INTRODUCTION

Immune checkpoint inhibitors (ICIs) have shown clinical efficacy in the treatment of various malignancies (1,2), such as melanoma, gastrointestinal tumors, urological cancers, otorhinolaryngological cancers, and respiratory cancers, including non–small cell lung cancer (3–5). ICIs are a class of immunotherapy medications that enhance T cell–mediated antitumor effects by targeting cytotoxic T lymphocyte–associated protein 4 (CTLA-4), programmed cell death protein 1 (PD1), and programmed death ligand 1 (3,6). However, ICIs also induce distinct adverse inflammatory reactions known as immune-related adverse events (irAEs) (7). The etiology of irAEs has been hypothesized as blockade of immune inhibitory mechanisms and activation of the immune system; notably, this process is similar to the mechanism involved in the therapeutic action of ICIs (8,9). Because the administration of ICIs in the management of various malignancies has rapidly increased in recent years, more precise evaluation and management of ICIs is necessary.

Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 has been widely used to evaluate and grade ICI-induced pancreatic injury (ICI-PI) with a focus on pancreatic enzymes (10). Many cases of ICI-PI are asymptomatic. In a recent systematic review and meta-analysis, the incidence of asymptomatic lipase elevation after ICI therapy was 2.7% and that of grade 2 pancreatitis was 1.9% (10). Although CTCAE version 4.0 classified ICI-PI into grades 1–4, scarce information is available for grades 1 and 2 ICI-PI, which may trigger pancreatitis. The incidence of pancreatitis is higher when CTLA-4 and PD1 inhibitors are used in combination than when CTLA-4 or PD1 inhibitors are used alone (10,11). In clinical practice, however, multiple ICIs are used simultaneously or asynchronously (dual immunotherapy), and comparisons between dual immunotherapy and monoimmunotherapy in patients with ICI-PI are limited. Incorporation of ICI-PI with symptoms has been proposed for CTCAE version 5.0. Although the term ICI-PI may not be used in this version, the grading of this condition may be similar to that of clinical acute pancreatitis.

The National Comprehensive Cancer Network (NCCN) Guidelines (12) include a pancreatitis grading system for the management of immunotherapy-related toxicities. This grading system for pancreatitis (ICI-associated pancreatitis) is based on elevations of pancreatic enzymes, radiologic findings, or clinical findings.

The imaging features of ICI-PI have not been sufficiently evaluated, although a few reports have described the imaging manifestations of both focal and diffuse pancreatic involvement (10,13–16). Alternative causes of enzyme elevations should be ruled out using additional information such as ultrasound and/or pathological findings.

This study was performed to investigate the incidence and imaging characteristics of ICI-PI in a large cohort. We compared the severity grade of ICI-PI based on simultaneous, asynchronous, and monoimmunotherapy. Furthermore, we evaluated the CTCAE severity grade (versions 5.0 and 4.0) and characteristics of ICI-associated pancreatitis (NCCN Guidelines) in this cohort.

METHODS Study cohort and design

We retrospectively evaluated consecutive patients with advanced malignancies treated with ICIs at Nagoya City University Graduate School of Medical Sciences from August 1, 2015, to October 31, 2022. The detailed study objectives, design, and methodology were reviewed and approved by the review board of Nagoya City University Graduate School of Medical Sciences (no. 60-22-0094) (UMIN000058565).

Definitions ICI-PI

CTCAE version 4.0 was used to assess ICI-PI, which was graded according to the serum pancreatic enzyme elevation as follows: grade 1, >upper limit of normal (ULN)–1.5 × ULN; grade 2, >1.5–2.0 × ULN; grade 3, >2.0–5.0 × ULN; and grade 4, >5.0 × ULN. The serum amylase and lipase concentrations were collected from the beginning of ICI therapy to the beginning of the next treatment, such as cytotoxic chemotherapy and/or radiotherapy.

CTCAE version 5.0 was used to assess ICI-PI (including symptoms), which was graded according to the degree of serum pancreatic enzyme elevation as follows: grade 1, >ULN–1.5 × ULN; grade 2, >1.5–2.0 × ULN or 2.5–5.0 × ULN with no symptoms; grade 3, 2.0–5.0 × ULN with symptoms or >5.0 × ULN with no symptoms; and grade 4, >5.0 × ULN with symptoms. The following factors were evaluated as predictive factors for ICI-PI in univariable and multivariable analyses: age, sex, body mass index, malignancy, number of ICI cycles, and method of ICI administration.

Imaging assessment

Because the time to resolution on imaging ranged from 24 to 201 days in patients with ICI-associated pancreatitis (17), we evaluated computed tomography (CT) images within 4 weeks of the time point of maximum serum pancreatic enzyme elevation. For comparison, we used CT images before pancreatic injury as a reference.

The severity of pancreatitis was assessed in all patients using the Balthazar CT severity index (CTSI) (18,19) and the Mortele modified (20) CTSI. Diffuse pancreatic enlargement was defined as enlargement extending from the head to the tail of the pancreas. Focal pancreatic enlargement was defined as localized pancreatic enlargement. The presence and extent of necrosis in each case were classified into 4 categories according to the Mortele modified CTSI. The Balthazar CTSI was calculated by adding the Mortele modified CTSI and categorized as the CTSI.

ICI-associated pancreatitis

ICI-associated pancreatitis was defined according to the NCCN Guidelines (12) and graded as follows: mild (grade 1): pancreatic enzyme elevation >3 × ULN or CT or clinical findings consistent with pancreatitis; moderate (grade 2): pancreatic enzyme elevation >3 × ULN, CT imaging findings consistent with pancreatitis, or clinical findings consistent with pancreatitis (at least 2 of these 3 criteria); and severe (grades 3 and 4): pancreatic enzyme elevation and CT imaging findings of severe symptoms. Other potential causes of pancreatitis, such as alcohol consumption, gallstones, hypertriglyceridemia, viral infection, genetic predisposition, tumors, or anatomical variants, were excluded based on clinical information and laboratory data for all patients.

Statistical analysis

Categorical variables were compared using the χ2 test and Fisher exact test, whereas continuous variables were compared using the Mann-Whitney U test. P values < 0.05 were considered statistically significant, and all statistical tests were 2-sided. Factors exhibiting significant associations (P < 0.2) in univariable analysis were subsequently subjected to multivariable analysis. The correlation between the number of ICI cycles and pancreatic injury was analyzed using the Pearson correlation coefficient. All statistical analyses were performed using SPSS software (version 23; IBM, Armonk, NY).

RESULTS Patient characteristics

In total, 843 consecutive patients with advanced malignancies treated by ICI therapy were enrolled in this study. Patients' demographic and clinical characteristics are summarized in Table 1. Their median age was 71 years (range: 26–91 years). The median number of ICI cycles was 10 (range: 1–191). In our cohort, no significant correlations were observed between the duration of ICI administration and ICI-PI occurrence (total, r = 0.14; grade ≥3, r = 0.08). A total of 158 (18.7%) patients received dual immunotherapy. Among those patients, 78 (9.3%) received simultaneous immunotherapy (i.e., a combination of PD1 and CTLA4 inhibitors). Eighty (9.5%) patients were treated with multiple asynchronous ICIs.

Table 1. - Patient characteristics (N = 843) Sex, male/female 596/247 Age, yr 71 (26–91) Median BMI, kg/m2 20.3 Malignancy  Respiratory cancer 294 (34.9)  Gastrointestinal cancer 164 (19.5)  Urological cancer 136 (16.1)  Otorhinolaryngological cancer 135 (16.0)  Melanoma 89 (10.6)  Other 25 (3.0) No. of cycles 10 (1–191) Dual or monoimmunotherapy  Dual 158 (18.7)   Simultaneous (nivolumab and ipilimumab) 78 (9.3)   Asynchronous 80 (9.5)  Mono 685 (81.2)

Data are presented as n, n (%), or median (range) unless otherwise indicated.

BMI, body mass index.

Comparison of ICI-PI according to CTCAE version 4.0 Dual vs monoimmunotherapy

As summarized in Table 2, the incidence of ICI-PI was higher in the dual immunotherapy group than in the monoimmunotherapy group (56.3% [89/158] vs 44.2% [303/685]; P = 0.008, distribution: P = 0.02). The incidence of grade ≥3 pancreatic injury was significantly higher in patients with dual immunotherapy than in those with monoimmunotherapy (16.5% [26/158] vs 7.9% [54/685]; P = 0.002). Supplementary Table 1 (see Supplementary Digital Content 1, https://links.lww.com/CTG/B46) summarizes the results of univariable and multivariable analyses of predictive factors for ICI-PI. In multivariable analyses, total and grade ≥3 pancreatic injuries were associated with the number of ICI cycles (≥10) and dual immunotherapy.

Table 2. - ICI-induced pancreatic injury according to CTCAE version 4.0 grade: comparison between patients who received dual or monoimmunotherapy CTCAE grade Dual immunotherapy (n = 158) Monoimmunotherapy (n = 685) P value Total 89 (56.3) 303 (44.2) 0.008a ≥3 26 (16.5) 54 (7.9) 0.002a 1 46 (29.1) 209 (30.5) 0.020b 2 17 (10.8) 40 (5.9) 3 20 (12.7) 36 (5.3) 4 6 (3.8) 18 (2.6)

Data are presented as n (%).

CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor.

aP < 0.01.

bP < 0.05.

Simultaneous vs monoimmunotherapy

Table 3 compares ICI-PI between patients who received simultaneous and monoimmunotherapy (all grades of ICI-PI: 60.3% [47/78] vs 44.2% [303/685]; P = 0.008, distribution: < 0.001). The incidence of grade ≥3 pancreatic injury was significantly higher in patients with simultaneous immunotherapy than that in those with monoimmunotherapy (23.1% [18/78] vs 7.9% [54/685], respectively; P < 0.001). Notably, total and grade ≥3 pancreatic injuries were associated with the number of ICI cycles (≥10) and simultaneous immunotherapy (see Supplementary Table 2, Supplementary Digital Content 1, https://links.lww.com/CTG/B46).

Table 3. - ICI-induced pancreatic injury according to CTCAE version 4.0 grade: comparison between patients who received simultaneous (nivolumab and ipilimumab) or monoimmunotherapy CTCAE grade Simultaneous immunotherapy (n = 78) Monoimmunotherapy (n = 685) P value Total 47 (60.3) 303 (44.2) 0.008a ≥3 18 (23.1) 54 (7.9) <0.001b 1 18 (23.1) 209 (30.5) <0.001b 2 11 (14.1) 40 (5.9) 3 15 (19.2) 36 (5.3) 4 3 (3.8) 18 (2.6)

Data are presented as n (%).

CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor.

aP < 0.01.

bP < 0.001.

Simultaneous vs asynchronous immunotherapy

Table 4 compares ICI-PI between the simultaneous and asynchronous immunotherapy groups. Although no significant differences were observed in the overall incidence (all grades of ICI-PI: 60.3% [47/78] vs 52.5% [42/80]; P = 0.341), the incidence of grade ≥3 pancreatic injury and its distribution were significantly different in patients who received simultaneous immunotherapy compared with asynchronous immunotherapy (P = 0.032 and P = 0.035, respectively). However, no factors had significant associations with these cohorts in multivariable analysis (see Supplementary Table 3, Supplementary Digital Content 1, https://links.lww.com/CTG/B46).

Table 4. - ICI-induced pancreatic injury according to CTCAE version 4.0 grade: comparison between patients who received simultaneous (nivolumab and ipilimumab) or asynchronous immunotherapy CTCAE grade Simultaneous immunotherapy (n = 78) Asynchronous immunotherapy (n = 80) P value Total 47 (60.3) 42 (52.5) 0.341 ≥3 18 (23.1) 8 (10.0) 0.032a 1 18 (23.1) 28 (35.0) 0.035a 2 11 (14.1) 6 (7.5) 3 15 (19.2) 5 (6.25) 4 3 (3.8) 3 (3.8)

Data are presented as n (%).

CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor.

aP < 0.05.

Imaging and clinical findings in patients with grade ≥3 pancreatic injury

Among all 843 patients, 80 (9.5%) had grade ≥3 ICI-PI. The imaging and clinical findings of these patients are summarized in Table 5. Among these 80 patients, CT images were available for 70 (87.5%). Imaging evidence of pancreatitis was observed in 16 (20.0%) patients. Diffuse pancreatic enlargement was present in 14/16 (87.5%) patients and focal pancreatic enlargement in 2/16 (12.5%) patients. Peripancreatic fat stranding was noted in 12/16 (75.0%) patients. No patients exhibited pancreatic necrosis. The CTSI was < 3 in all patients. Among the 16 patients with imaging evidence of pancreatitis, ICI-PI grades 3 and 4 were present in 1 and 15 patients, respectively.

Table 5. - Imaging and clinical findings of patients with CTCAE grade ≥3 (n = 80) CT images available within 4 wk 70 (87.5) Imaging evidence of pancreatitis 16/70 (20.0)  Pancreatic enlargement 16   Diffuse/focal 14/2  Peripancreatic inflammation 12  Necrosisa 0/8 (0.0)  CTSI, 1/2/≥3 2/14/0 Symptomatic 3/80 (3.8)  Steroid responsiveness, improvement/resistance 3/0

Data are presented as n or n (%).

CT, computed tomography; CTSI, computed tomography severity index; CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor.

aAmong 16 patients with imaging evidence of pancreatitis, contrast-enhanced images were available in 8.

Comparison of severity grade according to CTCAE versions 4.0 and 5.0

Supplemental Table 4 (see Supplementary Digital Content 1, https://links.lww.com/CTG/B46) compares the severity grade according to CTCAE versions 4.0 and 5.0. The number of cases categorized as grade 2 was higher in accordance with CTCAE version 5.0 than with version 4.0 (113 [13.4%] vs 57 [6.8%]; P < 0.001). However, the number of cases categorized as grade ≥3 was lower (24 [2.8%] vs 80 [9.5%], P < 0.001).

ICI-associated pancreatitis

Only 1 patient had imaging evidence of pancreatitis (Figure 1a and b) without abdominal pain or pancreatic enzyme elevation. In total, 33 (3.9%) cases of ICI-associated pancreatitis were classified as mild (grade 1), 12 (1.4%) as moderate (grade 2), and 3 (0.4%) as severe (grades 3 and 4). Steroid therapy was used to treat the severe cases (prednisone at 1 mg/kg/d, tapered slowly over 4–6 weeks), and all cases were cured. No patients developed organ failure that would be classified as mild acute pancreatitis according to the revised Atlanta classification.

Figure 1.:

Representative contrast-enhanced computed tomography images of immune checkpoint inhibitor–associated pancreatitis. (a, b) Diffuse pancreatic enlargement. (c, d) Focal pancreatic enlargement. These images demonstrate parenchymal enlargement with reduced contrast enhancement (yellow triangle) and/or perifocal fatty edema (yellow arrows).

Endoscopic ultrasound and pathological features of ICI-associated pancreatitis

Figure 2 shows endoscopic ultrasound (EUS) images from a patient who had ICI-associated pancreatitis with focal pancreatic enlargement. The head of the pancreas was mottled, showing a high and low echoic pattern with peripancreatic fat stranding. The main pancreatic duct was not dilated but exhibited a hyperechoic margin (Figure 2a), while the body and tail of the pancreas were normal in appearance (Figure 2b). An enlarged lymph node was punctured with an EUS-guided core biopsy needle to distinguish ICI-associated pancreatitis from recurrence of the baseline malignancy (Figure 2c).

Figure 2.:

Endoscopic ultrasound images and findings of immune checkpoint inhibitor–associated pancreatitis. (a) The head of the pancreas was swollen with scattered hyperechoic and hypoechoic areas, and the main pancreatic duct was not dilated (yellow triangle). (b) Relatively normal body and tail of the pancreas. (c) A swollen lymph node beside the pancreas was punctured with a 22-gauge needle.

Figure 3 shows the pathological findings of the specimen. Adequate tissue was obtained and showed severe lymphocytic infiltration (Figure 3a) without evidence of malignancy. Immunohistochemistry for CD4 (Figure 3b) and CD8 (Figure 3c) showed more severe infiltration of CD8+ lymphocytes than CD4+ lymphocytes.

Figure 3.:

Pathological findings of swollen peripancreatic lymph node. (a) Hematoxylin and eosin staining demonstrated lymphocytes clustered with other inflammatory cells. Immunohistochemical findings of (b) CD3, (c) CD4, and (d) CD8 are presented. The CD8+/CD4+ ratio was high, consistent with the findings for immune-related adverse events. Scale bar = 50 mm.

DISCUSSION

Checkpoint inhibition and immunomodulation represent notable advancements in the field of advanced malignancies. However, the irAEs associated with ICI therapy pose a challenge for clinical management. Pancreatitis is one such rare adverse event of ICI therapy for malignancies (11,15). In a recent systematic review and meta-analysis (10), the incidence of asymptomatic lipase elevation after ICI therapy was 2.7% (211/7,702) and that of grade 2 pancreatitis was 1.9% (150/7,702). The evaluation was based on CTCAE version 4.0 with a focus on ICI-PI. In the meta-analysis, the number of patients in the studies ranged from 29 to 682, and 6.4% (493/7,702) of all patients received simultaneous immunotherapy (nivolumab and ipilimumab). All other patients received monoimmunotherapy. We evaluated 843 patients treated with ICI therapy; among them, 392 (46.5%) developed any grade of ICI-PI based on CTCAE version 4.0, which includes asymptomatic pancreatic injury. Because most cases were asymptomatic, the rate of ICI-PI varied based on the frequency of blood examinations. ICI-PI does not reflect ICI-associated pancreatitis in spite of the indication for treatment. We adopted the definition of ICI-associated pancreatitis based on the NCCN Guidelines (12) and confirmed that 1.8% (15/843) of cases were grade ≥2, consistent with the results of the abovementioned recent systematic review and meta-analysis (10).

In previous studies, the risk of ICI-PI and ICI-associated pancreatitis was higher in patients treated with combination ICI therapy than in those treated with ICI monoimmunotherapy (21–24). Our study demonstrated that compared with monoimmunotherapy, both simultaneous immunotherapy and dual immunotherapy tended to be associated with a higher rate of both total pancreatic injury in multivariable analyses. Although no significant difference was found between simultaneous and asynchronous immunotherapy among all cases of pancreatic injury (P = 0.341), the incidence of grade ≥3 pancreatic injury tended to be higher in the simultaneous immunotherapy group (P = 0.032). The rates of simultaneous and dual immunotherapy were relatively high (9.3% and 18.7%, respectively) in our large cohort based on real clinical practice, which may explain the higher incidence of ICI-PI.

CTCAE version 5.0 includes assessment of ICI-PI and its symptoms. In our cohort, the number of cases of grade 2 ICI-PI was higher in accordance with CTCAE version 5.0 than 4.0 (113 [13.4%] vs 57 [6.8%]; P < 0.001). However, the number of cases of grade ≥3 ICI-PI was lower in accordance with CTCAE version 5.0 than with 4.0 (24 [2.8%] vs 80 [9.5%]; P < 0.001). Because a few cases required steroid therapy, the results obtained using CTCAE version 5.0 might be more appropriate. However, if we assess the severity of ICI-PI based only on the serum pancreatic enzyme levels, CTCAE version 4.0 might be more suitable.

In most of the patients, the radiological findings were similar to those of mild acute pancreatitis (25). Das et al (17) assessed contrast-enhanced CT (CECT) images in 25 patients receiving ICI therapy with the evidence of pancreatitis. They revealed diffuse pancreatic enlargement in 56.0% of the patients and focal enlargement in 44.0%. In our cohort, we found radiological evidence of pancreatitis in 16 patients among all those with grade ≥3 ICI-PI (Table 5), and 1 patient had no pancreatic enzyme elevation. In total, 17 (2.0%) of all 843 patients had imaging evidence of ICI-associated pancreatitis. Fourteen (82.4%) patients showed diffuse enlargement of the pancreas (Figure 1a and b), while 3 (17.6%) exhibited focal enlargement (Figure 1c and d). Similar to a previous report, all our cases were classified as mild pancreatitis without necrosis (17). Therefore, most patients with ICI-PI or ICI-associated pancreatitis in our cohort did not develop life-threatening conditions such as severe acute pancreatitis, which can lead to transient organ failure (26). Fatal irAEs occur in 0.36% of patients who receive ICI therapy (27) and are often caused by pneumonitis, hepatitis, and neurotoxic adverse events. However, life-threatening pancreatitis is rare (28,29). Clinicians in various departments should be aware of this possibility and collaborate with gastroenterologists in the management of such patients. Postpancreatic atrophy was observed in CT imaging in 7.7% of patients with ICI exposure (30). Although this does not always correlate with endocrine or exocrine dysfunction (31,32), further studies are warranted to clarify the long-term changes in pancreatic function following ICI administration.

No optimal treatment for ICI-associated pancreatitis has yet been established. The NCCN Guidelines (12) for the management of ICI-related toxicities do not recommend intervention for asymptomatic pancreatic enzyme elevations. Steroid therapy (prednisone/methylprednisolone at 0.5–1.0 mg/kg/d, tapered slowly over 4–6 weeks) should be used for patients with moderate-to-severe ICI-associated pancreatitis. We treated our patients with severe ICI-associated pancreatitis using steroid therapy, and all were cured. However, some researchers (33) have argued that steroids have no value in the management of ICI-associated pancreatitis. They indicated that steroids cannot prevent either short-term complications or long-term complications. Further studies are required to determine the optimal management of ICI-PI and ICI-associated pancreatitis.

For patients with suspected ICI-associated pancreatitis, the NCCN Guidelines recommend abdominal CECT as the first-line examination. However, some reports have indicated that CECT plays a limited role in the diagnosis of ICI-associated pancreatitis, with a sensitivity of only 17% (34). In patients with malignancy, it is important to exclude metastasis. Although EUS may play an important role in diagnosis, reports of EUS imaging findings of ICI-associated pancreatitis are rare. Only a few case reports have described the detection of diffuse hypoechoic pancreatic enlargement with scattered hypoechoic areas and patchy, heterogeneous parenchyma (35,36) or a hypoechoic mass in the head of the pancreas causing main pancreatic duct stricture (37). In this study, we found swelling of the pancreatic head (Figure 2a) with scattered hyperechoic and hypoechoic areas, without dilation of the main pancreatic duct and with a relatively normal body and tail of the pancreas (Figure 2b). No definitive ultrasound imaging features of ICI-associated pancreatitis have been established. EUS is somewhat useful for excluding space-occupying lesions, but EUS-guided fine-needle biopsy is the acquisition of tissue for histopathological diagnosis (36). Although there is limited information on the histopathological findings of ICI-associated pancreatitis, an elevated CD8+/CD4+ ratio may indicate features consistent with irAEs, similar to the findings observed in liver biopsies (38). We detected a swollen lymph node beside the head of the pancreas (Figure 2c) and punctured it with a 22-gauge needle to rule out underlying malignancy. The CD8+/CD4+ T-lymphocyte ratio was high in the specimen (Figure 3c and d), consistent with the findings of irAEs. Although diagnosing ICI-associated pancreatitis might be challenging in some cases, EUS (plus EUS-guided fine-needle biopsy) provides ultrasound imaging and pathological findings that can play an important diagnostic role.

A strength of this study is that it was based on a large series of patients undergoing ICI therapy. However, it also has certain limitations. First, this was a retrospective observational study conducted in various clinical departments, and the imaging modalities were chosen at the clinicians' discretion. Because many cases of ICI-PI are asymptomatic, clinicians do not always perform imaging tests, instead conducting ongoing pancreatic enzyme monitoring. Furthermore, not all patients diagnosed with pancreatitis underwent CECT, which led to an underestimation of grading outcomes. Second, the cause of pancreatic injury is usually complex and involves numerous factors. Therefore, although we were able to exclude most reported causes of pancreatitis, we could not confirm that every case of pancreatic injury was related to ICI therapy. Future prospective clinical trials and multicenter cancer registries should be performed to more closely evaluate asymptomatic biochemical and symptomatic pancreatitis.

In conclusion, we evaluated the incidence and imaging characteristics of ICI-PI in a large cohort. Compared with monoimmunotherapy, simultaneous and dual immunotherapy tend to be associated with a higher rate of both total and grade ≥3 pancreatic injuries. ICI-associated pancreatitis was observed in 5.7% of patients, including 1.8% with moderate or severe pancreatitis. We treated symptomatic patients with steroids and obtained favorable outcomes; however, the long-term outcomes of ICI-PI and ICI-associated pancreatitis require careful follow-up. Further studies are warranted to develop precise and appropriate treatment without compromising the efficacy of ICI therapy.

CONFLICTS OF INTEREST

Guarantor of the article: Yasuki Hori, MD, PhD, and Itaru Naitoh, MD, PhD.

Specific author contributions: Y.H. and I.N.: conception and design. Y.H., M.Y., A.K., K.K., H.S., A.A., T.T., and Y.K.: analysis and interpretation of the data. Y.H., A.N.-I., T.K., and T.Y.: imaging and pathological assessment. Y.H., A.N.-I., T.K., and I.N.: drafting of the article. S.T.: critical revision of the article for important intellectual content. H.K.: final approval of the article.

Financial support: This work was supported by JSPS KAKENHI Grant Number 22K16027 and The Hori Sciences & Arts Foundation Grant Number JOSE205003. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the paper.

Potential competing interests: None to report.

Clinical trial registration number: UMIN000058565.

Study Highlights

WHAT IS KNOWN ✓ Common Terminology Criteria for Adverse Events–based information regarding grade 1 and 2 immune checkpoint inhibitor–induced pancreatic injury (ICI-PI) is limited. ✓ Concurrent immunotherapy is associated with an increased risk of ICI-PI.

WHAT IS NEW HERE ✓ Less than half of all patients (46.5%) who received ICI therapy developed any grade of ICI-PI, with 9.5% experiencing grade ≥3 ICI-PI. ✓ Dual immunotherapy, administered asynchronously, is a risk factor of ICI-PI. ✓ The simultaneous administration group exhibited a higher incidence of grade ≥3 pancreatic injury than the asynchronous group. REFERENCES 1. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372(4):320–30. 2. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375(19):1823–33. 3. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet 2021;398(10304):1002–14. 4. Knight T, Cooksley T. Emergency presentations of immune checkpoint inhibitor-related endocrinopathies. J Emerg Med 2021;61(2):140–6. 5. Porcu M, Solinas C, Migali C, et al. 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