PMID- 34052705
OWN - NLM
STAT- MEDLINE
DCOM- 20210624
LR  - 20210624
IS  - 1872-8332 (Electronic)
IS  - 0169-5002 (Linking)
VI  - 157
DP  - 2021 Jul
TI  - A phase I study of binimetinib (MEK 162), a MEK inhibitor, plus carboplatin and 
      pemetrexed chemotherapy in non-squamous non-small cell lung cancer.
PG  - 21-29
LID - S0169-5002(21)00401-3 [pii]
LID - 10.1016/j.lungcan.2021.05.021 [doi]
AB  - INTRODUCTION: MEK inhibition is a potential therapeutic strategy in non-small 
      cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor 
      binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC 
      patients (NCT02185690). METHODS: A standard 3 + 3 dose-escalation design was 
      used. Binimetinib 30 mg BID (dose level 1 [DL1]) or 45 mg BID (dose level 2 
      [DL2]) was given with standard doses of carboplatin and pemetrexed using an 
      intermittent dosing schedule. The primary outcome was determination of the 
      recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes 
      included efficacy, pharmacokinetics, and an exploratory analysis of response 
      based on mutation subtype. RESULTS: Thirteen patients (6 DL1, 7 DL2) were 
      enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg 
      BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting 
      toxicities in 2 patients at DL2. Twelve patients were evaluated for response, 
      with an investigator-assessed objective response rate (ORR) of 50% (95% CI 
      21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% 
      (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% 
      CI 2.6 months-NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 
      19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory 
      analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 
      25% in KRAS/NRAS wild-type patients. In MAP2K1-mutated patients, the ORR was 
      42.8%. CONCLUSION: The addition of binimetinib to carboplatin and pemetrexed 
      appears to have manageable toxicity with evidence of activity in advanced 
      non-squamous NSCLC.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Fung, A S
AU  - Fung AS
AD  - Department of Oncology, Queen's University, Canada; Princess Margaret Cancer 
      Centre, University Health Network, Canada.
FAU - Graham, D M
AU  - Graham DM
AD  - Princess Margaret Cancer Centre, University Health Network, Canada; Division of 
      Medical Oncology, University of Toronto, Canada; The Christie NHSFoundation 
      Trust, Manchester, UK.
FAU - Chen, E X
AU  - Chen EX
AD  - Princess Margaret Cancer Centre, University Health Network, Canada; Division of 
      Medical Oncology, University of Toronto, Canada.
FAU - Stockley, T L
AU  - Stockley TL
AD  - Division of Clinical Laboratory Genetics, University Health Network, Canada; 
      Department of Laboratory Medicine and Pathobiology, University of Toronto, 
      Canada; Advanced Molecular Diagnostics Laboratory, University Health Network, 
      Canada.
FAU - Zhang, T
AU  - Zhang T
AD  - Division of Clinical Laboratory Genetics, University Health Network, Canada; 
      Advanced Molecular Diagnostics Laboratory, University Health Network, Canada.
FAU - Le, L W
AU  - Le LW
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Albaba, H
AU  - Albaba H
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Pisters, K M
AU  - Pisters KM
AD  - Princess Margaret Cancer Centre, University Health Network, Canada; MD Anderson 
      Cancer Centre, Houston, TX, United States.
FAU - Bradbury, P A
AU  - Bradbury PA
AD  - Princess Margaret Cancer Centre, University Health Network, Canada; Division of 
      Medical Oncology, University of Toronto, Canada.
FAU - Trinkaus, M
AU  - Trinkaus M
AD  - Division of Medical Oncology, University of Toronto, Canada; Markham Stouffville 
      Hospital, Markham, Canada.
FAU - Chan, M
AU  - Chan M
AD  - Division of Medical Oncology, University of Toronto, Canada; Trillium Health 
      Partners, Mississauga, Canada.
FAU - Arif, S
AU  - Arif S
AD  - Division of Medical Oncology, University of Toronto, Canada; Trillium Health 
      Partners, Mississauga, Canada.
FAU - Zurawska, U
AU  - Zurawska U
AD  - Division of Medical Oncology, University of Toronto, Canada; St. Joseph's Health 
      Centre, Toronto, Canada.
FAU - Rothenstein, J
AU  - Rothenstein J
AD  - Division of Medical Oncology, University of Toronto, Canada; RS McLaughlin Durham 
      Cancer Centre, Oshawa, Canada.
FAU - Zawisza, D
AU  - Zawisza D
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Effendi, S
AU  - Effendi S
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Gill, S
AU  - Gill S
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Sawczak, M
AU  - Sawczak M
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Law, J H
AU  - Law JH
AD  - Princess Margaret Cancer Centre, University Health Network, Canada.
FAU - Leighl, N B
AU  - Leighl NB
AD  - Princess Margaret Cancer Centre, University Health Network, Canada; Division of 
      Medical Oncology, University of Toronto, Canada. Electronic address: 
      Natasha.Leighl@uhn.ca.
LA  - eng
SI  - ClinicalTrials.gov/NCT02185690
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210524
PL  - Ireland
TA  - Lung Cancer
JT  - Lung cancer (Amsterdam, Netherlands)
JID - 8800805
RN  - 0 (Benzimidazoles)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 181R97MR71 (binimetinib)
RN  - BG3F62OND5 (Carboplatin)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Benzimidazoles
MH  - Carboplatin/therapeutic use
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - Humans
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - Mitogen-Activated Protein Kinase Kinases/therapeutic use
MH  - Pemetrexed/therapeutic use
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Binimetinib
OT  - Carboplatin
OT  - NSCLC
OT  - Pemetrexed
OT  - Phase I
EDAT- 2021/05/31 06:00
MHDA- 2021/06/25 06:00
CRDT- 2021/05/30 20:58
PHST- 2021/03/07 00:00 [received]
PHST- 2021/05/06 00:00 [revised]
PHST- 2021/05/11 00:00 [accepted]
PHST- 2021/05/31 06:00 [pubmed]
PHST- 2021/06/25 06:00 [medline]
PHST- 2021/05/30 20:58 [entrez]
AID - S0169-5002(21)00401-3 [pii]
AID - 10.1016/j.lungcan.2021.05.021 [doi]
PST - ppublish
SO  - Lung Cancer. 2021 Jul;157:21-29. doi: 10.1016/j.lungcan.2021.05.021. Epub 2021 
      May 24.