Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis
Publication: Journal of Comparative Effectiveness Research
Abstract
Aims: To evaluate the efficacy and safety of PD-1/PD-L1 and/or CTLA-4 inhibitors in the treatment of colorectal cancer (CRC) by meta-analysis. Methods: Electronic databases were searched. Eligible studies included investigations of efficacy and safety of anti-PD-1/PD-L1 or anti-CTLA-4 agents in patients with CRC. Corresponding indicators were calculated. Results: A total of 15 articles were included. The pooled objective response rate, overall survival rate, progression-free survival rate and adverse event rate were 33, 56, 46 and 59%, respectively. The objective response rates for CRC with deficient mismatch repair and CRC with proficient mismatch repair were 43 and 3%, respectively, in patients treated with PD-1 inhibitors. Conclusion: The authors' study indicates that PD-1/PD-L1 inhibitors manifest promising clinical responses in the treatment of CRC with deficient mismatch repair with acceptable treatment-related adverse events.
Formats available
You can view the full content in the following formats:
Supplementary Material
File (supplementary figure 1.tiff)
- Download
- 121.25 KB
File (supplementary figure 2.tiff)
- Download
- 100.96 KB
File (supplementary figure 3.tiff)
- Download
- 124.96 KB
File (supplementary figure 4.tiff)
- Download
- 130.23 KB
File (supplementary figure 5.tiff)
- Download
- 123.83 KB
File (supplementary figure 6.tiff)
- Download
- 95.55 KB
File (supplementary figure 7.tiff)
- Download
- 110.39 KB
File (supplementary figure 8.tiff)
- Download
- 104.03 KB
File (supplementary figure 9.tiff)
- Download
- 117.57 KB
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
1.
Kreidieh M, Mukherji D, Temraz S, Shamseddine A. Expanding the scope of immunotherapy in colorectal cancer: current clinical approaches and future directions. Biomed. Res. Int. 2020, 9037217 (2020).
2.
Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat. Rev. Gastroenterol. Hepatol. 16(12), 713–732 (2019).
• Provides important data regarding the global burden of colorectal cancer (CRC).
3.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
4.
Siegel RL, Miller KD, Fedewa SA et al. Colorectal cancer statistics, 2017. CA Cancer J. Clin. 67(3), 177–193 (2017).
5.
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet 394(10207), 1467–1480 (2019).
•• Provides comprehensive information on CRC.
6.
Willett WC. Diet and cancer: an evolving picture. JAMA 293(2), 233–234 (2005).
7.
Martinez-Useros J, Garcia-Foncillas J. Obesity and colorectal cancer: molecular features of adipose tissue. J. Transl. Med. 14, 21 (2016).
8.
Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135(4), 1079–1099 (2008).
9.
Ganesh K, Stadler ZK, Cercek A et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 16(6), 361–375 (2019).
10.
Wrobel P, Ahmed S. Current status of immunotherapy in metastatic colorectal cancer. Int. J. Colorectal Dis. 34(1), 13–25 (2019).
11.
Morse MA, Hochster H, Benson A. Perspectives on treatment of metastatic colorectal cancer with immune checkpoint inhibitor therapy. Oncologist 25(1), 33–45 (2020).
12.
Yiu AJ, Yiu CY. Biomarkers in colorectal cancer. Anticancer Res. 36(3), 1093–1102 (2016).
• Describes advances in CRC biomarkers.
13.
Chau I, Cunningham D. Treatment in advanced colorectal cancer: what, when and how? Br. J. Cancer 100(11), 1704–1719 (2009).
14.
Emambux S, Tachon G, Junca A, Tougeron D. Results and challenges of immune checkpoint inhibitors in colorectal cancer. Expert Opin. Biol. Ther. 18(5), 561–573 (2018).
15.
Salmaninejad A, Valilou SF, Shabgah AG et al. PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J. Cell. Physiol. 234(10), 16824–16837 (2019).
16.
Das S, Ciombor KK, Haraldsdottir S, Goldberg RM. Promising new agents for colorectal cancer. Curr. Treat. Options Oncol. 19(6), 29 (2018).
17.
Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr. Opin. Pharmacol. 23, 32–38 (2015).
18.
Wolf D. Checkpoint-inhibition in oncology. Oncol. Res. Treat. 39, 27 (2016).
19.
Yaghoubi N, Soltani A, Ghazvini K, Hassanian SM, Hashemy SI. PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed. Pharmacother. 110, 312–318 (2019).
20.
Cai J, Qi Q, Qian X et al. The role of PD-1/PD-L1 axis and macrophage in the progression and treatment of cancer. J. Cancer Res. Clin. Oncol. 145(6), 1377–1385 (2019).
21.
Chung KY, Gore I, Fong L et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J. Clin. Oncol. 28(21), 3485–3490 (2010).
22.
Hubbard JM, Patel MR, Bekaii-Saab TS et al. A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC). J. Clin. Oncol. 37(Suppl. 15), e14145 (2019).
23.
Le DT, Kim TW, Van Cutsem E et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J. Clin. Oncol. 38(1), 11–19 (2020).
•• Reports the results of an important phase II study of pembrolizumab.
24.
Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372(26), 2509–2520 (2015).
25.
Morris VK, Salem ME, Nimeiri H et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18(4), 446–453 (2017).
26.
Morse MA, Overman MJ, Hartman L et al. Safety of nivolumab plus low-dose ipilimumab in previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Oncologist 24(11), 1453–1461 (2019).
27.
O'Neil BH, Wallmark JM, Lorente D et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS One 12(12), e0189848 (2017).
•• Reports the safety and efficacy of pembrolizumab in advanced CRC.
28.
Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36(8), 773–779 (2018).
29.
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. Lancet Oncol. 18(9), 1182–1191 (2017).
30.
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. Clin. Oncol. 34(Suppl. 15), 3539 (2016).
31.
Sinicrope FA, Chakrabarti S, Eiring R et al. Clinical outcome of patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) treated with pembrolizumab. J. Clin. Oncol. 36(Suppl. 15), e24127 (2018).
32.
Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo) 2013, 857519 (2013).
33.
Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann. Oncol. 29(1), 71–83 (2018).
34.
Rotte A, Bhandaru M, Zhou Y, Mcelwee KJ. Immunotherapy of melanoma: present options and future promises. Cancer Metastasis Rev. 34(1), 115–128 (2015).
35.
Michot JM, Bigenwald C, Champiat S et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).
36.
Kanikarla-Marie P, Haymaker C, Parra ER et al. Pilot clinical trial of perioperative durvalumab and tremelimumab in the treatment of resectable colorectal cancer liver metastases. Clin. Cancer Res. 27(11), 3039–3049 (2021).
37.
Chen EX, Jonker DJ, Loree JM 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. JAMA Oncol. 6(6), 831–838 (2020).
38.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int. J. Surg. 8(5), 336–341 (2010).
•• Describes a widely used protocol for conducting systematic literature reviews.
39.
Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J. Surg. 73(9), 712–716 (2003).
40.
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45(2), 228–247 (2009).
41.
Lipson EJ, Sharfman WH, Drake CG et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin. Cancer Res. 19(2), 462–468 (2013).
42.
André T, Shiu KK, Kim TW et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med. 383(23), 2207–2218 (2020).
43.
Cohen R, Bennouna J, Meurisse A et al. RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study. J. Immunother. Cancer 8(2), e001499 (2020).
• Describes Response Evaluation Criteria in Solid Tumors (RECIST) and immune RECIST (iRECIST) in the treatment evaluation of CRC.
44.
Kim JH, Kim SY, Baek JY 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. Cancer Res. Treat. 52(4), 1135–1144 (2020).
45.
Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 5(1), 16 (2015).
46.
Roth MT, Das S. Pembrolizumab in unresectable or metastatic MSI-high colorectal cancer: safety and efficacy. Expert Rev. Anticancer Ther. 21(2), 229–238 (2021).
•• Describes the safety and efficacy of pembrolizumab in CRC with high levels of microsatellite instability (MSI).
47.
Smith KM, Desai J. Nivolumab for the treatment of colorectal cancer. Expert Rev. Anticancer Ther. 18(7), 611–618 (2018).
Information & Authors
Information
Published In
Pages: 203 - 212
PubMed: 35023361
Copyright
© 2021 Future Medicine Ltd.
History
Received: 7 June 2021
Accepted: 26 November 2021
Published online: 13 January 2022
Keywords:
Topics
Authors
Funding Information
Wuxi Key Talents Cultivation Objects: ZDRCPY011
Metrics & Citations
Metrics
Article Usage
Article usage data only available from February 2023. Historical article usage data, showing the number of article downloads, is available upon request.
Citations
How to Cite
Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis. (2022) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer-2021-0134
Export citation
Select the citation format you wish to export for this article or chapter.
Citing Literature
- Bing Han, Qiong Chai, Qian Chen, Min Liu, Ting Wang, Yu-li Zhang, Zan Li, Zhen Chen, Bo-wang Li, Xian Li, Hua Sui, Qingfeng Tang, Sodium butyrate inhibits colorectal cancer development by reducing M2 macrophage polarization and PD-L1 expression, mSystems, 10.1128/msystems.00692-25, (2025).
- Yu Zhang, Haixia Guan, Xixuan Feng, Mengyan Liu, Jinhuan Shao, Mengchi Liu, Jialei He, Yahui Jin, Jinglin Zhu, Chunli Zheng, Emerging strategies in colorectal cancer immunotherapy: enhancing efficacy and survival, Frontiers in Immunology, 10.3389/fimmu.2025.1616414, 16, (2025).
- Cheng Tong, Yue Wu, Renzhao Wu, New dimensions of PD-1/PD-L1 inhibitor combination therapy in cancer treatment: current advances and future perspectives, Frontiers in Immunology, 10.3389/fimmu.2025.1616872, 16, (2025).
- Long Ma, Wentao Zhou, Xizhi Ma, Xiaopo Li, Qian Zhang, Wenting Ma, Nafei Chen, XiaoTao Zhou, XiaoHui Tang, Preparation and property evaluation of oral colon targeted protein delivery system with sodium alginate and chitosan, Scientific Reports, 10.1038/s41598-025-04983-5, 15, 1, (2025).
- Jin Woong Lee, Carter Kim, Michael J. Poellmann, Zixian Zhu, Seungpyo Hong, The Role of Dendrimers in Improving Antibody and Peptide Biologics for Cancer Treatment, Langmuir, 10.1021/acs.langmuir.5c00934, 41, 27, (17322-17334), (2025).
- Ting Tian, Huan Han, Jingtao Huang, Jun’e Ma, Ruoxi Ran, DBI as a Novel Immunotherapeutic Candidate in Colorectal Cancer: Dissecting Genetic Risk and the Immune Landscape via GWAS, eQTL, and pQTL, Biomedicines, 10.3390/biomedicines13051115, 13, 5, (1115), (2025).
- Ali Rahimi, Zeinab Baghernejadan, Ali Hazrati, Kosar Malekpour, Leila Nejatbakhsh Samimi, Alireza Najafi, Reza Falak, Hossein Khorramdelazad, Combination therapy with immune checkpoint inhibitors in colorectal cancer: Challenges, resistance mechanisms, and the role of microbiota, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2025.118014, 186, (118014), (2025).
- Weigeng Liu, Clinical efficacy and predictive indicators of cindilizumab combined with XELIRI protocol in advanced colorectal carcinoma patients, American Journal of Translational Research, 10.62347/KZDR9031, 17, 8, (6180-6190), (2025).
- Lloyd Mabonga, Rebecca Leony Fourie, Abidemi Paul Kappo, Sylvester Lyantagaye, Zodwa Dlamini, Emerging treatment approaches for colorectal cancer treatment resistance, Colorectal Cancer Treatment Resistance, 10.1016/B978-0-443-33475-7.00001-9, (107-145), (2025).
- Dandan Song, Shufu Hou, Ning Ma, Bing Yan, Jing Gao, Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in the treatment of advanced colorectal cancer: a systematic review and meta-analysis, Frontiers in Immunology, 10.3389/fimmu.2024.1485303, 15, (2024).
- See more