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SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the
Alastair Greystoke1, Nicola Steele2, Hendrik-Tobias Arkenau3,4
1Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK.
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.
Insights
Selumetinib combined with pemetrexed/carboplatin chemotherapy showed tolerability in advanced non-small cell lung cancer. However, selumetinib combined with gemcitabine-based chemotherapy was not well tolerated.
Area of Science:
- Oncology
- Pharmacology
Background:
- Investigated selumetinib, a MEK1/2 inhibitor, in combination with platinum-doublet chemotherapy.
- Focused on patients with advanced or metastatic non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To assess the safety and tolerability of selumetinib plus chemotherapy in NSCLC.
- To determine recommended Phase II doses for selumetinib in combination regimens.
Main Methods:
- Phase I, open-label study involving treatment-naïve NSCLC patients.
- Administered selumetinib at varying doses (50, 75, 100 mg BID) with gemcitabine or pemetrexed plus cisplatin or carboplatin.
- Monitored for adverse events and determined dose-limiting toxicities.
Main Results:
- Fifty-five patients received treatment across different combination arms.
- Common adverse events included fatigue, nausea, diarrhea, and vomiting.
- Grade ≥3 selumetinib-related adverse events occurred in 55% of patients; dose-limiting toxicities were observed in specific arms.
- Partial responses were confirmed in 20% and unconfirmed in 16% of patients.
Conclusions:
- Pemetrexed/carboplatin or pemetrexed/cisplatin chemotherapy was tolerated with selumetinib (75 mg BID).
- Selumetinib combined with gemcitabine-containing regimens was not tolerated in this patient population.
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