Reference Detail

Ref Type Journal Article
PMID (23200175)
Authors Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P, Smith I, Crinò L
Title Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study.
Journal The Lancet. Oncology
Vol 14
Issue 1
Date 2013 Jan
URL
Abstract Text No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC.Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m(2) on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825.Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group).Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC.AstraZeneca.

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Molecular Profile Treatment Approach
KRAS Y40A MEK inhibitor (Pan)
KRAS D33E MEK inhibitor (Pan)
KRAS Q61L MEK inhibitor (Pan)
KRAS Q61H MEK inhibitor (Pan)
KRAS N116H MEK inhibitor (Pan)
KRAS V14I MEK inhibitor (Pan)
KRAS G60R MEK inhibitor (Pan)
KRAS E63K MEK inhibitor (Pan)
KRAS G13D MEK inhibitor (Pan)
KRAS A11_G12insGA MEK inhibitor (Pan)
KRAS Y32S MEK inhibitor (Pan)
KRAS K147E MEK inhibitor (Pan)
KRAS P34R MEK inhibitor (Pan)
KRAS G12V MEK inhibitor (Pan)
KRAS Q61E MEK inhibitor (Pan)
KRAS G12N MEK inhibitor (Pan)
KRAS P34L MEK inhibitor (Pan)
KRAS Q22K MEK inhibitor (Pan)
KRAS G12A MEK inhibitor (Pan)
KRAS Q22R MEK inhibitor (Pan)
KRAS F156L MEK inhibitor (Pan)
KRAS G12Y MEK inhibitor (Pan)
KRAS G12I MEK inhibitor (Pan)
KRAS D153V MEK inhibitor (Pan)
KRAS Q61R MEK inhibitor (Pan)
KRAS K5N MEK inhibitor (Pan)
KRAS G12L MEK inhibitor (Pan)
KRAS G13X MEK inhibitor (Pan)
KRAS G12F MEK inhibitor (Pan)
KRAS G13C MEK inhibitor (Pan)
KRAS A146T MEK inhibitor (Pan)
KRAS Q61P MEK inhibitor (Pan)
KRAS F28L MEK inhibitor (Pan)
KRAS Q22E MEK inhibitor (Pan)
KRAS T74P MEK inhibitor (Pan)
KRAS V14L MEK inhibitor (Pan)
KRAS A59G MEK inhibitor (Pan)
KRAS Y71H MEK inhibitor (Pan)
KRAS A146V MEK inhibitor (Pan)
KRAS E62K MEK inhibitor (Pan)
KRAS G12W MEK inhibitor (Pan)
KRAS L19F MEK inhibitor (Pan)
KRAS Q61X MEK inhibitor (Pan)
KRAS G10dup MEK inhibitor (Pan)
KRAS Q61K MEK inhibitor (Pan)
KRAS G12R MEK inhibitor (Pan)
KRAS G12D MEK inhibitor (Pan)
KRAS T58I MEK inhibitor (Pan)
KRAS G12S MEK inhibitor (Pan)
KRAS K117N MEK inhibitor (Pan)
KRAS G12C MEK inhibitor (Pan)
KRAS N116S MEK inhibitor (Pan)
KRAS C118S MEK inhibitor (Pan)
KRAS G12X MEK inhibitor (Pan)
KRAS Q61A MEK inhibitor (Pan)
KRAS G12E MEK inhibitor (Pan)
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS mutant non-small cell lung carcinoma no benefit Selumetinib + Docetaxel Phase III Actionable In a Phase II trial, Selumetinib (AZD6244) in combination with Taxotere (docetaxel) did not significantly improve median progression-free survival (3.9 vs 2.8 months), median overall survival (8.7 vs 7.9 months), and overall response rate (20.1% vs 13.7%) compared to placebo in KRAS-mutant non-small cell lung cancer patients (PMID: 28492898). 28492898
KRAS mutant non-small cell lung carcinoma no benefit Selumetinib + Docetaxel Phase II Actionable In a Phase II trial, Selumetinib (AZD6244) in combination with Taxotere (docetaxel) improved progression-free survival in KRAS-mutant non-small cell lung cancer patients (PMID: 23200175). 23200175