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Session: ePoster: Rectal Cancer 7 (Mon8)

EP672 - Neoadjuvant Combination ICI and ChemoXRT in dMMR Rectal Cancer: A Prospective Clinical Trial

Monday, May 12, 2025
8:16 AM – 8:21 AM PT
Location: Monitor 10, Sails Pavilion, Upper Level

    ePoster Presenter(s)

  • Jonathan B. Mitchem, MD (he/him/his)

    Cleveland Clinic Foundation
    Cleveland Clinic Foundation
    Cleveland, OH, US

    All of the relevant financial relationships listed below have been mitigated.
    This individual has no financial relationships with ineligible companies.

    • Senior Author(s)

  • David Liska, MD

    Associate Professor, Chair
    Department of Colorectal Surgery, Cleveland Clinic
    Cleveland Clinic, Cleveland, Ohio
    Cleveland, Ohio, United States

    Disclosure information not submitted.

    • Author(s)

  • AK

    Alok Khorana, MD

    Staff
    Cleveland Clinic Foundation-Main Campus
    Cleveland, Ohio, United States

    Disclosure information not submitted.

  • SK

    Smitha Krishnamurthi, MD

    Staff
    Cleveland Clinic Foundation-Main Campus
    Cleveland, Ohio, United States

    Disclosure information not submitted.

  • SA

    Sudha R. Amarnath, MD

    Staff Physician
    Cleveland Clinic Foundation-Main Campus
    Cleveland, Ohio, United States

    Disclosure information not submitted.

  • JS

    Josh Sommovilla, MD

    Assistant Professor of Surgery
    Cleveland Clinic
    Cleveland, Ohio, United States

    All of the relevant financial relationships listed below have been mitigated.
    This individual has no financial relationships with ineligible companies.

  • Hermann Kessler, MD, PhD, Professor of Surgery (he/him/his)

    Staff
    Cleveland Clinic Foundation-Main Campus
    Cleveland, OH, United States

    All of the relevant financial relationships listed below have been mitigated.
    This individual has no financial relationships with ineligible companies.

  • EG

    Emre Gorgun, MD, MBA

    Vice Chair, Department of Colorectal Surgery
    Cleveland Clinic Foundation-Main Campus
    Cleveland, Ohio, United States

    All of the relevant financial relationships listed below have been mitigated.
    This individual has no relevant relationships with ineligible companies.

  • David R. Rosen, MD

    Colorectal Surgeon
    Cleveland Clinic
    Cleveland Clinic Lerner College of Medicine
    Cleveland, Ohio, United States

    All of the relevant financial relationships listed below have been mitigated.
    This individual has no relevant relationships with ineligible companies.

  • Scott R. Steele, MD, MBA

    President, Cleveland Clinic, Main Campus Submarket and Rupert B. Turnbull M.D., Endowed Chair in Colorectal Surgery
    Cleveland Clinic
    Cleveland, OH, United States

    All of the relevant financial relationships listed below have been mitigated.
    This individual has no financial relationships with ineligible companies.

All of the relevant financial relationships listed below have been mitigated.
Jonathan B. Mitchem, MD: This individual has no financial relationships with ineligible companies.
Josh Sommovilla, MD: This individual has no financial relationships with ineligible companies.
Hermann Kessler, MD, PhD, Professor of Surgery: This individual has no financial relationships with ineligible companies.
Emre Gorgun, MD, MBA: This individual has no relevant relationships with ineligible companies.
David R. Rosen, MD: This individual has no relevant relationships with ineligible companies.
Scott R. Steele, MD, MBA: This individual has no financial relationships with ineligible companies.
Image or Table (Do Not add text here):

Purpose/Background: Standard of care treatment in locally advanced rectal cancer (LARC) includes neoadjuvant therapy including chemo- and radiotherapy. Recent studies have shown that immune checkpoint inhibitor (ICI) therapy improves outcomes in patients with mismatch repair deficient (dMMR) colorectal (CRC) tumors. However, there is limited prospective data on ICI therapy given in combination with standard neoadjuvant therapy in patients with dMMR LARC. In this prospective pilot study, we hypothesized that the addition of ICI with standard chemoradiotherapy in LARC was safe and would improve treatment response rates.

Methods/Interventions: This is a prospective, single arm, phase I study to determine the safety, feasibility, and efficacy of standard-of-care neoadjuvant chemoradiation with the addition of 3 cycles of pembrolizumab in patients with dMMR LARC. Patients with path confirmed dMMR LARC (T3-4, and/or N positive) were included. Primary outcomes were safety, defined as adverse events during therapy and after surgery; feasibility, defined as delay in surgery; and efficacy, defined as MR tumor regression grade (mrTRG) and pathologic tumor regression grade (TRG). This study was approved and supported by the Case Comprehensive Cancer Center and Cleveland Clinic (CASE 1220). Based on power analysis, planned accrual was 10 patients; however, the trial was ended early due to emerging data on the efficacy of ICI monotherapy and organ preservation in this group

Results/Outcomes: Six patients with dMMR LARC were enrolled between 8/2020 and 2/2023. The mean age was 56±15 years, with 5 male and 1 female patient(s). Three patients had Lynch syndrome. Tumors were a mean of 6.8±3.7cm (2-12) from the anal verge. All 6 patients completed all therapy including ICI. Two patients experienced non-delaying grade II complications (cystitis, hematemesis following EGD), and one patient had ICI therapy delayed due to supply issues. Five (4 LAR +DLI, 1 APR, 83%) patients underwent surgical resection at a mean of 9.5±1.5 weeks post-therapy completion. One patient elected to continue ICI therapy and is off protocol in watch and wait. Five of 6 patients had mrTRG score of 3 or 4, one patient had mrTRG1. Of patients undergoing surgery, 3 had pathologic complete response (TRG0) and 2 had partial response (TRG2). Of patients undergoing LAR with DLI, 3 (75%) experienced Clavien-Dindo ≥2 grade complications, 1 with pelvic abscess requiring drain, 1 anastomotic leak with takeback and reanastomosis, and 1 portal venous thrombus. Three of 4 patients with LAR + DLI underwent reversal at a median of 17 (14-31) weeks. The patient not yet reversed was diagnosed with recurrent mantle cell lymphoma after surgery and is receiving treatment. At a median follow up of 22 (range 10-36) months, all patients were alive without recurrence.

Conclusion/Discussion: In this study, we found that the addition of ICI to standard chemoradiation therapy in LARC was feasible, without delay to surgery or treatment interruptions. However, there was a higher than expected rate of post-operative complications. Additionally, pathologic complete response did not appear to be higher than rates observed with ICI alone in colon cancer. Given the small sample size, definitive conclusions cannot be made from his study; however, this data suggests that further studies are needed to better understand the implications of ICI in combination with standard neoadjuvant therapy in patients with dMMR LARC from the perspective of post-operative complications and treatment response.