LBA47_PR - Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-...

Date 10 October 2016
Event ESMO 2016 Congress
Session NSCLC, metastatic 2
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Presenter Pasi Jänne
Citation Annals of Oncology (2016) 27 (6): 1-36. 10.1093/annonc/mdw435
Authors 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, MA 02215 - Boston/US
  • 2Department Of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam/NL
  • 3Multidisciplinary Oncology And Therapeutic Innovations Department, Aix Marseille University APHM, Marseille/FR
  • 4Department Of Medical Oncology, Hospital Clinico Carlos Haya, Málaga/ES
  • 5Pulmonology Department, Toulouse University Hospital, Toulouse/FR
  • 6Division Of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia/IT
  • 7Department Of Medicine, Pavlov Medical University, St. Petersburg/RU
  • 8Medical Oncology, Manchester University and The Christie Hospital NHS Foundation Trust, Manchester/GB
  • 9Department Of Internal Medicine, Center For Integrated Oncology, University Hospital of Cologne, Cologne/DE
  • 10Medical Oncology Department, University Hospital Ramon Y Cajal, Madrid/ES
  • 11Department For Clinical And Pre-clinical Trials, Petrov Research Institute of Oncology, St. Petersburg/RU
  • 12Global Medicines Development, Oncology, AstraZeneca, Cambridge/GB
  • 13Oncology, AstraZeneca, Macclesfield/GB
  • 14Cancer Biosciences, AstraZeneca, Cambridge/GB
  • 15Personalised Healthcare And Biomarkers, Imed, AstraZeneca, Cambridge/GB
  • 16Innovative Medicines, AstraZeneca, Cambridge/GB
  • 17Biostatistics And Information Sciences, AstraZeneca, Cambridge/GB
  • 18Global Medicines Development, AstraZeneca, Gaithersburg/US
  • 19Respiratory Oncology Unit, Department Of Respiraory Diseases, University Hospital KU Leuven, Leuven/BE

Abstract

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

Funding

AstraZeneca

Disclosure

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.