Evaluation of tyrosine kinase inhibitors combined with antiprogrammed cell death protein 1 antibody in tyrosine kinase inhibitor-responsive patients with microsatellite stable/proficient mismatch repair metastatic colorectal adenocarcinoma: protocol for open-label, single-arm trial

Qian Dong, Yanwen Diao, Xin Sun, Yang Zhou, Jialing Ran, Jingdong Zhang, Qian Dong, Yanwen Diao, Xin Sun, Yang Zhou, Jialing Ran, Jingdong Zhang

Abstract

Introduction: The prognosis of patients with advanced metastatic colorectal adenocarcinoma (mCRC) after multiple-line therapy remains poor due to the high tumour load, high level of malignancy and strong drug resistance. The application of programmed cell death protein 1 (PD-1) blockade alone for patients with microsatellite stable/proficient mismatch repair (MSS/pMMR) mCRC is ineffective. PD-1 blockade combined with antiangiogenic therapy has synergistic effects and has initially shown therapeutic effects. The aim of this trial is to explore the efficiency and safety of tyrosine kinase inhibitors (TKIs) combined with PD-1 blockade therapy in patients with mCRC with MSS/pMMR.

Methods and analysis: The screening phase of the trial will involve administering one cycle of TKIs (fruquintinib or regorafenib). Patients will be divided into three arms-arm A (obvious response to TKIs), arm B (general response to TKIs) and arm C (poor response to TKIs)-according to their response to TKIs, as determined by significant changes in imaging findings. Patients in arm A will then receive TKIs in combination with anti-PD-1 antibody, patients in arm C will withdraw from the study, and those in arm B will continue to take TKIs for another one further cycle. Next, patients with obvious response to TKIs will be reallocated to arm A, those with general response to TKIs will stay in arm B and will continue to take TKIs, and patients with poor response to TKIs will withdraw from the study. Administration of arm A or arm B will last until disease progression or intolerable toxicity. Anti-PD-1 antibody can be administered for up to 2 years. This trial will provide necessary data to improve the prognosis of patients with MSS/pMMR mCRC.

Trial registration number: NCT04483219; Pre-results.

Keywords: gastroenterology; gastrointestinal tumours; immunology; protocols & guidelines.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study design and flow chart. mCRC, metastatic colorectal adenocarcinoma; MSS/pMMR, microsatellite stable/proficient mismatch repair; PD-1, programmed cell death protein 1; TKI, tyrosine kinase inhibitors.

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7–34. 10.3322/caac.21551
    1. Riihimäki M, Hemminki A, Sundquist J, et al. . Patterns of metastasis in colon and rectal cancer. Sci Rep 2016;6:29765. 10.1038/srep29765
    1. Bylsma LC, Gillezeau C, Garawin TA, et al. . Prevalence of Ras and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: a systematic review and meta-analysis. Cancer Med 2020;9:1044–57. 10.1002/cam4.2747
    1. Van Cutsem E, Köhne C-H, Hitre E, et al. . Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–17. 10.1056/NEJMoa0805019
    1. Qin S, Li J, Wang L, et al. . Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial. J Clin Oncol 2018;36:3031–9. 10.1200/JCO.2018.78.3183
    1. Heinemann V, von Weikersthal LF, Decker T, et al. . Folfiri plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:1065–75. 10.1016/S1470-2045(14)70330-4
    1. Douillard J-Y, Oliner KS, Siena S, et al. . Panitumumab-FOLFOX4 treatment and Ras mutations in colorectal cancer. N Engl J Med 2013;369:1023–34. 10.1056/NEJMoa1305275
    1. Guan Z-Z, Xu J-M, Luo R-C, et al. . Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III artist trial. Chin J Cancer 2011;30:682–9. 10.5732/cjc.011.10188
    1. Cremolini C, Loupakis F, Antoniotti C, et al. . Folfoxiri plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 tribe study. Lancet Oncol 2015;16:1306–15. 10.1016/S1470-2045(15)00122-9
    1. Cremolini C, Antoniotti C, Lonardi S, et al. . TRIBE2: a phase III, randomized strategy study by GONO in the 1st- and 2nd-line treatment of unresectable metastatic colorectal cancer (mCRC) patients (PTS). Annals of Oncology 2018;29:viii715. 10.1093/annonc/mdy424.021
    1. Cunningham D, Humblet Y, Siena S, et al. . Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–45. 10.1056/NEJMoa033025
    1. Grothey A, Van Cutsem E, Sobrero A, et al. . Regorafenib monotherapy for previously treated metastatic colorectal cancer (correct): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303–12. 10.1016/S0140-6736(12)61900-X
    1. Li J, Qin S, Xu R, et al. . Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (concur): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015;16:619–29. 10.1016/S1470-2045(15)70156-7
    1. Li J, Qin S, Xu R-H, et al. . Effect of Fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA 2018;319:2486–96. 10.1001/jama.2018.7855
    1. Xu J, Kim TW, Shen L, et al. . Results of a randomized, double-blind, placebo-controlled, phase III trial of Trifluridine/Tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol 2018;36:350–8. 10.1200/JCO.2017.74.3245
    1. Wu X, Gu Z, Chen Y, et al. . Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J 2019;17:661–74. 10.1016/j.csbj.2019.03.006
    1. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 2019;19:133–50. 10.1038/s41568-019-0116-x
    1. Picard E, Verschoor CP, Ma GW, et al. . Relationships between immune landscapes, genetic subtypes and responses to immunotherapy in colorectal cancer. Front Immunol 2020;11:369. 10.3389/fimmu.2020.00369
    1. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138:2073–87. 10.1053/j.gastro.2009.12.064
    1. Marmorino F, Boccaccino A, Germani MM, et al. . Immune checkpoint inhibitors in pMMR metastatic colorectal cancer: a tough challenge. Cancers 2020;12:2317. 10.3390/cancers12082317
    1. Morse MA, Hochster H, Benson A. Perspectives on treatment of metastatic colorectal cancer with immune checkpoint inhibitor therapy. Oncologist 2020;25:33–45. 10.1634/theoncologist.2019-0176
    1. 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 Clin Oncol 2020;38:2053–61. 10.1200/JCO.19.03296
    1. Finn RS, Qin S, Ikeda M, et al. . Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894–905. 10.1056/NEJMoa1915745
    1. Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res 2019;25:5449–57. 10.1158/1078-0432.CCR-18-1543
    1. Wu R-Y, Kong P-F, Xia L-P, et al. . Regorafenib promotes antitumor immunity via inhibiting PD-L1 and IDO1 expression in melanoma. Clin Cancer Res 2019;25:4530–41. 10.1158/1078-0432.CCR-18-2840
    1. Wang Y, Wei B, Gao J, et al. . Combination of Fruquintinib and anti-PD-1 for the treatment of colorectal cancer. J Immunol 2020;205:2905–15. 10.4049/jimmunol.2000463
    1. Gou M, Yan H, E LT, et al. . Fruquintinib combination with sintilimab in refractory metastatic colorectal cancer patients in China. Journal of Clinical Oncology 2020;38:4028–28. 10.1200/JCO.2020.38.15_suppl.4028
    1. Papadimitriou M, Papadimitriou CA. Antiangiogenic tyrosine kinase inhibitors in metastatic colorectal cancer: focusing on regorafenib. Anticancer Res 2021;41:567–82. 10.21873/anticanres.14809
    1. Qin S, Li A, Yi M, et al. . Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 2019;12:27. 10.1186/s13045-019-0718-5
    1. Khan K, Cascinu S, Cunningham D, et al. . Imaging and clinical correlates with regorafenib in metastatic colorectal cancer. Cancer Treat Rev 2020;86:102020. 10.1016/j.ctrv.2020.102020
    1. Choi H, Charnsangavej C, Faria SC, et al. . Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–9. 10.1200/JCO.2006.07.3049

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