Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer

Abstract

Background Immune checkpoint inhibitors (ICI) target microsatellite instability-high (MSI-H) tumors with success. The incidence and characteristics of ICI-related colitis (IMC) in patients with MSI-H colorectal cancers (CRC) are unclear.

Methods We performed a retrospective analysis of adult patients with CRC who received ICI between June 1, 2014, and December 31, 2022, including data on IMC observed up to 3 months after the last dose of ICI. Patients’ demographics, oncologic profile, endoscopic features, treatment and clinical outcomes were evaluated.

Results Of 474 patients with CRC receiving ICI during our study period, 18 developed IMC (3.8%). The majority were Caucasian (88.8%), male (61.1%), and their median age was 69.5 years. Of these patients, 50% received combination therapy with anti-PD-1/L1 and CTLA-4; 66.6% had MSI-H colorectal cancer, 11.1% had a second cancer-melanoma, while 61.2% and 66.7% had grade 1-2 colitis and diarrhea respectively. Endoscopic evaluation was used in 5 patients, of whom 2 had ulcerative inflammation necessitating selective immunosuppressive therapy with biologics. Therapy was withheld in 61.1% because of toxicity; 41.4% and 5.8% were noted to have median Common Terminology Criteria for Adverse Events grade 2 liver and pancreas toxicity respectively. The majority of our cohort received steroid therapy.

Conclusions The lower severity of IMC, compared to toxicity in other ICI-treated cancers, may be influenced by the tumor microenvironment in MSI-H colorectal cancer after ICI exposure. Larger prospective studies are necessary to determine the role of tumor biology and the gut microbiome in the disease profile and severity of IMC.

Keywords Immune checkpoint inhibitors, colorectal cancer, immune-related adverse event, colitis

Ann Gastroenterol 2025; 38 (1): 72-79

Introduction

Immune checkpoint inhibitors (ICIs) are a potent and increasingly important treatment option for various malignancies. To date, more than 8 ICI agents have been approved. While conferring an appreciable survival benefit, these agents also predispose to unique immune-related gastrointestinal adverse events (irAEs), with diarrhea and colitis amongst the most common [1]. Immune-mediated colitis (IMC) has been reported in up to 40% of patients treated with ICIs. It varies widely in severity [2,3], and can be a cause for discontinuation of ICI therapy [4]. Failure in early recognition and delayed or suboptimal treatment early in the disease course can lead to an increased risk of complications such as bowel perforation [5].

The use of ICIs to treat microsatellite instability-high (MSI-H) colon cancer is a relatively recent development. One clinical trial showed that pembrolizumab can lead to significantly longer progression-free survival than chemotherapy, when received as first-line therapy for MSI-H/mismatch repair deficient (dMMR)-metastatic colorectal cancer (CRC), with fewer treatment-related adverse events [6]. Several studies have shown activity and clinical benefit for ICIs in CRC [6-9]. However, much remains to be learned about irAEs for this patient population. Given their novelty, our knowledge of ICI’s potential irAEs in this setting is still limited. Ostensibly, the presence of malignancy in the bowel may uniquely impact the risk and severity of gastrointestinal irAEs specifically.

There have been limited large-scale studies investigating the safety of ICIs in patients with CRC in terms of irAE. In this retrospective study, we explored the incidence and clinical manifestations of IMC among patients with CRC.

Patients and methods

Results

Patient population, characteristics and oncologic history

We identified 474 patients with a diagnosis of CRC who had exposure to ICI between June 2014 and December 2022. Of these, only 18 patients met our inclusion criteria (Fig. 1). These patients had a median age of 69.5 years; 11 (61.1%) were male; and 16 (88.8%) were white (Table 1). Regarding oncological history, 18 patients (100%) were diagnosed with CRC, followed by overlapped melanoma in 2 patients (11.1%) and genitourinary cancer in 1 patient (5.5%). The majority of the patients (n=13, 72.2%), had stage IV cancer; 12 patients (66.6%) had an MSI-H CRC. With regard to the class of ICI that patients received, 9 (50%), 8 (44.4%), and 1 (5.5%) patients received a combination of PD-1/L1 and CTLA-4 combination therapy, PD-1/L1 inhibitor monotherapy and CTLA-4 monotherapy, respectively (Table 2). Patients underwent a median of 6 cycles of ICI. After the colitis event, 5 patients (27.7%) continued with ICI and 2 patients (5.8%) continued with other forms of cancer therapy.

Figure 1 Patient selection diagram

Table 1 Patient characteristics, N=18

Table 2 Individual patient characteristics

Characteristics and treatment of colitis

The predominant symptom was diarrhea in all 18 patients (100%), and abdominal pain in 18 patients (100%) (Table 3); colitis presented at a median of 259 days after ICI initiation (Table 1). The median fecal calprotectin before treatment was 641 μg/g. The median peak CTCAE was 1 for colitis and 2 for diarrhea (Table 3). The majority of the patients had grade 1 colitis (55.5%). Hospitalization was required for 4 patients (22.2%). As regards the treatment of colitis, steroids were used in the entire cohort, and in conjunction with vedolizumab (1 patient, 5.5%) or infliximab alone (3 patients, 16.6%). A fecal microbiota transplant was performed in 1 patient (5.5%). Of the 18 patients who received corticosteroid treatment for IMC, the median duration of steroid use in the first year after colitis diagnosis was 30.5 days, and the median number of taper events was 3. For those who received biologics as treatment, the median number of doses was 2 and median duration of biologic use in the first year after colitis diagnosis was 9 days. Of the 18 patients who received treatment for IMC, 13 achieved remission and 5 had recurrence of IMC. The median CTCAE grade of diarrhea in those who had recurrence of IMC was 2.25 (Table 4).

Table 3 Characteristics of gastrointestinal irAE in patients with colorectal cancer, N=18

Table 4 Treatment and outcomes in patients diagnosed with colitis, N=18

Endoscopic and histology-related characteristics

At the time of colitis diagnosis, only 5 patients underwent an endoscopic procedure. Non-ulcer inflammation was found in 2 patients (40%), and ulcerative inflammation was also found in 2 patients (40%). On histology, the majority had active inflammation (4 patients, 80%) (Table 5).

Table 5 Endoscopy-related characteristics for patients diagnosed with colitis, N=18

Discussion

This study, to our knowledge is the first to explore the incidence and clinical presentation of lower gastrointestinal toxicity to ICI among patients with CRC. While our initial concern was that the presence of malignancy along the colon may predispose to locoregional inflammatory processes, particularly after immune checkpoint inhibition, surprisingly, we found that the incidence of gastrointestinal irAEs in our sample was substantially lower than that found in the literature for other tumor types (14-37%), while also being potentially less severe [10-12]. Furthermore, our sample demonstrated a delayed onset of toxicity (median of 259 days after ICI) in comparison to the reported time window of 2-3 months. These findings pose interesting questions regarding the mechanism of immune-mediated toxicity and the role of the tumor microenvironment, as well as the gut microbiome, in their development.

CRC refers to any tumor of the inner lining of the rectum or colon. It is the third most common cancer type, comprising 8% of new cancer cases annually, and although its incidence and mortality rates have declined in the past decade, it remains among the deadliest types of malignancy when metastatic [13,14]. In CRCs not amenable to resection, systemic treatments are available, the choice of which highly depends on the tumor’s mutational profile. For instance, current guidelines from the National Comprehensive Cancer Network endorse the use of ICI for the treatment of dMMR/MSI-H CRC, which is predictive of response to ICIs [15-17]. Immunotherapy, however, comes with the risk of irAEs, of which gastrointestinal toxicities (primarily enterocolitis) are among the more common and severe [18]. This poses a unique situation where there is a regional overlap in cancer location and drug-related organ toxicity, a phenomenon that has yet to be studied adequately in the field of immunotherapy. Previous studies have suggested the existence of tumor-dependent irAE profiles. For instance, 1 study found that melanoma was associated with a higher incidence of gastrointestinal and cutaneous irAEs and a lower frequency of pulmonary irAEs [19]. Another study showed that patients with melanoma were more likely to develop cutaneous irAEs, while those with non-small cell lung cancer were more likely to develop pulmonary irAEs [20]. Together, these suggest the potential for locoregional tumor effects that influence the preponderance of inflammatory adverse events, highlighting the complexity of the tumor microenvironment. Though the specific immune phenotype varies greatly between types of cancers, depending on the interplay of increased immune activation in response to tumor neoantigens and the activation of immunosuppressive signaling pathways by the tumor to evade the body’s immune surveillance [21], there is a disruption of immune cell functioning regardless. This conceivably impacts local predisposition to autoimmunity induced by checkpoint inhibitors, and is supported by 2 studies that found that patients who received ipilimumab for active metastatic disease had a lower rate of severe irAEs than those who received it as post-surgical, adjuvant treatment [22,23]. In our study, we found that CRC could potentially mitigate the risk for luminal gastrointestinal irAEs among patients receiving immunotherapy. While these results need to be validated through further studies, it raises an interesting question regarding the impact of tumor burden and location on the incidence of related organ toxicities.

ICIs are an effective means of treating cancer by enhancing the human body’s natural immune defenses, allowing it to mount an anti-tumor response. Three classes of ICIs have FDA approval with different mechanisms. PD-1/L1 inhibitors block the activity of the programmed death-1/ligand 1 protein, which typically suppresses cytokine production and immune cell proliferation [24]. CTLA-4 inhibitors interfere with the activity of the cytotoxic T-lymphocyte antigen 4 protein, which serves the dual function of inhibiting T-cell costimulation while promoting the activity of regulatory T cells that dampen immune responses [25]. Finally, the recently approved lymphocyte activation gene 3 inhibitors help reconstitute the immune system after T-cell exhaustion [26]. These agents induce a potent antitumor immunity which, by the same mechanism, may also promote autoimmunity. Although the precise mechanism of development of these immune-related adverse events probably differs according to the class of ICI used and the system involved, T cells are heavily implicated in this process [27]. IrAEs can pose a significant obstacle to long-term treatment with ICIs, and extensive research is underway to elucidate the pathophysiology of irAEs and to identify predictive biomarkers for these toxicities [27]. Of all the risk factors explored, the aforementioned tumor microenvironment has received surprisingly little attention for its role in the pathogenesis of irAEs. Two tumor immunophenotypes are traditionally described, based on the degree of immune cell infiltration. Immunologically “hot” tumors are those with a preponderance of tumor-infiltrating lymphocytes, a strong immune signature, and activation of immune checkpoints by the tumor as a means of circumventing this inflammatory response [28]. “Cold” tumors, on the other hand, are those with sparse inflammatory infiltrate and typically dense, fibrotic stroma [29]. Some measure of immunosuppression is employed by both phenotypes to allow the cancer to escape immune surveillance, but their responsiveness to immunotherapy differs significantly [28]. Conceivably, this difference in tumor microenvironment may also impact the risk of irAEs. Microsatellite status is a well-known marker of genomic instability and has been associated with tumor immune phenotype—specifically, MSI-H tumors are considered “hot” and are responsive to ICIs [28,30]. As this remains an understudied phenomenon, future studies are needed to explore the influence of the tumor microenvironment on the risk of irAEs. The gut microbiome in particular closely interacts with the tumor microenvironment and is a promising avenue for future research.

The gut microbiome is a complex ecosystem consisting of symbiotic bacteria that has received immense attention in recent years concerning its influence on physiological functions. Bacterial metabolites such as short-chain fatty acids, bile acids and amino-acid derivatives have been implicated in various processes, including metabolism, inflammation, and immunity [31,32]. With the advent of immunotherapy, there is a growing body of research to show that the gut microbiome is also involved in carcinogenesis, and may modulate the effectiveness of cancer treatments, most notably immune checkpoint inhibition [33,34]. It does this by altering the composition of macrophages, natural killer cells, CD4⁺ and CD8⁺ T cells in the tumor immune microenvironment and enhancing tumor immunogenicity [33]. In this way, depending on the specific bacterial composition, the gut microbiome can potentially enhance antitumor immunity and increase cancer susceptibility to immunotherapy [35,36]. While beneficial in terms of cancer outcomes, this remodeling of the tumor immune microenvironment may also impact the risk of immune-related adverse events. One study by Chaput et al found that melanoma patients colonized with specific species of bacteria had significantly longer progression-free survival on ICIs, but had a much higher incidence of IMC [37]. Other studies since have demonstrated the impact of different microbial signatures on the incidence and severity of other irAEs. This is an especially important area to study in the realm of CRC, as gut dysbiosis is a key feature of the disease [38,39]. It is difficult to ascertain whether the altered microbiome in CRC precedes the cancer or results from it. Nonetheless, it opens up many new avenues in terms of diagnostics and therapeutics [40,41]. Fecal microbiota transplantation, in particular, has exploded in popularity, and is being explored in many clinical trials as a means to augment the efficacy of cancer therapy—especially immune checkpoint inhibition—and to mitigate toxicity to cancer medications [42-46]. It has proven to be highly effective in treating refractory IMC, leading to rapid symptom resolution in up to 85.1% of patients, and has had promising results as a first-line treatment for this irAE [47,48]. Furthermore, there are currently 2 trials underway to explore its utility in combination with ICI for treating CRC [49,50]. Its usefulness in CRC and as a means of preventing irAEs remains understudied, and could be an untapped vein for future research.

This study had several limitations. First, it was a retrospective study using electronic health records. As a result, missing information and subjective interpretation of medical records may have affected the accuracy of the data collected. Moreover, other information of interest, such as gut microbial composition, could not be collected. Given our small sample size, it is difficult to draw robust conclusions. Finally, the lack of a comparison group with different cancer types precludes the possibility of conducting further analysis beyond the descriptive findings presented.

Our study is among the first to explore the clinical manifestation of gastrointestinal irAEs in patients with CRC. We found that the CRC microenvironment may not necessarily predispose to more severe gastrointestinal irAEs compared to other cancer types. It is likely that multiple elements, such as tumor location, tumor microenvironment and gut microbiome, are all factors that affect the development of gastrointestinal irAEs in this population. More studies are needed to explore the complex interplay of these features and to further elucidate the mechanism of toxicity to checkpoint inhibition.