P2398 - Determinants of Treatment Refractoriness in Immune-Mediated Diarrhea and Colitis Following Immune Checkpoint Inhibitor Therapy

Carolina Cruz, MD¹, Maria Julia M. N.. Santos, MD², Sharada Wali, MBBS, MPH¹, Cristina Natha, MD³, Rohan Ahuja, MD⁴, Garrett Coleman, ⁵, Anirudha Chatterjee, MD⁶, Nina Quirk, MD, MS⁷, Yuhong Yang, ⁸, William Mitchell, ⁸, Agastya Bhatlapenumarthy, ⁹, Sandra Naffouj, ¹⁰, Sage Iwamoto, ¹¹, Gomathy Nageswaran, ¹², Rachel Niec, ⁸, Lisa Arnold, ¹³, Lucie Heinzerling, ¹³, Helga-Paula Török, ¹³, Meer A. Ali, MD¹⁴, Konstantinos Arnaoutakis, ¹², Douglas Johnson, ¹⁵, Karen Kim, ¹⁶, Emmanuelle Bellaguarda, ¹⁰, Shilpa Grover, MD, MPH⁹, David Falek, ⁸, Yinghong Wang, MD, PhD, MS¹
1University of Texas MD Anderson Cancer Center, Houston, TX; 2MD Anderson Cancer Center, Houston, TX; 3McGovern Medical School at UTHealth, Houston, TX; 4University of Texas at Houston, Houston, TX; 5University of Texas Medical Branch, Houston, TX; 6University of Texas Medical Branch, Galveston, TX; 7University of Texas Health Sciences Center in Houston, Houston, TX; 8Memorial Sloan Kettering Cancer Center, New York, NY; 9Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 10Northwestern University, Chicago, IL; 11Vanderbilt University Medical Center, Nashville, TN; 12University of Arkansas for Medical Sciences, Small City, AR; 13Ludwig Maximilian University of Munich, Munich, Bayern, Germany; 14University of Arkansas for Medical Sciences, Little Rock, AR; 15Vanderbilt University, Nashville, TN; 16Stanford University, Redwood City, CA

Introduction: Immune checkpoint inhibitors (ICIs) can lead to immune-mediated diarrhea and colitis (IMDC), disrupting treatment continuity. First-line therapy includes ICI discontinuation and steroids for moderate to severe cases; however, a subset of patients, with pancolitis or endoscopic ulcerations, may develop refractory symptoms. Toxicity may recur in 35% of patients rechallenged ICIs, despite initial response. Selective immunosuppressive therapy (SIT) with infliximab (IFX) or vedolizumab (VDZ) is often required. This study aims to identify risk factors associated with IMDC refractoriness to SIT.

Methods: In this international, retrospective study across 10 centers, 879 IMDC patients were categorized into two groups: responders to steroids or to subsequent SIT, and non-responders to both steroids and initial SIT agent. Treatment failure was defined as lack of ≥ 1-grade CTCAE improvement after 1^st SIT infusion, steroid escalation, or SIT switch for persistent symptoms. Cases with SIT change due to insurance or adverse effects were excluded.

Results: Among 879 patients, 60% were male and 93% white. Treatment regimens included anti-PD-1 / L1 (43.9%), anti-CTLA-4 (16.5%) and combined therapy (39.6%). Significant factors associated with refractoriness to SIT included: combined ICI regimen (OR:1.7 CI:1.2-2.4, p=0.001), concurrent gastrointestinal AEs (OR:2.1 CI:1.4-3.4, p=0.001), diarrhea CTCAE grade ≥ 2 (OR:3.4 CI: 1.8-6.5, p < 0.0001) and colitis CTCAE grade ≥ 2 (OR:6.5 CI:4.2-10, p < 0.0001), longer steroid duration (OR:1.02 CI:1.0-1.03, p=0.014), multiple steroid tapers attempts (OR:1.7 CI:1.4-2.0, p < 0.0001), initial use IFX (OR:2.3 CI:1.5-3.3, p < 0.0001), ulcerative features on colonoscopy (OR: 1.7 CI:1.1-2.5, p=0.006), acute histologic findings (OR:1.7 CI:1.1-2.4, p=0.005), positive lactoferrin (OR:2.0 CI:1.2-3.8, p=0.017), and elevated calprotectin (OR:1.0 CI:1.0-1.0, p < 0.0001). Protective factors included initial anti-CTLA-4 therapy (OR:0.2 CI:0.1-0.5, p < 0.0001), initial VDZ use (OR:0.4 CI:0.2-0.6, p < 0.0001), normal endoscopy (OR:0.3 CI:0.2-0.6, p < 0.0001) and histology (OR:0.4 CI:0.2-0.7, p=0.006).   

Discussion:

This is the first multi-center study to identify risk factors for IMDC refractoriness. Severe clinical, endoscopic, or histologic features may warrant early escalation or switch of SITs and/or alternative therapies such as fecal microbiota transplantation. Patients with mild disease or lack of objective inflammation may respond adequately to steroids.


Figure: Table1.


Figure: Table 2.

Disclosures:
Carolina Cruz indicated no relevant financial relationships.
Maria Julia Santos indicated no relevant financial relationships.
Sharada Wali indicated no relevant financial relationships.
Cristina Natha indicated no relevant financial relationships.
Rohan Ahuja indicated no relevant financial relationships.
Garrett Coleman indicated no relevant financial relationships.
Anirudha Chatterjee indicated no relevant financial relationships.
Nina Quirk indicated no relevant financial relationships.
Yuhong Yang indicated no relevant financial relationships.
William Mitchell indicated no relevant financial relationships.
Agastya Bhatlapenumarthy indicated no relevant financial relationships.
Sandra Naffouj indicated no relevant financial relationships.
Sage Iwamoto indicated no relevant financial relationships.
Gomathy Nageswaran indicated no relevant financial relationships.
Rachel Niec indicated no relevant financial relationships.
Lisa Arnold indicated no relevant financial relationships.
Lucie Heinzerling indicated no relevant financial relationships.
Helga-Paula Török indicated no relevant financial relationships.
Meer Ali indicated no relevant financial relationships.
Konstantinos Arnaoutakis indicated no relevant financial relationships.
Douglas Johnson indicated no relevant financial relationships.
Karen Kim indicated no relevant financial relationships.
Emmanuelle Bellaguarda indicated no relevant financial relationships.
Shilpa Grover: Takeda – Grant/Research Support.
David Falek indicated no relevant financial relationships.
Yinghong Wang indicated no relevant financial relationships.

Carolina Cruz, MD¹, Maria Julia M. N.. Santos, MD², Sharada Wali, MBBS, MPH¹, Cristina Natha, MD³, Rohan Ahuja, MD⁴, Garrett Coleman, ⁵, Anirudha Chatterjee, MD⁶, Nina Quirk, MD, MS⁷, Yuhong Yang, ⁸, William Mitchell, ⁸, Agastya Bhatlapenumarthy, ⁹, Sandra Naffouj, ¹⁰, Sage Iwamoto, ¹¹, Gomathy Nageswaran, ¹², Rachel Niec, ⁸, Lisa Arnold, ¹³, Lucie Heinzerling, ¹³, Helga-Paula Török, ¹³, Meer A. Ali, MD¹⁴, Konstantinos Arnaoutakis, ¹², Douglas Johnson, ¹⁵, Karen Kim, ¹⁶, Emmanuelle Bellaguarda, ¹⁰, Shilpa Grover, MD, MPH⁹, David Falek, ⁸, Yinghong Wang, MD, PhD, MS¹. P2398 - Determinants of Treatment Refractoriness in Immune-Mediated Diarrhea and Colitis Following Immune Checkpoint Inhibitor Therapy, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.