Disproportionality analysis of interstitial lung disease associated with novel antineoplastic agents during breast cancer treatment: a pharmacovigilance study

Abstract

Background: Studies have shown that some antineoplastic agents may be associated with interstitial lung disease (ILD), but large-scale real-world data are lacking. This study aimed to detect signals of disproportionate reporting for ILD associated with novel antineoplastic agents used in breast cancer treatment.

Methods: In this pharmacovigilance study, we collected data from the FDA Adverse Event Reporting System (FAERS; Jan 01, 2004-Dec 31, 2023) and the Japanese Adverse Drug Event Report (JADER; Jan 01, 2004-Mar 31, 2024) databases. Data retrieval involved direct download of structured datasets from the FDA and PMDA portals. Participant selection included reports of FDA-approved novel antineoplastic agents for breast cancer with documented ILD as a preferred term, excluding duplicates, non-breast cancer indications, unapproved drugs, and cases where drugs were classified as concomitant or interacting. Signals of disproportionate reporting were assessed using the reporting odds ratio (ROR), with statistical significance defined as a lower 95% confidence interval >1 and ≥3 ILD cases.

Findings: A total of 2913 patients with ILD from FAERS and 1868 from JADER were analysed. We identified 9 agents with reporting signals for ILD in FAERS: ROR and 95% confidence interval (CI) for trastuzumab deruxtecan was 12.17 (95% CI 11.04-13.41), atezolizumab 6.04 (5.02-7.28), everolimus 3.21 (2.95-3.50), abemaciclib 2.87 (2.52-3.27), pertuzumab 2.84 (2.49-3.25), olaparib 2.29 (1.65-3.19), trastuzumab emtansine 2.27 (1.91-2.69), pembrolizumab 2.06 (1.65-2.58), and trastuzumab 1.36 (1.25-1.49). 7 drugs associated with ILD in JADER are also captured in FAERS. Fatal cases presented with a shorter median onset time compared to nonfatal cases (56 vs. 71 days in FAERS, P = 0.015; 59 vs. 76.5 days in JADER, P = 0.046). Analyses indicated stronger reporting associations between novel antineoplastic agents and ILD compared to chemotherapeutics (FAERS: OR 2.47, 2.16-2.81; JADER: OR 1.61, 1.37-1.88; P < 0.0001). ILD reports were more frequent among older patients (FAERS: HR 1.0097, 1.0036-1.0159, P = 0.0020; JADER: HR 1.0183, 1.0094-1.0270, P < 0.0001), while higher weight correlated with fewer reports (FAERS: HR 0.9783, 0.9729-0.9836; P < 0.0001).

Interpretation: Our study detected signals of disproportionate reporting for ILD with some novel antineoplastic agents in breast cancer, fatal cases had a shorter median onset time than nonfatal ones. Novel antineoplastic agents showed stronger signal of disproportionate reporting associations with ILD than chemotherapeutics. Older age and lower weight were associated with more frequent ILD reports. The limitations-including incomplete data, inherent pharmacovigilance biases, and coprescription bias-preclude causal interpretation of the observed associations and may lead to overestimation or underestimation of reporting signals. These findings highlight the need for vigilant ILD monitoring but require validation through prospective studies to clarify true clinical risks.

Funding: None.

Keywords: Adverse event; Breast cancer; Interstitial lung disease; Novel antineoplastic agent.

Fig. 1

Flow chart of the study Abbreviations: FAERS, FDA Adverse Event Reporting System; JADER, Japanese Adverse Drug Event Report; MedDRA, Medical Dictionary for Regulatory Activities.

Fig. 2

The signal of ILD associated with novel antineoplastic agents in the treatment of breast cancer. (A) Forest plot of ROR values for different novel antineoplastic agents associated with ILD in the FAERS database. (B) Forest plot of ROR values for different novel antineoplastic agents associated with ILD in the JADER database (C) ROR values of the top 10 most frequently reported PTs under the SMQ level for ILD in the FAERS database. (D) Heatmap showing the signal of disproportionate reporting for the PT level in the FAERS database among different novel antineoplastic agents. Red indicates that the lower limit of the 95% CI of the ROR >1 and at least 3 cases of ILD were reported. Blue indicates that the lower limit of the 95% CI of the ROR <1, or fewer than 3 cases of ILD were reported. Gray indicates no ILD-related reports. Abbreviations: ROR, reporting odds ratio; CI, confidence interval; TKIs, tyrosine kinase inhibitors; mAbs, monoclonal antibodies; ADCs, antibody-drug conjugates; T-DM1, trastuzumab emtansine; T-Dxd, trastuzumab deruxtecan; SG, sacituzumab govitecan; ICIs, immune checkpoint inhibitors; CDK4/6, cyclin-dependent kinase 4/6; PARP, poly ADP-ribose polymerase; and PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; SMQ, standardized MedDRA query; ILD, interstitial lung disease; FAERS, FDA Adverse Event Reporting System; JADER, Japanese Adverse Drug Event Report; PT, preferred term.

Fig. 3

Cumulative distribution curves showing the time to onset of ILD after treatment with novel antineoplastic agents for all cases and fatal cases in the FAERS (A) and JADER (B) databases. Statistical significance was assessed using the nonparametric Wilcoxon rank sum test. Abbreviations: IQR, interquartile range; ILD, interstitial lung disease; FAERS, FDA Adverse Event Reporting System; JADER, Japanese Adverse Drug Event Report.

Fig. 4

Analysis of ILD-associated fatal cases with novel antineoplastic agents. (A) and (B) showing the fatality proportions and number for different novel antineoplastic agents in the FAERS and JADER databases, respectively. (C) and (D) showing the comparison of fatality risk between ILD and non-ILD (other PT) patients in the FAERS and JADER databases, respectively. Statistical significance was assessed using the chi-square test. Abbreviations: T-DM1, trastuzumab emtansine; T-Dxd, trastuzumab deruxtecan; Chisq, chi-square; ILD, interstitial lung disease; PT, preferred term; FAERS, FDA Adverse Event Reporting System; JADER, Japanese Adverse Drug Event Report.

Fig. 5

Volcano plot comparing ILD signal between novel antineoplastic agents and chemotherapeutic drugs. (A) and (B) show the comparison between novel antineoplastic agents and chemotherapeutic drugs in the FAERS and JADER databases, respectively. The x-axis represents the logarithm of the ROR, and the y-axis represents the negative base-10 logarithm of the adjusted P value, obtained from Fisher's exact test followed by Bonferroni correction. The colour intensity of each point indicates the number of reports, with warmer (redder) colours representing higher numbers of reports. Drugs in the upper right quadrant exhibit both higher ILD signals and significant statistical differences. Abbreviations: T-DM1, trastuzumab emtansine; T-Dxd, trastuzumab deruxtecan; Chisq, chi-square; ROR, reporting odds ratio; ILD, interstitial lung disease; FAERS, FDA Adverse Event Reporting System; JADER, Japanese Adverse Drug Event Report.