1242P - A Phase I study of the MEK1/2 inhibitor selumetinib in combination with first-line chemotherapy regimens for NSCLC

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Non-Small-Cell Lung Cancer, Metastatic
Presenter Emma Dean
Citation Annals of Oncology (2014) 25 (suppl_4): iv426-iv470. 10.1093/annonc/mdu349
Authors E. Dean1, N. Steele2, H. Arkenau3, F.H. Blackhall4, N.M. Haris5, C. Lindsay6, M. Saggese3, R. Califano7, A. Greystoke5, M. Voskoboynik3, D. Ghiorghiu8, A. Dymond9, I. Smith10, R. Plummer5
  • 1Clinical Trials Unit, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 2Medical Oncology, The Beatson West of Scotland Cancer Centre, Glasgow/GB
  • 3Oncology, Sarah Cannon Research Institute, London/GB
  • 4Department Of Medical Oncology, The Christie NHS Foundation Trust, Manchester/GB
  • 5Northern Centre For Cancer Care, Freeman Hospital, Newcastle upon Tyne/GB
  • 6Medical Oncology, Beatson West of Scotland Cancer Centre Gartnavel General Hospital, G12 0YN - Glasgow/GB
  • 7Department Of Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 8Imed Oncology, AstraZeneca, Macclesfield/GB
  • 9Global Clinical Development, AstraZeneca, Macclesfield/GB
  • 10Gmed Oncology New Opps, AstraZeneca, Macclesfield/GB

Abstract

Aim

Selumetinib (AZD6244, ARRY-142886) is an orally available MEK1/2 inhibitor with activity in combination with docetaxel in the second-line setting for KRAS mutation-positive advanced NSCLC. This Phase I study assessed the safety, tolerability, recommended Phase II combination dose (RP2D), pharmacokinetics (PK) and preliminary efficacy of selumetinib in combination with first-line chemotherapy regimens in unselected patients (pts) with advanced/metastatic NSCLC.

Methods

This open-label, multicentre study (NCT01809210) enrolled pts into dose-finding cohorts of orally administered selumetinib (50 mg bid [sel50] to 75 mg bid [sel75]) in combination with standard doses of gemcitabine (gem) or pemetrexed (pem) plus cisplatin (cis) or carboplatin (carb). Each dose cohort consisted of at least 3 and up to 6 evaluable pts. On completion of chemotherapy, pts had the option of maintenance selumetinib.

Results

As of 20 April 2014, 17 pts were evaluable (8 female; median age 63; 8 adenocarcinoma, 8 squamous, 1 non-squamous histology) to the following treatment cohorts: gem + cis + sel50, n = 3; gem + cis + sel75, n = 1; gem + carb + sel50, n = 7; pem + carb + sel50, n = 2; pem + carb + sel75, n = 4. Median total selumetinib exposure was 78 days (range 16–224). The majority of adverse events (AEs) were CTCAE Grade 1 or 2. Selumetinib-related AEs of Grade ≥3 were seen in 7 pts: gem + cis + sel50, 0/3; gem + cis + sel75, 0/1; gem + carb + sel50, 6/7; pem + carb + sel50, 1/2; pem + carb + sel75, 0/4. One DLT of thrombocytopenia was observed in the gem + carb + sel50 cohort. Combination therapy did not appear to show any marked effect on the PK profile of selumetinib. Across all cohorts, partial responses were seen in 6/17 (35%) pts evaluable for response, and 4/17 (24%) had stable disease.

Conclusions

The AE profile of selumetinib in combination with these chemotherapy regimens for NSCLC was consistent with the known profiles. Two tolerated dose regimens have been confirmed: gem + cis + sel50 and pem + carb + sel50. The activity of platinum-based regimens seems to be preserved in this unselected population. Dose escalation and expansion is ongoing; updated data including the RP2D and PK will be presented.

Disclosure

F. Blackhall: Research funding: AstraZeneca; R. Califano: Consultancy/honoraria: Roche, Lilly, Boehringer Ingelheim, Pfizer; D. Ghiorghiu: Employment and stock ownership: AstraZeneca; A. Dymond: Employment and stock ownership: AstraZeneca; I. Smith: Employment and stock ownership: AstraZeneca R. Plummer: Consultancy agreement (no remuneration to date): AstraZeneca. Institutional trial costs. All other authors have declared no conflicts of interest.