Adverse events profiles of pemetrexed: a Food and Drug Administration Adverse Event Reporting System

Our plain-English summary of Adverse events profiles of pemetrexed: a Food and Drug Administration Adverse Event Reporting System, by L. Wang, J. Su, C. Huang, et al (Frontiers in Medicine, 2026).

The study

• Authors: L. Wang, J. Su, C. Huang, Y. Yang, Y. Xu
• Journal: Frontiers in Medicine
• Published: 2026;13:1750861
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pemetrexed is a folate-pathway-targeting antineoplastic agent widely used in non-squamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma. We used the US Food and Drug Administration Adverse Event Reporting System (FAERS) to characterize pemetrexed-associated adverse events to inform clinical safety monitoring.

Methods: Pemetrexed-related reports were retrieved from the FAERS database from first quarter of 2004 through the fourth quarter of 2024. All reports were coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. We performed descriptive analyses and disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM), and Bayesian confidence propagation neural network (BCPNN; information component [IC]) to identify safety signals. Statistical significance was defined as ROR >1 with the lower 95% confidence interval (CI) >1.

Results: We identified 27,098 pemetrexed-associated reports in the FAERS database (2004-2024), in which pemetrexed was designated as the primary suspect drug. Signal detection based on these reports identified 653 significant signals of disproportionate reporting (SDR) spanning 27 System Organ Classes (SOCs). The strongest signals occurred in Blood and Lymphatic Disorders (ROR = 7.31, 95% CI = 7.16-7.47) and Endocrine disorders (ROR = 4.09, 95% CI = 3.83-4.37), the latter representing unlabeled findings. In addition, we detected previously unlisted AEs, including colitis, oral lesions, immune-mediated pancreatitis, pulmonary toxicity, lung consolidation and tubulointerstitial nephritis. Sex stratification revealed male predominance in respiratory toxicity vs. female predisposition to renal injury. A bimodal time-to-onset distribution was observed: 52.57% of AEs occurred within 0-30 days post-treatment, with a secondary peak (6.63%) at 181-360 days.

Conclusion: This large pharmacovigilance study identifies signals of disproportionate reporting (SDRs) consistent with pemetrexed's established toxicities (e.g., myelosuppression, nephrotoxicity) and detects additional unlabeled safety signals, particularly immune-mediated endocrine, renal, and dermatologic manifestations. The bimodal onset pattern of these SDRs highlights clinically relevant monitoring windows, and observed sex- and age-related differences in SDR reporting suggest a need for individualized risk mitigation. These findings underscore the importance of vigilant surveillance for potential immune-mediated toxicities and adherence to vitamin supplementation protocols to manage hematologic risk. Prospective studies are needed to validate these reporting associations and clarify potential causality for these novel signals.

Copyright © 2026 Wang, Su, Huang, Yang and Xu.

In plain English

This study searched the US Food and Drug Administration Adverse Event Reporting System (FAERS), a spontaneous reporting database, from 2004 to 2024. It looked for reports in which the cancer drug pemetrexed was the only primary suspect drug. Pemetrexed is used for non-small cell lung cancer and malignant pleural mesothelioma. Mesothelioma was the listed indication in 1,725 of the 27,098 reports. The authors used statistical methods that flag events reported disproportionately often with pemetrexed relative to other drugs, and found 653 such signals. The strongest organ-system signal was blood and lymphatic system disorders (reporting odds ratio 7.31, 95% CI 7.16 to 7.47). Next came endocrine disorders (4.09, 3.83 to 4.37), which the authors described as unlabeled. Of the events with timing information, 52.57% began within 0 to 30 days of starting treatment, with a smaller peak (6.63%) at 181 to 360 days. The authors stressed that these signals reflect reporting patterns, not how often adverse events occur or whether the drug causes them. They noted possible confounding by other cancer drugs and concluded that the new signals need confirmation in prospective studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: pharmacovigilance study: disproportionality analysis of spontaneous adverse event reports in the FDA Adverse Event Reporting System (FAERS)
• Who was studied: 27,098 FAERS reports from the first quarter of 2004 to the fourth quarter of 2024 in which pemetrexed was the unique primary suspect drug. The main indication was malignant lung neoplasm (17,640 reports), followed by mesothelioma (1,725 reports). Males accounted for 14,860 reports (54.8%) and females for 9,655 (35.6%). The top reporting countries were the United States (23.4%), France (18.8%) and Japan (10.7%).
• Exposure: Treatment with the chemotherapy drug pemetrexed (brand name ALIMTA). Reports could also list other suspect or concomitant drugs. A sensitivity analysis excluded reports that also listed cisplatin, carboplatin, pembrolizumab or bevacizumab.
• Main results:
  • 653 positive signals of disproportionate reporting were detected across 27 System Organ Classes.
  • Blood and lymphatic system disorders showed the strongest organ-system signal (n = 9,804, ROR = 7.31, 95% CI 7.16 to 7.47). Endocrine disorders followed (n = 905, ROR = 4.09, 95% CI 3.83 to 4.37), which the authors called an unlabeled signal.
  • Among individual event terms, pancytopenia had n = 1,396 reports and ROR = 18.26 (95% CI 17.30 to 19.26). Malignant neoplasm progression was the most frequently reported term (n = 2,418; ROR 17.91, 95% CI 17.19 to 18.65, per Table 3).
  • Reports in males showed signals for respiratory events, such as pneumonitis (ROR = 11.58, 95% CI 10.27 to 13.05). Reports in females showed a signal for tubulointerstitial nephritis (ROR = 30.94, 95% CI 26.87 to 35.62). The authors did not perform formal statistical tests for these sex differences.
  • Among reports with time-to-onset data, 52.57% of events occurred within 0 to 30 days, with a secondary peak at 181 to 360 days (6.63%, n = 1,436). The median time to onset was 28 days (interquartile range 8 to 84).
  • Death was coded as a serious outcome in 5,010 reports (18.5%) and hospitalization in 9,224 (34.0%). Death showed an inverse association in consumer reports (ROR = 0.80, 95% CI 0.73 to 0.88) and a positive signal in healthcare professional reports (ROR = 1.29, 95% CI 1.17 to 1.43). The authors attributed this difference to differences in reporting, not to a difference in mortality risk.
  • After excluding reports that also listed cisplatin, carboplatin, pembrolizumab or bevacizumab, 1,951 reports remained. In this subset, core signals such as anemia and thrombocytopenia remained statistically significant.
• The authors' conclusion: The authors concluded that the signals were consistent with pemetrexed's known toxicities (hematologic, gastrointestinal, renal). They also reported novel unlabeled signals, particularly immune-mediated endocrine, renal and dermatologic manifestations. They stated that these signals reflect reporting patterns, not confirmed causation, and need validation in prospective studies.
• Limitations the authors state:
  • FAERS is a spontaneous reporting system subject to underreporting, incomplete documentation and variable reporting practices.
  • Causality could not be confirmed because of confounders such as the underlying cancer, concomitant medications (for example immune checkpoint inhibitors and platinum agents), prior therapies and unrecorded comorbidities.
  • The sensitivity analysis lost most of the sample (from 27,098 to 1,951 reports), which reduced statistical power for rare signals.
  • Only four co-administered drugs were excluded. Other immune checkpoint inhibitors (for example nivolumab, atezolizumab) could not be excluded, so confounding of immune-mediated signals remains.
  • Western and Japanese reports were overrepresented, which limits generalizability to other populations.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Pleural Mesothelioma, Odds Ratio, Statistical Significance, confidence interval, Consolidation, Nephrotoxicity.

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