TY - JOUR
T1 - Recent Advances in the Clinical Development of Immune Checkpoint Blockade Therapy for Mismatch Repair Proficient (pMMR)/non-MSI-H Metastatic Colorectal Cancer
AU - Lee, James J.
AU - Chu, Edward
N1 - Funding Information:
The authors would like to thank the members of the UPMC Hillman Cancer Center Cancer Therapeutics Program and Phase I Team for their input on this manuscript. This work was done, in part, with support from NCI P30 CA147904 and NCI UM1 CA099168.
Funding Information:
The authors would like to thank the members of the UPMC Hillman Cancer Center Cancer Therapeutics Program and Phase I Team for their input on this manuscript. This work was done, in part, with support from NCI P30 CA147904 and NCI UM1 CA099168.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/12
Y1 - 2018/12
N2 - Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair proficient (pMMR)/non-MSI-H mCRC. The immune resistance mechanisms in pMMR/non-MSI-H mCRC have not yet been clearly elucidated. Significant efforts are currently focused on identifying effective combination immunotherapy regimens for the treatment of patients with pMMR/non-MSI-H mCRC. The combination of atezolizumab with cobimetinib had shown promising clinical activity in an early-phase clinical trial. Unfortunately, the IMblaze 370 (COTEZO) phase III trial of atezolizumab/cobimetinib combination in patients with mCRC failed to show significant improvement in overall survival in patients treated with the atezolizumab/combimetinib combination in comparison with regorafenib alone. This review summarizes the recent major advances in the clinical development of immunotherapy regimens for patients with pMMR/non-MSI-H mCRC.
AB - Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair proficient (pMMR)/non-MSI-H mCRC. The immune resistance mechanisms in pMMR/non-MSI-H mCRC have not yet been clearly elucidated. Significant efforts are currently focused on identifying effective combination immunotherapy regimens for the treatment of patients with pMMR/non-MSI-H mCRC. The combination of atezolizumab with cobimetinib had shown promising clinical activity in an early-phase clinical trial. Unfortunately, the IMblaze 370 (COTEZO) phase III trial of atezolizumab/cobimetinib combination in patients with mCRC failed to show significant improvement in overall survival in patients treated with the atezolizumab/combimetinib combination in comparison with regorafenib alone. This review summarizes the recent major advances in the clinical development of immunotherapy regimens for patients with pMMR/non-MSI-H mCRC.
KW - Immunogenic cell death (ICD)
KW - Immunotherapy
KW - Microsatellite instability
KW - PD-1
KW - Tumor microenvironment
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U2 - 10.1016/j.clcc.2018.06.004
DO - 10.1016/j.clcc.2018.06.004
M3 - Review article
C2 - 30072278
AN - SCOPUS:85050674285
SN - 1533-0028
VL - 17
SP - 258
EP - 273
JO - Clinical colorectal cancer
JF - Clinical colorectal cancer
IS - 4
ER -
