Immune Checkpoint Inhibitor–Induced Diabetes in PD-1/PD-L1 Cancer Trials

Immune Checkpoint Inhibitor–Induced Diabetes (ICI-D) is a rare yet serious immune-related adverse event that can arise in patients undergoing cancer immunotherapy, specifically in clinical trials involving programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) inhibitors. Below is a detailed overview of findings related to ICI-D based on the evaluation of patients enrolled in National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) trials:

### Study Overview:

• **Objective:** To assess the distribution, incidence, and clinical characteristics of ICI-D among cancer patients receiving PD-1/PD-L1 inhibitors.
• **Data Source:** Adverse event reports from the NCI-CTEP database.
• **Study Population:** 13,966 patients treated across 158 clinical trials between June 2015 and December 2022.
• **Treatment Regimens:** Trials included PD-1/PD-L1 monotherapy and combination immunotherapy regimens.

### Key Findings:

1. **Incidence:**

• **Overall Incidence:** The cumulative incidence of ICI-D was **0.52 per 100 treated patients**, indicating that it is a rare adverse event.
• **Variation by Treatment Setting:**
• **Lower Risk:** Patients receiving concurrent chemotherapy had significantly lower risk of developing ICI-D.
• **Higher Risk:** Combination immunotherapy regimens were associated with a markedly higher incidence compared to PD-1 or PD-L1 monotherapy.

2. **Clinical Characteristics:**

• **Hospitalization:** Most patients diagnosed with ICI-D required hospitalization.
• **Intensive Care:** Nearly half of the patients required intensive care, highlighting the severity of the condition.
• **Severe Hyperglycemia:** A key distinguishing feature of ICI-D was severe hyperglycemia, which set it apart from other causes of hyperglycemia such as pre-existing diabetes or metabolic disorders.

3. **Risk Factors:**

• **Combination Immunotherapy:** Patients exposed to combination regimens involving multiple immune checkpoint inhibitors were at higher risk for ICI-D.
• **Concurrent Chemotherapy:** Concurrent chemotherapy appeared to mitigate the risk of ICI-D compared to immunotherapy alone.

4. **Health Care Burden:**

• Despite its rarity, ICI-D imposes a significant health care burden due to the need for extensive medical intervention, including hospitalizations and intensive care management.

### Clinical Implications:

• **Recognition and Management:** Clinicians should be aware of ICI-D as a potential immune-related adverse event, especially when treating patients with combination immunotherapy regimens.
• **Risk Assessment:** Identifying patients at higher risk based on treatment regimens can help guide monitoring strategies and improve clinical outcomes.
• **Treatment Adjustments:** Concurrent chemotherapy may offer protective effects against ICI-D, suggesting potential avenues for optimizing treatment protocols.

### Conclusion:

ICI-D is an uncommon but highly morbid adverse event associated with PD-1/PD-L1 cancer immunotherapy. The risk varies significantly depending on the type of immunotherapy regimen and concurrent treatments. While rare, its severe clinical presentation and substantial health care burden underscore the need for heightened awareness, early diagnosis, and effective management strategies in clinical practice.