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.
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.
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.
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
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.