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

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-naive patients received selumetinib (50, 75, 100mg 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 75mg plus gemcitabine/cisplatin (n = 10); selumetinib 50mg plus gemcitabine/carboplatin (n = 9); selumetinib 50, 75 or 100mg plus pemetrexed/carboplatin (n = 21); selumetinib 75mg 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 75mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75mg 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 75mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.