Comparison of pneumonitis risk between immunotherapy alone and in combination with chemotherapy: an observational, retrospective pharmacovigilance study

Huixia Li; Yifan Zheng; Peihang Xu; Zimu Li; Yukun Kuang; Xiaoqing Feng; Junhao He; Jia Li; Xiao Chen; Lihong Bai; Ke-Jing Tang

doi:10.3389/fphar.2023.1142016

Comparison of pneumonitis risk between immunotherapy alone and in combination with chemotherapy: an observational, retrospective pharmacovigilance study

Front Pharmacol. 2023 Apr 13:14:1142016. doi: 10.3389/fphar.2023.1142016. eCollection 2023.

Authors

Huixia Li¹, Yifan Zheng², Peihang Xu³, Zimu Li⁴, Yukun Kuang¹, Xiaoqing Feng⁵, Junhao He⁵, Jia Li⁶, Xiao Chen⁶, Lihong Bai¹, Ke-Jing Tang^{1

6}

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Clinical Pharmacy Translational Science, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
³ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
⁴ Department of Pulmonary and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
⁵ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
⁶ Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Abstract

Importance: Checkpoint inhibitor pneumonitis (CIP) is a rare but serious adverse event that may impact treatment decisions. However, there is limited information comparing CIP risks between immune checkpoint inhibitor (ICI) monotherapy and combination with chemotherapy due to a lack of direct cross-comparison in clinical trials. Objective: To determine whether ICI combination with chemotherapy is superior to ICI in other drug regimens (including monotherapy) in terms of CIP risk. Study Design and Methods: This observational, cross-sectional and worldwide pharmacovigilance cohort study included patients who developed CIP from the World Health Organization database (WHO) VigiBase and the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Individual case safety reports (ICSR) were extracted from 2015 to 2020 in FAERS and from 1967 to 2020 in VigiBase. Timing and reporting odds ratio (ROR) of CIP in different treatment strategies were used to detect time-to-onset and the risk of pneumonitis after different immunotherapy regimens. Results: A total of 93,623 and 114,704 ICI-associated ICSRs were included in this study from VigiBase and FAERS databases respectively. 3450 (3.69%) and 3278 (2.86%) CIPs occurred after therapy initiation with a median of 62 days (VigiBase) and 40 days (FAERS). Among all the CIPs, 274 (7.9%) and 537 (16.4%) CIPs were associated with combination therapies. ICIs plus chemotherapy combination was associated with pneumonitis in both VigiBase [ROR 1.35, 95% CI 1.18-1.52] and FAERS [ROR 1.39, 95% CI 1.27-1.53]. The combination of anti-PD-1 antibodies and anti-CTLA-4 antibodies with chemotherapy demonstrated an association with pneumonitis in both VigiBase [PD-1+chemotherapy: 1.76, 95% CI 1.52-2.05; CTLA-4+chemotherapy: 2.36, 95% CI 1.67-3.35] and FAERS [PD-1+chemotherapy: 1.70, 95% CI 1.52-1.91; CTLA-4+chemotherapy: 1.70, 95% CI 1.31-2.20]. Anti-PD-L1 antibodies plus chemotherapy combinations did not show the association. Conclusion: Compared to ICI in other drug regimens (including monotherapy), the combination of ICI plus chemotherapy is significantly associated with higher pneumonitis toxicity. Anti-PD-1/CTLA4 medications in combination with chemotherapy should be obviated in patients with potential risk factors for CIP. Trial Registration: clinicaltrials.gov, ChiCTR2200059067.

Keywords: checkpoint inhibitor pneumonitis; chemotherapy; immune checkpoint inhibitor (ICI); immune-related adverse events (IRAE); immunotherapy.