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

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.

MEK inhibitors for the treatment of non-small cell lung cancer

“…Fifty-five patients were enrolled. Most frequent adverse events (AEs) were fatigue, nausea, diarrhea, and vomiting (Table 3 ) [ 50 ]. Another phase I study evaluated the safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as a second-line therapy for Japanese patients with advanced NSCLC.…”

Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer

“…MEKis are in diverse phases of clinical development, including trametinib, which has been approved in combination with the BRAF inhibitor dabrafenib for the treatment of a subset of NSCLC with BRAF V600E mutation (Friday and Adjei, 2008; Greystoke et al, 2017; Planchard et al., 2017; Stinchcombe and Johnson, 2014). However, despite promising co-clinical studies in mouse models and clinical trials (Chen et al, 2012; Greystoke et al, 2017; Planchard et al, 2017), resistance to MEKis is often observed (Soria et al, 2017).…”

“…MEKis are in diverse phases of clinical development, including trametinib, which has been approved in combination with the BRAF inhibitor dabrafenib for the treatment of a subset of NSCLC with BRAF V600E mutation (Friday and Adjei, 2008; Greystoke et al, 2017; Planchard et al., 2017; Stinchcombe and Johnson, 2014). However, despite promising co-clinical studies in mouse models and clinical trials (Chen et al, 2012; Greystoke et al, 2017; Planchard et al, 2017), resistance to MEKis is often observed (Soria et al, 2017). This resistance has been attributed to the heterogeneity of the tumor (Jamal-Hanjani et al, 2017; Swanton and Govindan, 2016) and to intrinsic and acquired resistance from both cancer cells and the tumor microenvironment (Ebert et al, 2016; Manchado et al, 2016).…”

Novel Small Molecule MEK Inhibitor URML-3881 Enhances Cisplatin Sensitivity in Clear Cell Ovarian Cancer

“…An agent that can increase chemotherapy susceptibility in this resistant disease has the potential to substantially prolong patients' lives and enhance cure rates. The combination of MEK inhibition with URML-3881 and cisplatin was well tolerated by animals, mirroring early phase clinical trials in patients that have reported an acceptable side effect profile for combined MEK inhibition and chemotherapy [20], [31].…”