LUGANO-COPENHAGEN – MEK inhibitor selumetinib in combination with docetaxel does not improve progression free or overall survival in individuals with KRAS-mutant non-small-cell lung cancer (NSCLC), according to data presented at the ESMO 2016 Congress in Copenhagen1.
“KRAS-mutant lung cancer is the largest genomically defined subset of lung cancer where we do not have effective targeted therapies,” said principal investigator Dr Pasi Jänne, from the Dana-Farber Cancer Institute in Boston, US.
Selumetinib inhibits an effector protein immediately downstream from KRAS, which was thought to turn off KRAS-mediated signalling in KRAS-mutant cancers.
An earlier phase II trial in KRAS-mutant NSCLC had shown significant improvements in progression-free survival and objective response rate in patients treated with selumetinib plus docetaxel compared to docetaxel alone.
In the phase III, double-blind, randomized SELECT-1 trial, 510 patients with KRAS-mutant non-small-cell lung cancer were randomized either to oral selumetinib (75mg, twice daily) plus intravenous docetaxel (75mg/m2 on day 1 of a 21 day-cycle), or docetaxel plus placebo.
At data cut-off, median progression-free survival was not significantly different between the selumetinib arm and placebo arm (3.9 months vs. 2.8 months, HR 0.93, p=0.44), nor was there a significant difference in median overall survival (8.7 months vs. 7.9 months, HR 1.05, p=0.64).
There was a trend towards a higher objective response rate in the selumetinib group compared to the placebo group (20.1% vs. 13.7%, OR 1.61, p=0.051).
Serious adverse events occurred more frequently in patients treated with the selumetinib plus docetaxel combination compared to placebo (49% vs. 32%), as did adverse events leading to hospitalisation (46% vs. 30%).
“The results of the phase III trial demonstrate that the addition of selumetinib to docetaxel, in patients with advanced KRAS mutant lung cancer, does not provide clinical benefit in terms of improving progression free or overall survival,” Jänne said.
“Hence it is not a treatment approach that should be adapted moving forward, and there remains a desperate need and an opportunity to develop new treatments for this subset of NSCLC patients.”
Commenting on the study, Dr Alex Adjei, director of the Early Cancer Therapeutics Program and Global Oncology at the Mayo Clinic in Rochester, US, said “Dr Jänne and colleagues should be congratulated for performing a well-designed genotype-driven trial, however the preclinical rationale for studying this combination specifically in KRAS mutant NSCLC was weak, at best.”
“Selumetinib and other MEK inhibitors are not effective in KRAS mutant NSCLC cell lines and, while there are preclinical data that demonstrate cytotoxic synergy between selumetinib and other MEK inhibitors combined with docetaxel in a number of tumor types, including NSCLC, such synergy is independent of KRAS status,” Adjei said.
“A randomized phase II trial of the combination of another MEK inhibitor, trametinib and docetaxel failed to show any difference in efficacy between KRAS mutant and wild-type NSCLC. Furthermore, the phase II study on which this phase III trial design was based had a very small sample size and historically, such small randomized phase II studies have led to negative phase III trials,” concluded Adjei.
Notes to Editors
LBA47_PR “Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial” will be presented by Prof Pasi Jänne during the Proffered Paper session, NSCLC, metastatic 2 on Monday, 10 October 2016, 09:15 to 10:15 CEST in Room Vienna.
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Abstract for LBA47_PR
Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial
P.A. Jänne1, M. van den Heuvel2, F. Barlesi3, M. Cobo4, J. Mazieres5, L. Crinò6, S. Orlov7, F. Blackhall8, J. Wolf9, P. Garrido10, A. Poltoratskiy11, G. Mariani12, D. Ghiorghiu12, E. Kilgour13, P. Smith14, A. Kohlmann15, D. Carlile16, D. Lawrence17, K. Bowen18, J.F. Vansteenkiste19
1Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA, 2Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands, 3Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University APHM, Marseille, France, 4Department of Medical Oncology, Hospital Clinico Carlos Haya, Málaga, Spain, 5Pulmonology Department, Toulouse University Hospital, Toulouse, France, 6Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy, 7Department of Medicine, Pavlov Medical University, St. Petersburg, Russian Federation, 8Medical Oncology, Manchester University and The Christie Hospital NHS Foundation Trust, Manchester, UK, 9Department of Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany, 10Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain, 11Department for Clinical and Pre-Clinical Trials, Petrov Research Institute of Oncology, St. Petersburg, Russian Federation, 12Global Medicines Development, Oncology, AstraZeneca, Cambridge, UK, 13Oncology, AstraZeneca, Macclesfield, UK, 14Cancer Biosciences, AstraZeneca, Cambridge, UK, 15Personalised Healthcare and Biomarkers, IMED, AstraZeneca, Cambridge, UK, 16Innovative Medicines, AstraZeneca, Cambridge, UK, 17Biostatistics and Information Sciences, AstraZeneca, Cambridge, UK, 18Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA, 19Respiratory Oncology Unit, Department of Respiraory Diseases, University Hospital KU Leuven, Leuven, Belgium
Background: KRAS-mutant (KRASm) NSCLC is the largest molecular genomic NSCLC subset. Selumetinib (SEL; AZD6244, ARRY-142886) is an oral, potent and selective MEK1/2 inhibitor with a short half-life. In a Phase II KRASm advanced NSCLC trial (n=87), 2L SEL + docetaxel (DOC) significantly improved PFS (median 5.3 vs 2.1 mo) and ORR (37 vs 0%), and numerically improved OS (median 9.4 vs 5.2 mo; primary endpoint) compared with DOC. SELECT-1 (NCT01933932), a Phase III, double-blind, randomised trial aimed to confirm the clinical benefit of SEL + DOC for pts with locally advanced or metastatic KRASm NSCLC.
Methods: Enrolment completed in January 2016 with 3323 pts screened at 202 sites in 25 countries. 510 pts with a centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to SEL 75 mg BID, PO + DOC 75 mg/m2 IV on day 1 of every 21-day cycle (n=254), or placebo (PBO) + DOC (n=256); pts also received prophylactic G-CSF. Primary objective was PFS by investigator assessment (RECIST 1.1). Secondary objectives included OS, ORR (RECIST 1.1) and safety and tolerability. The trial was powered to characterise differences in both PFS and OS.
Results: At data cut-off, 447 pts (88%) had progressed; 346 pts (68%) had died. Median PFS was 3.9 mo with SEL + DOC and 2.8 mo with PBO + DOC; HR for PFS was 0.93 (95% CI 0.77, 1.12; 2-sided p=0.44). Median OS was 8.7 mo with SEL + DOC and 7.9 mo with PBO + DOC (HR 1.05, 95% CI: 0.85, 1.30; 2-sided p=0.64). ORR was 20.1% with SEL + DOC and 13.7% with PBO + DOC (odds ratio: 1.61; 95% CI: 1.00, 2.62; 2-sided p=0.051). AEs (all causality) were reported by 99% and 95% pts in the SEL + DOC and PBO + DOC groups, respectively; ≥G3 AEs were more frequent in the SEL + DOC group (67 vs 45% pts). SAEs (49 vs 32%) and AEs leading to hospitalisation (46 vs 30%) were also more frequent in the SEL + DOC group than the PBO + DOC group. Mean (SD) actual dose intensity relative to intended dose intensity of DOC over 6 cycles was similar between groups: 86.7% (15.90) with SEL+DOC and 90.3% (15.01) with PBO + DOC.
Conclusions: SELECT-1 was the first prospective Phase III trial in KRASm NSCLC. SEL + DOC did not significantly improve PFS, OS or ORR vs PBO + DOC. The safety profile was consistent with historical data.
Clinical trial identification: NCT01933932 August 29, 2013
Legal entity responsible for the study: AstraZeneca
P. A. Jänne: Grants and fees from AstraZeneca. Fees from Roche and Chugai. Grant from Astellas. Fees from Merrimack, Ariad and Boehringer Ingelheim. Stock ownership in Gatekeeper Pharmaceuticals.
F. Barlesi: Participation in advisory board for AstraZeneca
J. Wolf: Personal fees and grants from MSD, Novartis, Pfizer and Roche. Personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Clovis.
P. Garrido: Fees and non-financial support from AstraZeneca, fees from Roche, Celgene, fees and non-financial support from Boeringher, fees from Pfizer, BMS and MSD, outside the submitted work.
G. Mariani: AstraZeneca full time employee.
D. Ghiorghiu, P. Smith, A. Kohlmann, K. Bowen: AstraZeneca employee and shareholder.
E. Kilgour: Employee of, and shareholder in, AstraZeneca.
D. Carlile: AstraZeneca Employee.
D. Lawrence: Employee of AstraZeneca during the conduct of the study.
J.F. Vansteenkiste: Receipt of grants/research supports: Astra Zeneca / Amgen Receipt of honoraria or consultation fees: BMS / Boehringer / MSD Medical lectures: Eli-Lilly / Novartis / Boehringer.
All other authors have declared no conflicts of interest.
Keywords: Phase III, selumetinib, non-small cell lung cancer (NSCLC), metastatic disease