Research progress of immune checkpoint inhibitors in the treatment of metastatic colorectal cancer

doi:10.3969/j.issn.1674-8115.2023.02.016

Abstract

Abstract:

Colorectal cancer (CRC) is a common malignancy with a high incidence of metastatic events in China and the world. Immunotherapy has received increasing attention as an emerging therapy in the treatment of metastatic colorectal cancer (mCRC). Immune checkpoint inhibitor (ICI) is one of the important methods, mainly represented by programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies. The strong potential of ICIs in the treatment of mCRC has been confirmed by completed and ongoing clinical trials. The U.S. Food and Drug Administration has approved some ICIs for the first-line treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) mCRC. ICI cannot yet replace the conventional therapy in the treatment of microsatellite stable (MSS)/mismatch repair proficient (pMMR) mCRC, but an increasing number of ICI combination programs have entered the clinical trial phase and have initially shown good clinical efficacy and application prospects. Finding new markers to identify potentially beneficial patients, validating new combination regimens, and developing new immune checkpoints are all important to the future of ICI research.

Key words: metastatic colorectal cancer, immune checkpoint inhibitor, programmed death-1 (PD-1)

CLC Number:

R735.3

TU Juanjuan, JIN Zhiming. Research progress of immune checkpoint inhibitors in the treatment of metastatic colorectal cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(2): 250-255.

Figures/Tables 1

TrendMD

References 29

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Trial (stage)	Target population	Regimen (total)	Key-outcome	TRAE of grade≥3
NCT03274804^［10］ (Ⅰ)	MSS/pMMR mCRC	Pembrolizumab+maraviroc (20)	ORR: 5.3%; mPFS: 2.10 months; mOS: 9.83 months	5% (hyperglycemia)
NCT02407990^［13］ (Ⅰ)	Advanced CRC	Tislelizumab (21)	ORR: 14.3%	‒
NCT03712943^［12］ (Ⅰ/Ⅰb)	Refractory, MSS/pMMR mCRC	Nivolumab+regorafenib (51)	mPFS: 4.3 months; mOS: 11.1 months	51% (hypertension 16%, rash 10% and lymphopenia 8%)
CheckMate142^［11］ (NCT02060188) (Ⅱ)	First-line treatment intolerance or disease progression, MSI-H/dMMR mCRC	Nivolumab (74)	ORR: 31.1%; PFS rate: 50%; OS rate: 73% (median follow-up was 60.9 months); DDC≥12 weeks: 69%	20% (lipase elevation 8%, amylase elevation 3%)
NCT03150706^［7］ (Ⅱ)	Age≥20 years, failure of first-line chemotherapy, MSI-H/dMMR or POLE-mutated mCRC	Avelumab (33)	ORR: 28.6%; DCR: 90.5%; mPFS: 3.9 months; mOS: 13.2 months	18.20%
NCT02873195^［16］ (Ⅱ)	Disease progression, 89.4% were MSS/pMMR mCRC	Capecitabine+bevacizumab+atezolizumab (87) vs capecitabine+bevacizumab+placebo (46)	mPFS: 4.4 vs 3.6 months; mOS: 10.2 vs 10.3 months	61.6% vs 58.7% (skeptical)
NCT03186326^［17］ (Ⅱ)	Age 18‒75 years, failure of first-line therapy, MSI-H/dMMR mCRC	Avelumab vs second-line theray±targeted therapy	Ongoing	‒
NCT04561336^［18］ (Ⅱ)	Chemotherapy-refractory, wild-type RAS, 92.2% were MSS/pMMR mCRC	Avelumab+cetuximab (77)	mPFS: 3.6 months; mOS: 11.6 months	Rash 14% and diarrhea 4% included
NCT03608046^［19］ (Ⅱ)	Wild-type BRAFV600E, MSS/pMMR mCRC	Avelumab+cetuximab+irinotecan (10)	mPFS: 4.2 months; mOS: 12.7 months	0
CheckMate142^［22］ (NCT04008030) (Ⅱ)	MSI-H/dMMR mCRC	Nivolumab+low-dose ipilimumab (45)	OS rate at 12, 18 and 24 months were 84.1%, 81.7% and 79.4%; PFS rate at 12, 18 and 24 months were 76.4%, 76.4% and 73.6%	22% (colitis 4%, respiratory failure 2%)
NCT02870920^［24］ (Ⅱ)	Refractory CRC	Durvalumab+tremelimumab (118) vs best supportive care (61)	mPFS: 1.8 vs 1.9 months; mOS: 6.6 vs 4.1 months	62% vs 20%
NCT03122509^［25］ (Ⅱ)	Chemotherapy-refractory, MSS/pMMR mCRC	Durvalumab+tremelimumab+radiotherapy (24)	ORR: 8.3%; mPFS: 1.8 months; mOS: 11.4 months (median follow-up was 21.8 months)	25% (diarrhea 13%, colitis 8% and hyperglycemia 8%)
KEYNOTE-177^［8］ (NCT02563002)(Ⅲ)	MSI-H/dMMR mCRC	Pembrolizumab (153) vs mFOLFOX6 or FOLFIRI (±bevacizumab/cetuximab) (154)	mPFS: 16.5 months; mOS: 8.2 months	22% (colitis 3%, hepatitis 3%) vs 66%
IMblaze370^［15］ (NCT02788279)(Ⅲ)	Have received other treatments	Atezolizumab+cobimetinib (183) vs atezolizumab (90) vs regorafenib (90)	mOS: 8.87 vs 7.10 vs 8.51 months	61% vs 31% vs 58%

Trial (stage)	Target population	Regimen (total)	Key-outcome	TRAE of grade≥3
NCT03274804^［10］ (Ⅰ)	MSS/pMMR mCRC	Pembrolizumab+maraviroc (20)	ORR: 5.3%; mPFS: 2.10 months; mOS: 9.83 months	5% (hyperglycemia)
NCT02407990^［13］ (Ⅰ)	Advanced CRC	Tislelizumab (21)	ORR: 14.3%	‒
NCT03712943^［12］ (Ⅰ/Ⅰb)	Refractory, MSS/pMMR mCRC	Nivolumab+regorafenib (51)	mPFS: 4.3 months; mOS: 11.1 months	51% (hypertension 16%, rash 10% and lymphopenia 8%)
CheckMate142^［11］ (NCT02060188) (Ⅱ)	First-line treatment intolerance or disease progression, MSI-H/dMMR mCRC	Nivolumab (74)	ORR: 31.1%; PFS rate: 50%; OS rate: 73% (median follow-up was 60.9 months); DDC≥12 weeks: 69%	20% (lipase elevation 8%, amylase elevation 3%)
NCT03150706^［7］ (Ⅱ)	Age≥20 years, failure of first-line chemotherapy, MSI-H/dMMR or POLE-mutated mCRC	Avelumab (33)	ORR: 28.6%; DCR: 90.5%; mPFS: 3.9 months; mOS: 13.2 months	18.20%
NCT02873195^［16］ (Ⅱ)	Disease progression, 89.4% were MSS/pMMR mCRC	Capecitabine+bevacizumab+atezolizumab (87) vs capecitabine+bevacizumab+placebo (46)	mPFS: 4.4 vs 3.6 months; mOS: 10.2 vs 10.3 months	61.6% vs 58.7% (skeptical)
NCT03186326^［17］ (Ⅱ)	Age 18‒75 years, failure of first-line therapy, MSI-H/dMMR mCRC	Avelumab vs second-line theray±targeted therapy	Ongoing	‒
NCT04561336^［18］ (Ⅱ)	Chemotherapy-refractory, wild-type RAS, 92.2% were MSS/pMMR mCRC	Avelumab+cetuximab (77)	mPFS: 3.6 months; mOS: 11.6 months	Rash 14% and diarrhea 4% included
NCT03608046^［19］ (Ⅱ)	Wild-type BRAFV600E, MSS/pMMR mCRC	Avelumab+cetuximab+irinotecan (10)	mPFS: 4.2 months; mOS: 12.7 months	0
CheckMate142^［22］ (NCT04008030) (Ⅱ)	MSI-H/dMMR mCRC	Nivolumab+low-dose ipilimumab (45)	OS rate at 12, 18 and 24 months were 84.1%, 81.7% and 79.4%; PFS rate at 12, 18 and 24 months were 76.4%, 76.4% and 73.6%	22% (colitis 4%, respiratory failure 2%)
NCT02870920^［24］ (Ⅱ)	Refractory CRC	Durvalumab+tremelimumab (118) vs best supportive care (61)	mPFS: 1.8 vs 1.9 months; mOS: 6.6 vs 4.1 months	62% vs 20%
NCT03122509^［25］ (Ⅱ)	Chemotherapy-refractory, MSS/pMMR mCRC	Durvalumab+tremelimumab+radiotherapy (24)	ORR: 8.3%; mPFS: 1.8 months; mOS: 11.4 months (median follow-up was 21.8 months)	25% (diarrhea 13%, colitis 8% and hyperglycemia 8%)
KEYNOTE-177^［8］ (NCT02563002)(Ⅲ)	MSI-H/dMMR mCRC	Pembrolizumab (153) vs mFOLFOX6 or FOLFIRI (±bevacizumab/cetuximab) (154)	mPFS: 16.5 months; mOS: 8.2 months	22% (colitis 3%, hepatitis 3%) vs 66%
IMblaze370^［15］ (NCT02788279)(Ⅲ)	Have received other treatments	Atezolizumab+cobimetinib (183) vs atezolizumab (90) vs regorafenib (90)	mOS: 8.87 vs 7.10 vs 8.51 months	61% vs 31% vs 58%

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