Consecutive Uncontrolled Gastrointestinal Immune-Related Adverse Events Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma: A Case Report Open Access

Immune-checkpoint inhibitors (ICIs), such as pembrolizumab, are the standard treatment for stage IV non-small cell lung cancer. In cases with high programmed death-ligand 1 (PD-L1) expression, ICI monotherapy has been associated with improved overall survival. However, immune-related adverse events (irAEs) are common, and their management is crucial for the safety and efficacy of ICI treatment.

Gastrointestinal irAEs are frequent, with lower gastrointestinal disorders such as diarrhea and colitis occurring in 4.5–8.7% of patients treated with pembrolizumab. Upper gastrointestinal irAEs, including gastritis, are rare, with an incidence of 0.1–0.2%. Although no standard treatment exists for upper gastrointestinal irAEs, they are generally considered manageable.

Herein, we present a case of a patient treated with pembrolizumab monotherapy who developed irAE gastritis, followed by recurrent gastritis, interstitial lung disease (ILD), and enteritis after re-administration of pembrolizumab. These irAEs remained uncontrolled despite steroid and immunosuppressive therapy.

A 71-year-old female with no smoking history presented to the hospital with headaches and vision problems and was diagnosed with a brain tumor. She underwent surgery for that was pathologically confirmed as a metastasis of lung adenocarcinoma. Contrast-enhanced computed tomography (CT) revealed a 57 × 53 mm mass in the upper lobe of the left lung. Additional tests including ¹⁸F-fluorodeoxyglucose positron emission tomography/CT and brain magnetic resonance imaging showed no metastases other than brain metastases, confirming clinical stage IVB (cT3N0M1c). The Oncomine™ Dx Target Test detected no oncogenic driver mutations, and PD-L1 expression was 50% (22C3 assay). The patient’s ECOG performance status score was 1.

Pembrolizumab monotherapy (200 mg, once every 3 weeks) was initiated based on PD-L1 expression. After five cycles, a partial response was achieved. However, the patient developed anorexia and abdominal pain without hematemesis and was admitted to our hospital because of dehydration. Despite transvenous nutrition and proton pump inhibitors, symptoms worsened. Abdominal CT showed thickening of the gastric wall, and esophagogastroduodenoscopy (EGD) revealed hemorrhagic gastroenteritis with bleeding even on contact at endoscopy (Fig. 1a, b).

The patient was diagnosed with grade 3 irAE hemorrhagic gastritis, and systemic steroid therapy (prednisolone 1 mg/kg) was initiated. The patient’s gastritis had improved (Fig. 1c), and steroids were tapered and discontinued after 2 months.

Although pembrolizumab was discontinued, the primary tumor continued to progress, leading to the re-administration of pembrolizumab. However, 21 days after re-treatment, the patient developed shortness of breath, cough, and hypoxemia. Chest CT revealed ground-glass shadows in both the lungs (Fig. 2a), and grade 3 ILD was diagnosed. Steroid (prednisolone, 1 mg/kg) and antibacterial therapies were initiated and pembrolizumab was discontinued.

As ILD and associated symptoms improved, steroids were tapered. However, when the prednisolone dose was reduced to 10 mg, the patient developed abdominal pain, nausea, and anorexia without hematemesis. Contrast-enhanced CT showed thickening of the gastric and intestinal walls, despite the primary tumor being controlled. EGD revealed recurrent gastritis (Fig. 2b). In addition, the endoscopy revealed findings of Candida esophagitis (data not shown). Cytomegalovirus antigen and Clostridioides difficile toxin test results were negative. Based on EGD and CT findings (Fig. 2c), the patient was diagnosed with recurrent grade 3 irAE gastritis and newly developed grade 3 irAE enteritis. The systemic steroid dosage was increased to 60 mg (1 mg/kg).

Despite steroid escalation, the patient’s diarrhea and abdominal pain from enteritis did not improve. On day 12, infliximab (50 mg/kg, once a day), an anti-tumor necrosis factor agent, was added. However, the irAEs remained uncontrolled, and the patient eventually passed away due to systemic deterioration associated with irAEs.

This case represents the consecutive development of ILD and gastrointestinal irAEs that could not be controlled. While colitis and diarrhea are more common gastrointestinal irAEs, upper gastrointestinal irAEs, such as gastritis, are rare. Although there are no established standard treatment guidelines for upper gastrointestinal irAEs [1], case reports suggest that they are manageable with 0.5–1.0 mg/kg prednisolone. However, a meta-analysis indicated that gastrointestinal irAEs are more likely to recur with a higher grade of irAEs when ICIs are re-administered, necessitating careful management [2].

A unique aspect of this case was the sequential onset of multiple gastrointestinal irAEs and ILDs. A large retrospective study reported an incidence rate of 0.45% for multiple gastrointestinal irAEs, with a good response to steroids and immunosuppressive agents such as infliximab and vedolizumab [3]. In this case, the primary tumor remained controlled when irAE enteritis developed, but the multiple gastrointestinal irAEs during ILD treatment could not be managed with steroids and immunosuppressive agents.

Generally, the development of irAEs correlates with prognosis. Patients with multiple irAEs, including skin and endocrine involvement, often have a good prognosis, whereas those with ILD-related irAEs tend to have a poor prognosis [4].

There is no evidence on the optimal timing of immunosuppressive therapy in steroid-resistant irAEs. For irAE colitis, immunosuppressive drugs are recommended within 3–5 days if no improvement is seen with steroids [1], and early administration has been linked to better outcomes [5]. In this case, infliximab was administered 12 days after steroid administration, but grade 3 diarrhea did not improve.

While the development of ILD likely contributed to the poor prognosis, earlier administration of immunosuppressive agents may have improved survival. Further case studies are required to determine the optimal timing of immunosuppressive therapy in refractory irAEs. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546295).

Re-administration of ICIs should be carefully considered in patients who develop upper gastrointestinal irAEs. Clinicians should also make comprehensive decisions regarding the timing of immunosuppressive drug administration to manage these adverse events effectively.

We would like to thank the patient, family, and the investigators involved for their support and participation in this study.

This case report was approved by the Ethics Committee of the Institutional Review Board of the Teine Keijinkai Hospital (permit No.: 3-024421-00). Written informed consent was obtained from the patient’s relatives for the publication of this case report and the accompanying images. This study was performed in accordance with the Declaration of Helsinki. This human study was approved by the Ethics Committee of the Institutional Review Board of the Teine Keijinkai Hospital (approval No.: 3-024421-00). All adult participants provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for publication of the details of their medical case and any accompanying images.

Yoshikazu Toshima received personal fees from Chugai Pharmaceutical Co. Ltd. Keiki Yokoo received personal fees from MSD K.K., AstraZeneca, Takeda Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Boehringer-Ingelheim, Bristol-Myers Squibb, NIPPON KAYAKU, and Merck Serono. In addition, payments and honoraria were received for lectures and presentations. Gen. Yamada received personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ltd., and Boehringer-Ingelheim. In addition, payments and honoraria were received for lectures and presentations. All other authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Yoshikazu Toshima and Keiki Yokoo drafted and revised the manuscript. Yoshikazu Toshima, Keiki Yokoo, Koki Kamata, Takayuki Nagao, Satoshi Ota, and Gen Yamada were involved in the diagnosis and treatment of the patient and approved the manuscript. Hirofumi Chiba reviewed this manuscript. All authors have approved the final version and agreed to be accountable for all aspects of this work.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.