Research progress of PD-1/PD-L1 inhibitors in the treatment of metastatic colorectal cancer
YIN Zhucheng LIANG Xinjun
Departments of Abdominal Oncology, Hubei Clinical Medical Research Center for Colorectal Cancer, Wuhan Colorectal Cancer Clinical Medical Research Center, Hubei Cancer Hospital, Hubei Province, Wuhan 430070, China
Abstract：Colorectal cancer is one of the most common malignant tumors in the world. Most patients have metastases at diagnosis, the prognosis is poor. In recent years, immune checkpoint inhibitors have made a breakthrough progress in the treatment of a variety of malignant tumors, which is one of the current research hotspots. Monotherapy or combination therapy with programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors may provide clinical benefit for patients with DNA mismatch repair defects/high microsatellite instability metastatic colorectal cancer (mCRC). The efficacy of monotherapy in patients with mismatch repair proficient/microsatellite stable mCRC is poor, and the feasibility of combination therapy with PD-1/PD-L1 inhibitors is being explored. This article reviews the application of PD-1/PD-L1 inhibitors in first-line, second-line, and posterior line treatment of mCRC patients, as well as the clinical research status and progress of PD-1/PD-L1 inhibitors monotherapy and combination therapy in different types of mCRC patients, so as to provide evidence for clinical application.
[1] 陈万青，李贺，孙可欣，等.2014年中国恶性肿瘤发病和死亡分析[J].中华肿瘤杂志，2018，40（1）：5-13.
[2] Le DT，Uram JN，Wang H，et al. PD-1 blockade in tumors with mismatch-repair deficiency [J]. N Engl J Med，2015， 372（26）：2509-2520.
[3] Le DT，Kim TW，Cutsem EV，et al. Phase Ⅱ Open-Label Study of Pembrolizumab in Treatment-Refractory，Micros-atellite Instability-High/Mismatch Repair-Deficient Meta-static Colorectal Cancer：KEYNOTE-164 [J]. J Clin Oncol，2020，38（1）：11-19.
[4] Overman MJ，McDermott R，Leach JL，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.
[5] Andre T，Berton D，Braud F，et al. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients（pts）with mismatch repair deficient（dMMR）GI cancers [J]. J Clin Oncol，2020，38（4_suppl）：218.
[6] Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer [J]. J Exp Clin Cancer Res，2019，38（1）：255.
[7] Overman MJ，Lonardi S，Wong KY，et al. Durable Clinical Benefit with Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Met-astatic Colorectal Cancer [J]. J Clin Oncol，2018，36（8）：773-779.
[8] Andre T，Shiu KK，Kim TW，et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer [J]. N Engl J Med，2020，383（23）：2207-2218.
[9] Shiu KK，Andre T，Kim TW，et al. KEYNOTE-177：Phase Ⅲ randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer [J]. J Clin Oncol，2021，39（3_suppl）：6.
[10] Lenz HJ，Lonardi S，Zagonel V，et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient met-astatic colorectal cancer：Clinical update [J]. J Clin Oncol，2020，38（4_suppl）：11.
[11] Wang M，Wang S，Desai J，et al. Therapeutic strategies to remodel immunologically cold tumors [J]. Clin Transl Immunology，2020，9（12）：e1226.
[12] Chen EX，Jonker D，Kennecke HF，et al. CCTG CO.26：Updated analysis and impact of plasma-detected microsatellite stability （MSS） and tumor mutation burden（TMB）in a phase Ⅱ trial of durvalumab（D）plus tremelimumab（T）and best supportive care（BSC）versus BSC alone in patients（pts）with refractory metastatic colorectal carcinoma（rmCRC）[J]. J Clin Oncol，2019，37（15_suppl）：3512.
[13] Fukuoka S，Hara H，Takahashi N，et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer：An Open-Label，Dose-Escalation，and Dose-Expansion Phase Ⅰb Trial（REGONIVO，EPOC1603）[J]. J Clin Oncol，2020，38（18）：2053-2061.
[14] Wang F，He MM，Yao YC，et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer：a phase Ⅰb/Ⅱ clinical trial and gut microbiome analysis [J]. Cell Rep Med，2021，2（9）：100383.
[15] Gou MM，Yan H，Liu TE，et al. Fruquintinib combination with sintilimab in refractory metastatic colorectal cancer patients in China [J]. J Clin Oncol，2020，38（15_suppl）：4028.
[16] Xiao L，Zhang Y，Lin Q. Camrelizumab combined with apatinib in the treatment of patients with advanced gastric cancer and colorectal cancer：One-arm exploratory clinical trial [J]. Ann Oncol，2020，31：S429.
[17] Cousin S，Bellera CA，Guegan JP，et al. REGOMUNE：A phase Ⅱ study of regorafenib plus avelumab in solid tumors-Results of the non-MSI-H metastatic colorectal cancer（mCRC）cohort [J]. J Clin Oncol，2020，38（15）：4019.
[18] Lwin Z，Oca CG，Bouzid ES，et al. LEAP005：Phase Ⅱ study of lenvatinib（len）plus pembrolizumab（pembro）in patients（pts）with previously treated advanced solid tumours [J]. Ann Oncol，2020，31：S1170.
[19] Wang L，Wei Y，Fang W，et al. Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer [J]. Cell Physiol Biochem，2017，44（3）：1038-1050.
[20] Lee MS，Loehrer PJ，Imanirad I，et al. Phase Ⅱ study of ipilimumab，nivolumab，and panitumumab in patients with KRAS/NRAS/BRAF wild-type（WT）microsatellite stable（MSS）metastatic colorectal cancer（mCRC）[J]. J Clin Oncol，2021，39（3_suppl）：7.
[21] Martinelli E，Martini G，Troiani T，et al. Avelumab plus cetuximab in pre-treated RAS wild type metastatic colorectal cancer patients as a rechallenge strategy：The phase Ⅱ CAVE（cetuximab-avelumab）mCRC study [J]. Ann Oncol，2020，31：S409-S410.
[22] Ebert PJR，Cheung J，Yang Y，et al. MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade [J]. Immunity，2016，44（3）：609-621.
[23] Eng C，Kim TW，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.
[24] Lieu CH，Davis SL，Leong S，et al. Results from the safety lead-in for a phase Ⅱ study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer（mCRC）[J]. J Clin Oncol，2020，38（15_suppl）：abstr 4031.
[25] Segal NH，Kemeny NE，Cercek A，et al． Non-randomized phase Ⅱ study to assess the efficacy of pembrolizumab（Pem）plus radiotherapy（RT）or ablation in mismatch repair proficient（pMMR）metastatic colorectal cancer（mCRC）patients [J]. J Clin Oncol，2016，34（15_suppl）：3539.
[26] Parikh AR，Clark JW，Wo JYL，et al． A phase Ⅱ study of ipilimumab and nivolumab with radiation in microsatellite stable（MSS）metastatic colorectal adenocarcinoma（mCRC）[J]. J Clin Oncol，2019，37（15_suppl）：3514.
[27] Monge C，Xie C，Brar G，et al. A phase Ⅰ/Ⅱ study of JX-594 oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer [J]. Eur J Cancer，2020，138（2_suppl）：S57-S58.
[28] Tabernero J，Melero I，Ros W，et al. Phase Ⅰa and Ⅰb studies of the novel carcinoembryonic antigen（CEA）T-cell bispecific（CEA CD3 TCB）antibody as a single agent and in combination with atezolizumab：Preliminary efficacy and safety in patients with metastatic colorectal cancer（mCRC）[J]. J Clin Oncol，2017，35（Suppl 15）：3002.
[29] Dosset M，Vargas TR，Lagrange A，et al. PD-1/PD-L1 pathway：an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer [J]. Oncoimmunology，2018，7（6）：e1433981.
[30] Kim R，Chaves J，Kavan P，et al. Pembrolizumab（pembro）plus mFOLFOX7 or FOLFIRI in patients（pts）with metastatic colorectal cancer（mCRC）：Updated results from KEYNOTE-651 cohorts B and D [J]. Ann Oncol，2020， 31：S450.
[31] Ghiringhelli F，Chibaudel B，Taieb J，et al. Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated，microsatellite-stable，previously untreated metastatic colorectal cancer（MCRC）：Results of the first intermediate analysis of the phase Ⅰb/Ⅱ MEDETREME trial [J]. J Clin Oncol，2020，38（15_ suppl）：3006.
[32] Cremolini C，Rossini D，Antoniotti C，et al. LBA20 FOLFOXIRI plus bevacizumab（bev）plus atezolizumab（atezo）versus FOLFOXIRI plus bev as first-line treatment of unresectable metastatic colorectal cancer（mCRC）patients：Results of the phase Ⅱ randomized AtezoTRIBE study by GONO [J]. Ann Oncol，2021，32（5_suppl）：S1294-S1295.
京公网安备 11010502046598号