PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events: a Cohort Study

• Conditions: Carcinoma, Non-Small-Cell Lung; Immune-Related Adverse Events
• Interventions: Drug: PD-1 inhibitor; Drug: Chemotherapy Drugs, Cancer

• Registration Number: NCT04115410
• Lead Sponsor: Sungkyunkwan University

Brief Summary

The objective of our study is to assess the risk of immune-related adverse events associated with PD-1 inhibitors use compared to standard chemotherapy use in patients with non small cell lung cancer, using nationwide healthcare database.

Detailed Description

This observational, retrospective cohort study will evaluate the risk of immune-related adverse events associated with PD-1 inhibitors use compared to standard chemotherapy use in patients with non small cell lung cancer, using nationwide healthcare database. PD-1 inhibitors will be defined as nivolumab, pembrolizumab, and atezolizumab. Standard chemotherapy will be defined as cytotoxic chemotherapy or tyrosine kinase inhibitors (epidermal growth cell receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors). The investigators will assess exposure on the cohort entry using the intention-to-treat approach with the 6-month exposure risk window from the first PD-1 inhibitor prescription to avoid bias from informative censoring. Immune-related adverse events will be defined by using pre-specified algorithms using diagnosis and corticosteroid prescription records (high dose of oral corticosteroids, defined as ≥ 30 mg/day, or systemic corticosteroid injection) to reduce outcome misclassification. The investigators will use a multivariable Cox proportional hazard model to estimate hazard ratio (HR) and 95% confidence intervals (CI). The model will be adjusted for pre-existing autoimmunity, history of lung cancer surgery, radiation therapy, tyrosine kinase inhibitor use, and previous systemic corticosteroid use. All analyses will be undertaken using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Study Timeline

• Study First Submitted: 2019-10-02
• Study First Submitted QC: 2019-10-02
• Study First Posted: 2019-10-04
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-27
• Last Update Posted: 2020-05-28
• Study Start: 2020-07-01
• Primary Completion: 2021-09-23
• Study Completion: 2021-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 4724

Inclusion Criteria

• Individuals who were diagnosed with lung cancer (ICD-10: C33-C34) between 2017 and 2018.

Exclusion Criteria

• Individuals less than 18 years of age
• Individuals received any systemic anticancer therapies in 2007
• Having no records of prescription of PD-1 inhibitors or standard chemotherapy at least once between 2017 and 2018
• Individuals received treatments indicated for small cell lung cancer (etoposide, ifosfamide, irinotecan, belotecan, and topotecan) on or before the first date of standard chemotherapy to restrict study subjects to patients with non small cell lung cancer only.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
PD-1 inhibitor	PD-1 inhibitor	Patients over 18 years of age with a diagnosis of non-small cell lung cancer and being received PD-1 inhibitors as a second line treatment from cytotoxic chemotherapy or as a third line for those received tyrosine kinase inhibitors as a first line, from August 2017 (the first month PD-1 inhibitors were reimbursed in South Korea) to September 2018.
Chemotherapy Drugs, Cancer	Chemotherapy Drugs, Cancer	Patients over 18 years of age with a diagnosis of non-small cell lung cancer and being received cytotoxic chemotherapy or tyrosine kinase inhibitors (epidermal growth cell receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors) from August 2017 to September 2018. Each patient switching to PD-1 inhibitor will be matched to three reference standard chemotherapy users.

Primary Outcome Measures

Name	Time	Method
Hazard ratio for immune-related adverse events	August 2017 to December 2018	The ratio of hazard rates of immune-related adverse events in PD-1 inhibitor users vs. standard chemotherapy users

Secondary Outcome Measures

Name	Time	Method
Hazard ratio for eleven subdivided groups of immune-related adverse events by organ class	August 2017 to December 2018	The ratio of hazard rates of eleven subdivided organ-specific immune-related adverse events (pulmonary, endocrine, cardiovascular, gastrointestinal, hepatic, muscluoskeletal, neurological, ocular, renal, skin, and hematologic) in PD-1 inhibitor users vs. standard chemotherapy users