Selumetinib (AZD6244, ARRY-142886), an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life, has shown clinical activity in a Phase II study of patients (pts) with KRAS-mutant advanced NSCLC in the second-line setting. This study investigated selumetinib plus platinum doublet chemotherapy as first-line treatment for pts with advanced/metastatic NSCLC, unselected for KRAS mutation status.
This Phase I, open-label, multicentre study (NCT01809210) enrolled pts into dose-finding cohorts of selumetinib (50 [sel50], 75 [sel75] or 100 [sel100] mg BID PO) plus standard doses of gemcitabine (gem) or pemetrexed (pem) plus cisplatin (cis) or carboplatin (carb). Escalation cohorts comprised 3–6 evaluable pts, and optional expansion cohorts (n ≤ 12) further assessed safety. For each dose regimen, safety, tolerability, pharmacokinetics (PK), and preliminary efficacy were assessed to select recommended Phase II doses (RP2D).
In total, 55 pts were treated (26 female; median age 62 years; 38 adenocarcinoma, 13 squamous) in seven cohorts: C1/C3 sel50/75 + gem + cis, n = 3/7; C2 sel50 + gem + carb, n = 9; C4/5/7 sel50/75/100 + pem + carb, n = 3/6/12; C6 sel75 + pem + cis, n = 15. Median total selumetinib exposure was 84 days (range 4–266). Most frequent AEs were fatigue, nausea, diarrhoea and vomiting. Grade (G) ≥3 selumetinib-related AEs were seen in 30 (55%) pts. Dose-limiting toxicities (DLTs; all n = 1) were reported in: C2, G4 thrombocytopenia/epistaxis and G4 thrombocytopenia; C3, G4 anaemia; C6, G3 lethargy; C7, G4 febrile neutropenia. Nine pts died during the study; none were causally related to selumetinib. Selumetinib PK was similar across the combination regimens. Of the 55 patients treated, confirmed partial responses were observed in 11 (20%) pts and unconfirmed in 9 (16%) pts, and 21 (38%) pts had stable disease (≥6 weeks).
In the first-line setting, RP2Ds were identified as selumetinib 75 mg BID plus standard doses of pem + carb or pem + cis, which were tolerated with AE profiles consistent with the individual agents. RP2Ds were not determined for gem containing regimens. Preliminary anti-tumour activity was observed across all cohorts. We thank Stuart Hossack of Covance who provided analysis and interpretation of the pharmacokinetic data.
Clinical trial identification
NCT01809210 - Clinical trial identification release date: March 8, 2013
Legal entity responsible for the study
E. Dean: The Christie NHS Foundation Trust received income from the commercial sponsor AstraZeneca for the conduct of this study. F. Blackhall, R. Califano: Personal fees from Astrazeneca, outside of the submitted work. R. Plummer: Clinical research costs from AstraZeneca and personal fees from AstraZeneca, outside of the submitted work. Y.J. Summers, A. Greystoke: Personal fees from AstraZeneca, outside the submitted work. D. Ghiorghiu, A. Dymond: AstraZeneca employee and shareholder. K. So: AstraZeneca employee. All other authors have declared no conflicts of interest.