SELECT-2: a phase II, double-blind, randomized, placebo-controlled study to assess the efficacy of selumetinib plus docetaxel as a second-line treatment of patients with advanced or metastatic non-small-cell lung cancer

J-C Soria, A Fülöp, C Maciel, J R Fischer, G Girotto, S Lago, E Smit, G Ostoros, W E E Eberhardt, P Lishkovska, S Lovick, G Mariani, A McKeown, E Kilgour, P Smith, K Bowen, A Kohlmann, D J Carlile, P A Jänne, J-C Soria, A Fülöp, C Maciel, J R Fischer, G Girotto, S Lago, E Smit, G Ostoros, W E E Eberhardt, P Lishkovska, S Lovick, G Mariani, A McKeown, E Kilgour, P Smith, K Bowen, A Kohlmann, D J Carlile, P A Jänne

Abstract

Background: Combination of selumetinib plus docetaxel provided clinical benefit in a previous phase II trial for patients with KRAS-mutant advanced non-small-cell lung cancer (NSCLC). The phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC.

Patients and methods: Patients who had disease progression after first-line anti-cancer therapy were randomized (2 : 2 : 1) to selumetinib 75 mg b.i.d. plus docetaxel 60 or 75 mg/m2 (SEL + DOC 60; SEL + DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO + DOC 75). Patients were initially enrolled independently of KRAS mutation status, but the protocol was amended to include only patients with centrally confirmed KRAS wild-type NSCLC. Primary end point was progression-free survival (PFS; RECIST 1.1); statistical analyses compared each selumetinib group with PBO + DOC 75 for KRAS wild-type and overall (KRAS mutant or wild-type) populations.

Results: A total of 212 patients were randomized; 69% were KRAS wild-type. There were no statistically significant improvements in PFS or overall survival for overall or KRAS wild-type populations in either selumetinib group compared with PBO + DOC 75. Overall population median PFS for SEL + DOC 60, SEL + DOC 75 compared with PBO + DOC 75 was 3.0, 4.2, and 4.3 months, HRs: 1.12 (90% CI: 0.8, 1.61) and 0.92 (90% CI: 0.65, 1.31), respectively. In the overall population, a higher objective response rate (ORR; investigator assessed) was observed for SEL + DOC 75 (33%) compared with PBO + DOC 75 (14%); odds ratio: 3.26 (90% CI: 1.47, 7.95). Overall the tolerability profile of SEL + DOC was consistent with historical data, without new or unexpected safety concerns identified.

Conclusion: The primary end point (PFS) was not met. The higher ORR with SEL + DOC 75 did not translate into prolonged PFS for the overall or KRAS wild-type patient populations. No clinical benefit was observed with SEL + DOC in KRAS wild-type patients compared with docetaxel alone. No unexpected safety concerns were reported.

Trial identifier: Clinicaltrials.gov NCT01750281.

Keywords: KRAS; MEK1/2; advanced non-small-cell lung cancer (NSCLC); docetaxel; metastatic disease; selumetinib.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Randomization and treatment. Data cut-off 27 January 2016. aInformed consent received. bAny reason not specifically recorded.
Figure 2.
Figure 2.
Kaplan–Meier estimates of progression-free survival for the overall population (A) and the KRAS wild-type population (B).
Figure 3.
Figure 3.
Kaplan–Meier estimates of overall survival for the overall population (A) and the KRAS wild-type population (B).
Figure 4.
Figure 4.
Best change in tumour size and associated duration of response for the SEL + DOC 60 (A), SEL + DOC 75 (B) and PBO + DOC 75 (C) cohorts.

References

    1. Yeh TC, Marsh V, Bernat BA. et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 2007; 13(5): 1576–1583.
    1. Banerji U, Camidge DR, Verheul HM. et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 2010; 16(5): 1613–1623.
    1. Denton CL, Gustafson DL.. Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol 2011; 67(2): 349–360.
    1. Roberts PJ, Stinchcombe TE.. KRAS mutation: should we test for it, and does it matter? J Clin Oncol 2013; 31(8): 1112–1121.
    1. Davies BR, Logie A, McKay JS. et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 2007; 6(8): 2209–2219.
    1. Hatzivassiliou G, Song K, Yen I. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464(7287): 431–435.
    1. Dombi E, Baldwin A, Marcus LJ. et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 2016; 375(26): 2550–2560.
    1. Jänne PA, Shaw AT, Pereira JR. et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013; 14(1): 38–47.
    1. Farley J, Brady WE, Vathipadiekal V. et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013; 14(2): 134–140.
    1. Kelly K, Mazieres J, Leighl NB. et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial. J Clin Oncol 2013; 31(Suppl 15), Abstract 8027.
    1. Gandara D, Hiret S, Blumenschein G. et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial. J Clin Oncol 2013; 31(Suppl): 8028.
    1. Jänne PA, Heuvel MMvd, Barlesi F. et al. Effect of selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA 2017; 317(18): 1844–1853.
    1. Gandara DR, Leighl N, Delord JP. et al. A phase 1/1b study evaluating trametinib plus docetaxel or pemetrexed in patients with advanced non-small cell lung cancer. J Thorac Oncol 2017; 12(3): 556–566.
    1. Harvey V, Mouridsen H, Semiglazov V. et al. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006; 24(31): 4963–4970.
    1. Chappell WH, Steelman LS, Long JM. et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011; 2(3): 135–164.
    1. Dry JR, Pavey S, Pratilas CA. et al. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res 2010; 70(6): 2264–2273.
    1. Brant RG, Sharpe A, Liptrot T. et al. Clinically viable gene expression assays with potential for predicting benefit from MEK inhibitors. Clin Cancer Res 2017; 23(6): 1471–1480.
    1. Holderfield M, Deuker MM, McCormick F, McMahon M.. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 2014; 14(7): 455–467.
    1. Lito P, Saborowski A, Yue J. et al. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell 2014; 25(5): 697–710.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다