免疫检查点抑制剂治疗转移性结直肠癌的研究进展

doi:10.3969/j.issn.1674-8115.2023.02.016

摘要/Abstract

摘要：

结直肠癌（colorectal cancer，CRC）是我国乃至全世界常见的恶性肿瘤，转移事件发生率高。免疫治疗在转移性结直肠癌（metastatic CRC，mCRC）的治疗中作为一种新兴的治疗方法，受到的关注越来越多。免疫检查点抑制剂（immune checkpoint inhibitor，ICI）是其中一种重要手段，主要以程序性死亡受体1（programmed death-1，PD-1）、程序性死亡受体配体1（programmed death-ligand 1，PD-L1）和细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen 4，CTLA-4）抗体为代表。已经完成的和正在进行中的相关临床试验均肯定了ICI在mCRC治疗中的巨大潜力。美国食品药品监督管理局已经批准多个ICI用于微卫星高不稳定性（microsatellite instability-high，MSI-H）/错配修复缺陷（mismatch repair deficient，dMMR）的mCRC的一线治疗。尽管ICI在微卫星稳定（microsatellite stable，MSS）/错配修复正常（mismatch repair proficient，pMMR）的mCRC的治疗中尚不能撼动传统治疗的地位，但越来越多的ICI联合方案相继进入临床试验阶段，初步显示了良好的临床疗效和应用前景。寻找新的标志物用以甄别可能获益的患者群体和试验验证新的联合方案疗效，以及开发新的免疫检查点都将是ICI未来研究的重要方向。

关键词: 转移性结直肠癌, 免疫检查点抑制剂, 程序性死亡受体1

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)

中图分类号:

R735.3

涂娟娟, 金志明. 免疫检查点抑制剂治疗转移性结直肠癌的研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(2): 250-255.

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.

图/表 1

参考文献 29

1	中华人民共和国国家卫生健康委员会. 中国结直肠癌诊疗规范(2020年版)[J]. 中华外科杂志, 2020, 58(8): 561-585.
	National Health Commission of the People's Republic of China. Chinese protocol of diagnosis and treatment of colorectal cancer (2020 edition)[J]. Chinese Journal of Surgery, 2020, 58(8): 561-585.
2	VAN CUTSEM E, CERVANTES A, ADAM R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer[J]. Ann Oncol, 2016, 27(8): 1386-1422.
3	ZHANG Y Y, SUN Z, MAO X X, et al. Impact of mismatch-repair deficiency on the colorectal cancer immune microenvironment[J]. Oncotarget, 2017, 8(49): 85526-85536.
4	MABY P, TOUGERON D, HAMIEH M, et al. Correlation between density of CD8⁺ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy[J]. Cancer Res, 2015, 75(17): 3446-3455.
5	MARCUS L, LEMERY S J, KEEGAN P, et al. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors[J]. Clin Cancer Res, 2019, 25(13): 3753-3758.
6	BENSON A B, VENOOK A P, AL-HAWARY M M, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2021, 19(3): 329-359.
7	KIM J H, KIM S Y, BAEK J Y, et al. A phase Ⅱ study of avelumab monotherapy in patients with mismatch repair-deficient/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer[J]. Cancer Res Treat, 2020, 52(4): 1135-1144.
8	ANDRÉ T, SHIU K K, KIM T W, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer[J]. N Engl J Med, 2020, 383(23): 2207-2218.
9	GOMAR M, NAJAFI M, AGHILI M, et al. Durable complete response to pembrolizumab in microsatellite stable colorectal cancer[J]. Daru, 2021, 29(2): 501-506.
10	HAAG G M, SPRINGFELD C, GRÜN B, et al. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer: the PICCASSO phase Ⅰ trial[J]. Eur J Cancer, 2022, 167: 112-122.
11	OVERMAN M J, MCDERMOTT R, LEACH J L, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study[J]. Lancet Oncol, 2017, 18(9): 1182-1191.
12	KIM R D, KOVARI B P, MARTINEZ M, et al. A phase Ⅰ/Ⅰb study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer[J]. Eur J Cancer, 2022, 169: 93-102.
13	DESAI J, DEVA S, LEE J S, et al. Phase ⅠA/ⅠB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors[J]. J Immunother Cancer, 2020, 8(1): e000453.
14	TAPIA RICO G, PRICE T J. Atezolizumab for the treatment of colorectal cancer: the latest evidence and clinical potential[J]. Expert Opin Biol Ther, 2018, 18(4): 449-457.
15	ENG C, KIM T W, BENDELL J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial[J]. Lancet Oncol, 2019, 20(6): 849-861.
16	METTU N B, OU F S, ZEMLA T J, et al. Assessment of capecitabine and bevacizumab with or without atezolizumab for the treatment of refractory metastatic colorectal cancer: a randomized clinical trial[J]. JAMA Netw Open, 2022, 5(2): e2149040.
17	TAÏEB J, ANDRÉ T, EL HAJBI F, et al. Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: the SAMCO-PRODIGE 54 randomised phase Ⅱ trial[J]. Dig Liver Dis, 2021, 53(3): 318-323.
18	MARTINELLI E, MARTINI G, FAMIGLIETTI V, et al. Cetuximab rechallenge plus avelumab in pretreated patients with RAS wild-type metastatic colorectal cancer: the phase 2 single-arm clinical CAVE trial[J]. JAMA Oncol, 2021, 7(10): 1529-1535.
19	VAN DEN EYNDE M, HUYGHE N, DE CUYPER A, et al. Interim analysis of the AVETUXIRI trial: avelumab combined with cetuximab and irinotecan for treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC)—a proof of concept, open-label, nonrandomized phase Ⅱa study[J]. J Clin Oncol, 2021, 39(3_suppl): 80.
20	MORSE M A, HOCHSTER H, BENSON A. Perspectives on treatment of metastatic colorectal cancer with immune checkpoint inhibitor therapy[J]. Oncologist, 2020, 25(1): 33-45.
21	SUZUKI S, KAWAKAMI H, MIIKE T, et al. Complete remission of colon cancer with ipilimumab monotherapy[J]. Intern Med, 2021, 60(6): 957-958.
22	LENZ H J, VAN CUTSEM E, LUISA LIMON M, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase Ⅱ CheckMate 142 study[J]. J Clin Oncol, 2022, 40(2): 161-170.
23	FUMET J D, ISAMBERT N, HERVIEU A, et al. Phase Ⅰb/Ⅱ trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer[J]. ESMO Open, 2018, 3(4): e000375.
24	CHEN E X, JONKER D J, LOREE J M, et al. Effect of combined immune checkpoint inhibition vs best supportive care alone in patients with advanced colorectal cancer: the Canadian cancer trials group CO.26 study[J]. JAMA Oncol, 2020, 6(6): 831-838.
25	SEGAL N H, CERCEK A, KU G, et al. Phase Ⅱ single-arm study of durvalumab and tremelimumab with concurrent radiotherapy in patients with mismatch repair-proficient metastatic colorectal cancer[J]. Clin Cancer Res, 2021, 27(8): 2200-2208.
26	LIANG R P, ZHU X D, LAN T Y, et al. TIGIT promotes CD8⁺T cells exhaustion and predicts poor prognosis of colorectal cancer[J]. Cancer Immunol Immunother, 2021, 70(10): 2781-2793.
27	THIBAUDIN M, LIMAGNE E, HAMPE L, et al. Targeting PD-L1 and TIGIT could restore intratumoral CD8 T cell function in human colorectal cancer[J]. Cancer Immunol Immunother, 2022, 71(10): 2549-2563.
28	KOYAMA S, AKBAY E A, LI Y Y, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints[J]. Nat Commun, 2016, 7: 10501.
29	MA Q, LIU J N, WU G L, et al. Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients[J]. Clin Exp Pharmacol Physiol, 2018, 45(10): 1002-1009.

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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