Initially, 1290 patients were enrolled in this retrospective analysis; 221 patients who did not undergo pancreatic enzyme measurement during the study period were excluded, Finally, 1069 patients were eligible for study inclusion (Fig. 1). Table S2 provides information on the participating hospitals and the number of eligible patients. The patient characteristics are presented in Table 1. The study population predominantly comprised men, and lung cancer (60.4%) was the most common primary disease. At the time of ICI administration, 68.7% of patients had stage IV disease, followed by stage III disease in 15.3% and postoperative cancer recurrence in 14.7% of patients. Most patients were treated with programmed cell death (PD)-1 inhibitors (91.4%), followed by PD-L1 inhibitors (9.4%), and cytotoxic T lymphocyte antigen (CTLA)-4 inhibitors (1.6%). Multiple ICI monotherapy regimens (with different drugs) were administered to 1.9% of patients and combination therapy with different ICIs was administered to 0.9% of patients. 762 patients had prior use of cytotoxic anticancer drugs, of which 707 (92.8%), the majority of patients, had prior use of multiple cytotoxic anticancer drugs. 32 (3.0%) patients had prior use of interferon (IFN) therapy. 427 patients had prior use of molecular targeted drugs, of these, 132 (30.9%) patients were on multiple monotherapy regimens and 8 (1.9%) patients were on combination regimens of multiple drugs. There was no concomitant use of ICI and cytotoxic anticancer or molecular targeted drugs at the same time.

Flowchart of eligible patients. This study initially enrolled 1290 patients. Of these, 221 patients whose pancreatic enzymes were not measured during the study period were excluded, and finally 1069 patients were considered eligible for inclusion in the study

Other organ disorders considered to be irAEs were observed in 324 (30.3%) patients. The most common type of irAE is endocrine disorders such as thyroid and adrenal dysfunction, followed by liver disorders, gastrointestinal disorders, pneumonia, and dermatitis.

The median number of ICI treatments was 6, and the median duration of ICI treatment was 3.3 months. The median observational period was 12.3 months and the median OS was 15.8 months.

The incidences of pancreatic enzyme elevation and ICI -related pancreatic injury are shown in Table 2. Four grades of pancreatic enzyme elevation were observed in 160 (15%) of 1069 patients. The primary endpoint, i.e., ICI-PI, was present in 19 (1.8%) patients, of which 18 (1.7%) patients had grade 3 ICI-PI and 1 (0.1%) patient had grade 4 ICI-PI. Five (0.5%) patients developed pancreatitis: 4 patients had grade 2 pancreatitis, and 1 patient had severe pancreatitis culminating in death (grade 5). Except for the patient with severe pancreatitis, all patients with ICI-PI were asymptomatic.

Table 3 shows the results of the univariate analysis investigating the risk factors related to ICI-PI. Renal cancer (OR 7.33, 95% CI 2.90–18.04, p < 0.001), malignant melanoma (OR 4.96, 95% CI 1.59–15.51, p = 0.015), CTLA-4 inhibitors (OR 21.27, 95% CI 6.21–72.86, p < 0.001), multiple ICI monotherapy (OR 6.75, 95% CI 1.45–31.38, p = 0.047), combination ICI therapy (OR 27.94, 95% CI 6.62–117.90, p < 0.001), past history of IFN therapy (OR 13.53, 95% CI 4.55–40.26, p < 0.001), and complications such as irAEs in other organs (OR 9.00, 95% CI 2.96–27.31, p < 0.001), especially in the liver (OR 6.36, 95% CI 2.35–17.25, p < 0.001) and endocrine system (OR 6.62, 95% CI 2.60–16.82, p = 0.001), were associated with a significantly higher risk of ICI-PI. Of the 15 ICI-PI patients with irAEs in other organs, ICI-PI preceded the other irAEs in 2 (13%) patients, ICI-PI occurred concomitantly with other irAEs in 3 (20%) patients, and ICI-PI occurred after other irAEs in 10 (67%) patients. The other irAEs associated with ICI-PI were endocrine disorders in 8 (42.1%) cases, liver disorders in 6 (31.6%) cases, gastrointestinal disorders in 2 (10.5%) cases, and pneumonia and dermatitis in 1 (5.3%) case.

On the other hand, the risk of ICI-PI was significantly lower for lung cancer (OR 0.17, 95% CI 0.056–0.52, p < 0.001) and prior treatment with cytotoxic anticancer agents (OR 0.18, 95% CI 0.068–0.49, p < 0.001). The participants’ OS is shown in Table 3, while Fig. 2 depicts the Kaplan–Meier curve stratified by the presence or absence of ICI-PI. There was no significant difference in the OS of patients with and without ICI-PI (21.8 months, 95% CI 5.5–38.0 vs 15.8 months, 95% CI 13.4–17.7, p = 0.41).

Kaplan–Meier curve stratified by the presence or absence of ICI-related pancreatic injury (ICI-PI). There was no significant difference in the overall survival between patients with and without ICI-PI

The clinical course of patients with ICI-PI is shown in Fig. 3. The median time from commencement of ICI therapy to the onset of ICI-PI was 92 days (19–706). Five of 19 patients developed ICI-PI after discontinuation of ICI (2 weeks, 1 month, 1 month, 1 month, 5 months,) and 14 developed ICI-PI during ICI administration. ICI was discontinued because of ICI-PI in 13 of the 14 patients. One patient continued ICI for 6 weeks, which was subsequently discontinued due to pneumonia. Steroid therapy was administered to 7 of 19 patients, and ICI-PI improved in 5 patients. On the other hand, 12 patients were not administered steroid therapy, and ICI-PI improved in 9 of these patients.

Clinical course of patients with ICI-related pancreatic injury (ICI-PI). Five of 19 patients developed ICI-PI after discontinuation of ICI and 14 developed it during administration of ICI. ICI was discontinued in 13 of the 14 patients, and 1 patient continued ICI therapy. Steroid therapy was administered to 7 of 19 patients, and ICI-PI improved in 5 patients. Twelve patients were not administered steroid therapy, and ICI-PI improved in 9 of them

Six of the 14 patients with ICI-PI improvement were rechallenged with ICIs. All six cases were Grade 3 ICI-PI without pancreatitis. Five of 6 patients were rechallenged with the same ICI (PD-1 inhibitor), and while 1 patient changed ICI from CTLA-4 inhibitor to PD-L1 inhibitor. ICI-PI relapse was observed in only 1 patient (16.7%), which improved with ICI discontinuation and steroid therapy (Fig. 4).

Rechallenge with ICI after improvement in ICI-PI. Six of 14 patients with ICI-PI improvement faced the ICI rechallenge: 5 of 6 patients were rechallenged with the same ICI, and 1 patient received another ICI. ICI-PI relapse was observed in only 1 patient, which improved with ICI discontinuation and steroid therapy

Table S3 summarizes the cases of 5 patients with ICI-PI with pancreatitis [27, 28]. Two of 5 patients developed ICI-PI after discontinuation of ICI (1.5 months, 3 months) and 3 development pancreatic injury during ICI treatment. One of the 3 patients (No. 4) had a recurrence of asymptomatic pancreatic enzyme elevation during rechallenge with the same ICI and new pancreatitis findings on CT. Regarding CT findings, 1 showed severe AP-like findings, 3 had AIP-like findings, and 1 was classified as “other” (pancreatic atrophy).

ICI was discontinued because of ICI-PI in all patients. Steroid therapy was administered in 4 of the 5 cases. Two patients (No.4,5) started steroids when the findings of pancreatitis were discovered, 1 patient (No.3) started for pituitaritis occurring at the same period. One patient (No.1) started them 2 months later, at the time he developed colitis. As for outcome, 4 patients had improved ICI-PI with pancreatitis. One patient (No.5) with a history of nivolumab use and prior liver injury, who had asymptomatic elevated pancreatic enzymes, was admitted 2 days later with severe pancreatitis with abdominal pain and died 3 days later despite steroid and fluid infusion therapy [28]. Since the patient had a history of both nivolumab and pazopanib use, a pathological autopsy was performed to determine the cause of death. the gross specimen of pancreas showed parenchymal and fat necrosis with bleeding, and Inflammation had spread to the retroperitoneum, abdominal cavity, transverse colon, and left adrenal gland. Microscopically, the fat necrosis was observed around the parenchymal necrosis. Inflammatory cell infiltration centering on neutrophils was observed in necrotic lesions of the pancreatic parenchyma. In the remaining pancreatic parenchyma, In addition, markedly more CD8-positive T cells were detected than CD4-positive T cells. The result of pathological autopsy was suggestive of ICI-PI, but the possibility of pancreatitis caused by pazopanib could not be eliminated. Because of previous liver injury, the liver was markedly infiltrated with inflammatory cells in the portal region and parenchyma, and a CD8-predominant T lymphocyte infiltrate was also present. There were no findings suspicious of cardiac irAE or other causes of the acute course of the disease. The cause of death was thought to be multiple organ failure, mainly due to acute pancreatitis.