Related Experiment Video
Updated: May 16, 2026
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre,
Pasi A Jänne1, Alice T Shaw, José Rodrigues Pereira
1Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. pjanne@partners.org
Background:
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.
Methods:
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.
Findings:
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).
Interpretation:
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.
Funding:
AstraZeneca.
Insights
This study investigated selumetinib plus docetaxel for KRAS-mutant non-small-cell lung cancer (NSCLC). The combination showed improved progression-free survival and objective response rates, warranting further investigation despite increased adverse events.
Area of Science:
- Oncology
- Pharmacology
Background:
- KRAS-mutant non-small-cell lung cancer (NSCLC) currently lacks targeted therapies.
- Selumetinib, a MEK1/MEK2 inhibitor, demonstrated preclinical synergy with docetaxel in KRAS-mutated cancers.
- A phase 2 trial was conducted to evaluate selumetinib combined with docetaxel in pre-treated advanced NSCLC patients with KRAS mutations.
Purpose of the Study:
- To assess the efficacy and safety of selumetinib plus docetaxel versus docetaxel alone in patients with previously treated advanced KRAS-mutant NSCLC.
- To determine the impact of selumetinib on overall survival and progression-free survival.
- To evaluate objective response rates and adverse events associated with the combination therapy.
Main Methods:
- A prospective, randomized, phase 2 trial was performed with 87 patients.
- Patients were assigned 1:1 to receive either oral selumetinib (75 mg twice daily) or placebo, with all patients receiving intravenous docetaxel (75 mg/m²).
- The primary endpoint was overall survival, with secondary endpoints including progression-free survival and objective response rate. Patients had advanced KRAS-mutant NSCLC and had failed first-line therapy.
Main Results:
- Median progression-free survival was significantly improved in the selumetinib group (5.3 months) compared to the placebo group (2.1 months) (p=0.014).
- Objective response rates were higher in the selumetinib group (37%) versus the placebo group (0%) (p<0.0001).
- While overall survival showed a trend favoring selumetinib (9.4 months vs 5.2 months), it did not reach statistical significance (p=0.21). Grade 3 or higher adverse events were more frequent in the selumetinib group (82% vs 67%).
Conclusions:
- Selumetinib plus docetaxel demonstrates promising efficacy in previously treated advanced KRAS-mutant NSCLC, particularly in improving progression-free survival and response rates.
- The combination therapy is associated with a higher incidence of adverse events compared to docetaxel alone.
- Further clinical investigation of selumetinib plus docetaxel is warranted for KRAS-mutant NSCLC.
More Related Videos
04:04Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
09:29Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016