in 510 patients receiving 2nd-line treatment for KRASm locally advanced or metastatic NSCLC (stage IIIB-IV), confirmed by central testing of tumour tissue using the cobas KRAS Mutation Test (Roche Molecular Systems).

The primary endpoint is PFS, and secondary endpoints include OS, objective response rate (ORR), duration of response (DoR), and safety and tolerability.