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

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04115410
• Other study ID #: SKKU-2019-PD1ICI
• Status: Not yet recruiting
• Start date: July 1, 2020
• Est. completion date: December 31, 2021

Study information

• Verified date: May 2020
• Source: Sungkyunkwan University
• Contact: Yeon-Hee Baek
• Phone: +82-31-299-4377
• Email: waterlily9[@]skku.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 4724
• Est. completion date: December 31, 2021
• Est. primary completion date: September 23, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Immune-Related Adverse Events

Intervention

Drug:
• PD-1 inhibitor
PD-1 inhibitors are a group of checkpoint inhibitors being developed for the treatment of cancer. PD-1 and PD-L1 are both proteins present on the surface of cells. Immune checkpoint inhibitors such as these are emerging as a front-line treatment for several types of cancer. The investigators will include nivolumab, pembrolizumab, and atezolizumab as PD-1 inhibitors as these drugs are reimbursed by health authority of South Korea.
• Chemotherapy Drugs, Cancer
Chemotherapy is a type of pharmacotherapy for cancer, that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. The investigators will include cytotoxic chemotherapy and tyrosine kinase inhibitors (epidermal growth cell receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors).

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Sungkyunkwan University	Ministry of Food and Drug Safety, Korea

References & Publications (9)

Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018 Mar 14;360:k793. doi: 10.1136/bmj.k793. Review. — View Citation

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27. — View Citation

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31. — View Citation

Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer. 2017 Jun 1;123(11):1904-1911. doi: 10.1002/cncr.30642. Epub 2017 Feb 27. Review. — View Citation

Kobayashi K, Nakachi I, Naoki K, Satomi R, Nakamura M, Inoue T, Tateno H, Sakamaki F, Sayama K, Terashima T, Koh H, Abe T, Nishino M, Arai D, Yasuda H, Kawada I, Soejima K, Betsuyaku T; Keio Lung Oncology Group (KLOG). Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung Cancer: A Retrospective Multicenter Analysis. Clin Lung Cancer. 2018 May;19(3):e349-e358. doi: 10.1016/j.cllc.2018.01.001. Epub 2018 Jan 5. — View Citation

Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, Chaft JE, Segal NH, Callahan MK, Lesokhin AM, Rosenberg J, Voss MH, Rudin CM, Rizvi H, Hou X, Rodriguez K, Albano M, Gordon RA, Leduc C, Rekhtman N, Harris B, Menzies AM, Guminski AD, Carlino MS, Kong BY, Wolchok JD, Postow MA, Long GV, Hellmann MD. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2017 Mar;35(7):709-717. doi: 10.1200/JCO.2016.68.2005. Epub 2016 Sep 30. Erratum in: J Clin Oncol. 2017 Aug 1;35(22):2590. — View Citation

Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018 Jan 11;378(2):158-168. doi: 10.1056/NEJMra1703481. Review. — View Citation

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. — View Citation

Remon J, Mezquita L, Corral J, Vilariño N, Reguart N. Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients. J Thorac Dis. 2018 May;10(Suppl 13):S1516-S1533. doi: 10.21037/jtd.2017.12.52. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hazard ratio for immune-related adverse events	The ratio of hazard rates of immune-related adverse events in PD-1 inhibitor users vs. standard chemotherapy users	August 2017 to December 2018
Secondary	Hazard ratio for eleven subdivided groups of immune-related adverse events by organ class	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	August 2017 to December 2018