A PHASE I STUDY OF THE MEK1/2 INHIBITOR SELUMETINIB IN COMBINATION WITH FIRST-LINE CHEMOTHERAPY REGIMENS FOR NSCLC

E. Dean, N. Steele, H. Arkenau, Fiona Blackhall, N.M. Haris, C. Lindsay, M. Saggese, R. Califano, A. Greystoke, M. Voskoboynik, D. Ghiorghiu, A. Dymond, I. Smith, R. Plummer

Research output: Contribution to journalComment/debatepeer-review

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.
Original languageEnglish
Pages (from-to)434-435
JournalAnnals of Oncology
Volume25
Issue number4 abstract 1242P
Publication statusPublished - 2014

Keywords

  • selumetinib

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