Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair–Deficient Colorectal Cancer

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Bin-Yi XiaoSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Xuan ZhangDepartment of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Guangzhou, China

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Tai-Yuan CaoDepartment of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

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Dan-Dan LiSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Wu JiangSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Ling-Heng KongSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Jing-Hua TangSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Kai HanSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Chen-Zhi ZhangSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Wei-Jian MeiSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Jian XiaoDepartment of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

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Zhi-Zhong PanSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Yun-Feng LiDepartment of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Guangzhou, China

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Xiao-Shi ZhangSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Pei-Rong DingSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

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Background: Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti–PD-1 treatment for localized mismatch repair–deficient (dMMR) colorectal cancer (CRC). Patients and Methods: The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. Results: A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2–3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4–45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3–4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. Conclusions: Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.

Submitted June 11, 2022; final revision received August 1, 2022; accepted for publication August 1, 2022.

Author contributions: Conception and design: Y.F. Li, X.S. Zhang, Ding. Administrative support: Pan, Ding. Provision of study materials or patients: D.D. Li, J. Xiao, Pan, Y.F. Li, X.S. Zhang, Ding. Collection and assembly of data: B.Y. Xiao, X. Zhang, Cao, Jiang, Kong, Tang, Han, C.Z. Zhang, Mei. Data analysis and interpretation: B.Y. Xiao, X. Zhang, Cao. Manuscript writing: B.Y. Xiao, X. Zhang, Ding. Final approval of manuscript: All authors.

Data availability statement: The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit public platform (www.researchdata.org.cn), with the approval RDD number as RDDA2022876429.

Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the National Natural Science Foundation of China under award numbers 81871971 and 82073159 (P.R. Ding), as well as the Chinese Society of Clinical Oncology under award numbers T-XD2019-073 and Y-Genecast-055 (P.R. Ding).

Disclaimer: This retrospective study was performed in accordance with the Declaration of Helsinki and the Institutional Review Board of Sun Yat-sen University Cancer Center approved to waive informed patient consent due to the observational and noninterventional study (approval number B2020-064-01).

Correspondence: Pei-Rong Ding, MD, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, People’s Republic of China. Email: dingpr@sysucc.org.cn;
Xiao-Shi Zhang, MD, Biotherapy Center, Sun Yat-sen University Cancer Center, Sun Yat-sen University, 651 Dongfeng East Road, Guangzhou 510060, People’s Republic of China. Email: zhangxsh@sysucc.org.cn;
Yun-Feng Li, MD, Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunzhou Road 519, Kunming 650118, People’s Republic of China. Email: liyunfeng@kmmu.edu.cn; and
Zhi-Zhong Pan, MD, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, People’s Republic of China. Email: panzhzh@sysucc.org.cn

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  • Expand
  • 1.

    George TJ, Frampton GM, Sun J, et al. Tumor mutational burden as a potential biomarker for PD1/PD-L1 therapy in colorectal cancer [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 3587.

    • Search Google Scholar
    • Export Citation
  • 2.

    Germano G, Lamba S, Rospo G, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017;552:116120.

  • 3.

    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. Cancer Res 2015;75:34463455.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:25092520.

  • 5.

    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 2017;18:11821191.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Overman MJ, Lonardi S, Wong KY, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/ microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36:773779.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite- instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 8.

    Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 1.2022. Accessed April 1, 2022. To view the most recent version, visit https://www.nccn.org

    • Search Google Scholar
    • Export Citation
  • 9.

    Greenson JK, Huang SC, Herron C, et al. Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol 2009;33:126133.

  • 10.

    Seymour MT, Morton D. FOxTROT: an international randomised controlled trial in 1052 patients (pts) evaluating neoadjuvant chemotherapy (NAC) for colon cancer [abstract]. J Clin Oncol 2019;37(Suppl):Abstract 3504.

    • Search Google Scholar
    • Export Citation
  • 11.

    Cercek A, Dos Santos Fernandes G, Roxburgh CS, et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res 2020;26:32713279.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566576.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386:23632376.

  • 14.

    Zhang J, Cai J, Deng Y, et al. Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab. Oncoimmunology 2019;8:e1663108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Liu DX, Li DD, He W, et al. PD-1 blockade in neoadjuvant setting of DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer. Oncoimmunology 2020;9:1711650.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008;61:344349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228247.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Burgart LJ, Kakar S, Shi C, et al. Protocol for the examination of resection specimens from patients with primary carcinoma of the colon and rectum: version 4.1.0.0. Accessed April 1, 2022. Available at: https://documents.cap.org/protocols/cp-gilower-colonrectum-resection-20-4100.pdf

    • Search Google Scholar
    • Export Citation
  • 19.

    Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:16551661.

  • 20.

    Cloughesy TF, Mochizuki AY, Orpilla JR, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 2019;25:477486.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Hu H, Kang L, Zhang J, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7:3848.

    • Search Google Scholar
    • Export Citation
  • 22.

    Kothari A, White MG, Peacock O, et al. Pathological response following neoadjuvant immunotherapy in mismatch repair-deficient/microsatellite instability-high locally advanced, non-metastatic colorectal cancer: neoadjuvant checkpoint inhibition in locally advanced colorectal cancer. Br J Surg 2022;109:489492.

    • Search Google Scholar
    • Export Citation
  • 23.

    FOxTROT Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 2012;13:11521160.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Belt EJ, te Velde EA, Krijgsman O, et al. High lymph node yield is related to microsatellite instability in colon cancer. Ann Surg Oncol 2012;19:12221230.

  • 25.

    Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 2020;6:38.

  • 26.

    Fleshman J, Branda M, Sargent DJ, et al. Effect of laparoscopic-assisted resection vs open resection of stage II or III rectal cancer on pathologic outcomes: the ACOSOG Z6051 randomized clinical trial. JAMA 2015;314:13461355.

    • Search Google Scholar
    • Export Citation
  • 27.

    Veldkamp R, Kuhry E, Hop WC, et al. Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. Lancet Oncol 2005;6:477484.

    • PubMed
    • Search Google Scholar
    • Export Citation
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