PMID- 30918950
OWN - NLM
STAT- MEDLINE
DCOM- 20200623
LR  - 20240229
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Print)
IS  - 0923-7534 (Linking)
VI  - 30
IP  - 7
DP  - 2019 Jul 1
TI  - Phase Ib study of atezolizumab combined with cobimetinib in patients with solid 
      tumors.
PG  - 1134-1142
LID - S0923-7534(19)31228-1 [pii]
LID - 10.1093/annonc/mdz113 [doi]
AB  - BACKGROUND: Preclinical evidence suggests that MEK inhibition promotes 
      accumulation and survival of intratumoral tumor-specific T cells and can 
      synergize with immune checkpoint inhibition. We investigated the safety and 
      clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed 
      cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid 
      tumors. PATIENTS AND METHODS: This phase I/Ib study treated PD-L1/PD-1-naive 
      patients with solid tumors in a dose-escalation stage and then in multiple, 
      indication-specific dose-expansion cohorts. In most patients, cobimetinib was 
      dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 
      800 mg intravenously every 2 weeks. The primary objectives were safety and 
      tolerability. Secondary end points included objective response rate, 
      progression-free survival, and overall survival. RESULTS: Between 27 December 
      2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 
      patients received >/=1 dose of atezolizumab, including 14 in the dose-escalation 
      cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal 
      cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; 
      n = 28), and other solid tumors (n = 16). The most common all-grade 
      treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and 
      fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. 
      One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 
      patients (15%) had AEs that led to discontinuation of cobimetinib and 
      atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients 
      (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite 
      instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with 
      NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases. 
      CONCLUSIONS: Atezolizumab plus cobimetinib had manageable safety and clinical 
      activity irrespective of KRAS/BRAF status. Although potential synergistic 
      activity was seen in mCRC, this was not confirmed in a subsequent phase III 
      study. CLINICALTRIALS.GOV IDENTIFIER: NCT01988896 (the investigators in the 
      NCT01988896 study are listed in the supplementary Appendix, available at Annals 
      of Oncology online).
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      European Society for Medical Oncology. All rights reserved. For permissions, 
      please email: journals.permissions@oup.com.
FAU - Hellmann, M D
AU  - Hellmann MD
AD  - Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering 
      Cancer Center, New York, USA. Electronic address: hellmanm@mskcc.org.
FAU - Kim, T-W
AU  - Kim TW
AD  - Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South 
      Korea.
FAU - Lee, C B
AU  - Lee CB
AD  - UNC Lineberger Comprehensive Cancer Center, Division of Hematology and Oncology, 
      University of North Carolina at Chapel Hill, USA.
FAU - Goh, B-C
AU  - Goh BC
AD  - Department of Haematology-Oncology, National University Cancer Institute, 
      Singapore, National University Hospital, Singapore.
FAU - Miller, W H Jr
AU  - Miller WH Jr
AD  - Segal Cancer Center, Jewish General Hospital, Department of Medicine, Division of 
      Experimental Medicine, McGill University, Montreal, Canada.
FAU - Oh, D-Y
AU  - Oh DY
AD  - Department of Internal Medicine, Seoul National University College of Medicine, 
      Seoul, South Korea.
FAU - Jamal, R
AU  - Jamal R
AD  - Department of Hematology-Oncology, Centre Hospitalier de l'Universite de Montreal 
      (CHUM), University of Montreal, Montreal, Canada.
FAU - Chee, C-E
AU  - Chee CE
AD  - Department of Haematology-Oncology, National University Cancer Institute, 
      Singapore, National University Hospital, Singapore.
FAU - Chow, L Q M
AU  - Chow LQM
AD  - Division of Medical Oncology, Department of Medicine, University of Washington, 
      Seattle.
FAU - Gainor, J F
AU  - Gainor JF
AD  - Massachusetts General Hospital Cancer Center and Department of Medicine, 
      Massachusetts General Hospital, Boston, USA.
FAU - Desai, J
AU  - Desai J
AD  - Department of Medical Oncology, Royal Melbourne Hospital, University of 
      Melbourne, Melbourne.
FAU - Solomon, B J
AU  - Solomon BJ
AD  - Department of Medical Oncology, Peter MacCallum Cancer Center, Melbourne, 
      Australia.
FAU - Das Thakur, M
AU  - Das Thakur M
AD  - Oncology Biomarker Development, Genentech, Inc., South San Francisco, USA.
FAU - Pitcher, B
AU  - Pitcher B
AD  - Biostatistics, Hoffmann-La Roche Ltd, Mississuaga, Canada.
FAU - Foster, P
AU  - Foster P
AD  - Product Development Oncology, Genentech, Inc., South San Francisco, USA.
FAU - Hernandez, G
AU  - Hernandez G
AD  - Oncology Biomarker Development, Genentech, Inc., South San Francisco, USA.
FAU - Wongchenko, M J
AU  - Wongchenko MJ
AD  - Oncology Biomarker Development, Genentech, Inc., South San Francisco, USA.
FAU - Cha, E
AU  - Cha E
AD  - Product Development Oncology, Genentech, Inc., South San Francisco, USA.
FAU - Bang, Y-J
AU  - Bang YJ
AD  - Department of Internal Medicine, Seoul National University College of Medicine, 
      Seoul, South Korea.
FAU - Siu, L L
AU  - Siu LL
AD  - Department of Medicine, Princess Margaret Cancer Centre-University Health 
      Network, University of Toronto, Toronto, Canada.
FAU - Bendell, J
AU  - Bendell J
AD  - Drug Development Unit Nashville, Sarah Cannon Research Institute/Tennessee 
      Oncology, Nashville, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01988896
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA016086/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Azetidines)
RN  - 0 (Piperidines)
RN  - 52CMI0WC3Y (atezolizumab)
RN  - ER29L26N1X (cobimetinib)
SB  - IM
CIN - Ann Oncol. 2019 Jul 1;30(7):1033-1037. PMID: 31114864
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal, Humanized/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use
MH  - Azetidines/administration & dosage
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/metabolism/pathology
MH  - Piperidines/administration & dosage
MH  - Prognosis
MH  - Survival Rate
MH  - Tissue Distribution
MH  - Young Adult
PMC - PMC6931236
OTO - NOTNLM
OT  - PD-L1
OT  - atezolizumab
OT  - cobimetinib
OT  - melanoma
OT  - metastatic colorectal cancer
OT  - non-small-cell lung cancer
EDAT- 2019/03/29 06:00
MHDA- 2020/06/24 06:00
PMCR- 2020/07/01
CRDT- 2019/03/29 06:00
PHST- 2019/03/29 06:00 [pubmed]
PHST- 2020/06/24 06:00 [medline]
PHST- 2019/03/29 06:00 [entrez]
PHST- 2020/07/01 00:00 [pmc-release]
AID - S0923-7534(19)31228-1 [pii]
AID - mdz113 [pii]
AID - 10.1093/annonc/mdz113 [doi]
PST - ppublish
SO  - Ann Oncol. 2019 Jul 1;30(7):1134-1142. doi: 10.1093/annonc/mdz113.