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Clinical Trial
. 2017 Sep 26;117(7):938-946.
doi: 10.1038/bjc.2017.271. Epub 2017 Aug 24.

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

Alastair Greystoke  1 , Nicola Steele  2 , Hendrik-Tobias Arkenau  3   4 , Fiona Blackhall  5 , Noor Md Haris  1 , Colin R Lindsay  2 , Raffaele Califano  5 , Mark Voskoboynik  3 , Yvonne Summers  5 , Karen So  6 , Dana Ghiorghiu  6 , Angela W Dymond  7 , Stuart Hossack  8 , Ruth Plummer  1 , Emma Dean  5
Affiliations
Clinical Trial

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting

Alastair Greystoke et al. Br J Cancer. .

Abstract

Background: We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer.

Methods: In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses.

Results: Fifty-five patients received treatment: selumetinib 50 or 75 mg plus gemcitabine/cisplatin (n=10); selumetinib 50 mg plus gemcitabine/carboplatin (n=9); selumetinib 50, 75 or 100 mg plus pemetrexed/carboplatin (n=21); selumetinib 75 mg plus pemetrexed/cisplatin (n=15). Most frequent adverse events (AEs) were fatigue, nausea, diarrhoea and vomiting. Grade ⩾3 selumetinib-related AEs were reported in 30 (55%) patients. Dose-limiting toxicities (all n=1) were Grade 4 anaemia (selumetinib 75 mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50 mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100 mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75 mg plus pemetrexed/cisplatin). Partial responses were confirmed in 11 (20%) and unconfirmed in 9 (16%) patients.

Conclusions: Standard doses of pemetrexed/carboplatin or pemetrexed/cisplatin were tolerated with selumetinib 75 mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.

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Conflict of interest statement

AG received consultancy fees from AstraZeneca. KS, DG and AWD are employees of AstraZeneca, and DG and AWD hold stock options. FB received a grant and personal fees from, and is a Board Member for AstraZeneca. NS has received travel costs from AstraZeneca for her attendance at AstraZeneca-funded meetings. RC, RP and YS have received honorarium for advisory boards from AstraZeneca. H-TA, NMD, CRL, SH and MV have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Dose-escalation cohorts. *Includes patients from expansion cohort, after selumetinib 75 mg BID dose was declared tolerated in combination with pemetrexed and cisplatin.
Figure 2
Figure 2
Scatter plots of selumetinib (A–C) and N-desmethyl selumetinib (D–E) PK parameters (PK analysis set). AUCT = area under the plasma concentration time curve in the dosing interval; Carb = carboplatin; Css,max = maximum observed plasma concentration at steady state; Cis = cisplatin; CL/F = apparent oral plasma clearance; Gem = gemcitabine; Pem = pemetrexed; Sel = selumetinib.
Figure 3
Figure 3
Best percentage change in tumour size. Abbreviations: carb=carboplatin; cis=cisplatin; gem=gemcitabine; pem=pemetrexed; sel=selumetinib. n=47. Eight patients were excluded due to incomplete post-baseline assessments of tumour response. Best change in target lesion size is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. *Patients with detected KRAS mutation.
See this image and copyright information in PMC

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