---
title: "Reporting signal for interstitial pneumonitis with combined EGFR-TKI and PD-1/PD-L1 inhibitor ther"
id: "frontiers-in-immunology-6-increased-reporting-of-interstitial-pneumonitis-with-combined-egfr-tki-and-pd-1"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-increased-reporting-of-interstitial-pneumonitis-with-combined-egfr-tki-and-pd-1"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901390"
published_at: "2026-08-28T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Reporting signal for interstitial pneumonitis with combined EGFR-TKI and PD-1/PD-L1 inhibitor ther
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-increased-reporting-of-interstitial-pneumonitis-with-combined-egfr-tki-and-pd-1
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1901390)
- **Published At:** 2026-08-28T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study analyzed 67,818 non–small cell lung cancer (NSCLC) reports from the FDA Adverse Event Reporting System (FAERS) covering 2015–2024 to evaluate reporting of **interstitial pneumonitis (IP)** with EGFR-TKI monotherapy, PD-1/PD-L1 inhibitor monotherapy, and co-reported combination exposure. - Reports included 13,678 EGFR-TKI monotherapy, 30,722 PD-1/PD-L1 inhibitor monotherapy, and 307 co-reported combination cases; 23,111 reports were not classifiable for exposure and excluded from comparative analyses. - Overall, 3,970 reports (5.85% of NSCLC cases) contained IP-related MedDRA preferred terms. Reporting proportions were 4.88% for **EGFR-TKIs**, 10.59% for **PD-1/PD-L1 inhibitors**, and 15.64% for co-reported **combination therapy**. - Multivariable logistic regression adjusted for age and sex found higher adjusted reporting odds for PD-1/PD-L1 inhibitor monotherapy (aOR 1.77; 95% CI 1.60–1.96) and the largest increase for combination therapy (aOR 3.46; 95% CI 2.46–4.88), using EGFR-TKI monotherapy as reference. - Agent-specific exploratory findings indicated heterogeneity: durvalumab plus EGFR-TKI showed the highest reporting proportion (47.22%) and a large aOR (16.58; 95% CI 7.89–35.51), nivolumab plus EGFR-TKI had elevated reporting (21.05%; aOR 4.26; 95% CI 2.57–6.79), while pembrolizumab- and atezolizumab-based combinations did not show significant increases; subgroup sizes were small and exploratory. - Demographic associations: male sex and older age groups had higher adjusted reporting odds of IP (male aOR 1.49; ages 45–70 aOR 1.44; >70 aOR 1.95 vs <45 years). - The authors emphasize that FAERS is a spontaneous reporting system without exposure denominators or timing information; co-reported “combination” does not differentiate concurrent from closely sequential administration. - Conclusions stress that the findings represent a pharmacovigilance signal and reporting association rather than a confirmed causal incidence; they call for vigilant clinical monitoring and prospective studies to clarify safety when combining EGFR-TKIs and PD-1/PD-L1 inhibitors. - The study followed a prespecified protocol (ClinicalTrials.gov NCT07036016) and adhered to STROBE reporting guidance; duplicate reports were removed and IP cases were reviewed by two investigators for coding consistency.
## Clinical Analysis & Structured Key Points
Frontiers | Increased reporting of interstitial pneumonitis with combined EGFR-TKI and PD-1/PD-L1 inhibitor therapy in NSCLC: a pharmacovigilance analysis of 67,818 reports ORIGINAL RESEARCH article Front. Immunol. , 28 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1901390 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Combination Cancer Therapies and Systems Immunology 43k views 27 articles Editor & Reviewers Edited by S R SRINIVASA REDDY TELUKUTLA Reviewed by A S Aysu Sinem Koc P C Pierfranco Conte S J Seda Jeral Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Characteristics of 67,818 NSCLC-related FAERS reports and 3,970 reports with interstitial pneumonitis. View in article Table 2 Association between EGFR-TKIs and PD-1/PD-L1 inhibitors with reporting of interstitial pneumonitis among NSCLC cases in FAERS. View in article Table 3 Association between EGFR-TKIs combined with different PD-1/PD-L1 inhibitors and reporting of interstitial pneumonitis among NSCLC cases in FAERS. View in article ORIGINAL RESEARCH article Front. Immunol. , 28 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1901390 Increased reporting of interstitial pneumonitis with combined EGFR-TKI and PD-1/PD-L1 inhibitor therapy in NSCLC: a pharmacovigilance analysis of 67,818 reports J T Jinyi Tao Z F Zhiwen Fu * Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China Article metrics View details Abstract Importance: Both epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and PD-1/PD-L1 inhibitors are widely used in non–small cell lung cancer (NSCLC). The safety of their combination, particularly the risk of interstitial pneumonitis (IP), remains unclear but has critical implications for treatment strategies. Objective: To evaluate reporting patterns of IP associated with EGFR-TKI monotherapy, PD-1/PD-L1 inhibitor monotherapy, and their combination among NSCLC cases. Design: Retrospective, observational pharmacovigilance study using reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) submitted from January 1, 2015, to December 31, 2024. Multivariable logistic regression was applied to estimate adjusted odds ratios (aORs) with 95% CIs. Setting: Spontaneous adverse event reporting system capturing voluntary reports submitted globally by healthcare professionals, patients, and manufacturers; it is not a population-based registry, and the total number of patients exposed to each drug is unknown. Participants: A total of 67,818 NSCLC-related FAERS reports were identified, including 13,678 reporting EGFR-TKI monotherapy, 30,722 reporting PD-1/PD-L1 inhibitor monotherapy, and 307 reporting co-reported combination therapy. Reports were included if they indicated NSCLC and exposure to at least one EGFR-TKI or PD-1/PD-L1 inhibitor. IP was defined using standardized MedDRA preferred terms. Results: Among 67,818 NSCLC reports, 3,970 (5.85%) included IP-related preferred terms. The reporting proportions were 4.88% (668/13,678) for EGFR-TKIs, 10.59% (3,254/30,722) for PD-1/PD-L1 inhibitors, and 15.64% (48/307) for combination therapy. Compared with EGFR-TKIs, PD-1/PD-L1 inhibitors were associated with higher adjusted reporting odds (aOR, 1.77; 95% CI, 1.60–1.96), and combination therapy showed the highest adjusted reporting odds (aOR, 3.46; 95% CI, 2.46–4.88). Agent-specific variation was observed: durvalumab plus EGFR-TKI (IP reporting proportion, 47.22%; aOR, 16.58; 95% CI, 7.89–35.51) and nivolumab plus EGFR-TKI (IP reporting proportion, 21.05%; aOR, 4.26; 95% CI, 2.57–6.79) showed the highest reporting odds, whereas pembrolizumab plus EGFR-TKI (3.85%) and atezolizumab plus EGFR-TKI (5.06%) did not show significantly increased reporting odds; these small combination subgroups are exploratory. Conclusions and relevance: In this large FAERS-based pharmacovigilance analysis, combination therapy with EGFR-TKIs and PD-1/PD-L1 inhibitors was associated with markedly increased reporting of IP, with apparent heterogeneity across agents. As a spontaneous-reporting study without a defined denominator, these findings reflect a reporting association and safety signal rather than a confirmed clinical risk estimate. They support continued pharmacovigilance and prospective studies to clarify the safety of combining these therapies in NSCLC. Highlights Question: Is combining EGFR-TKIs with PD-1/PD-L1 inhibitors associated with disproportionately increased reporting of interstitial pneumonitis (IP) among NSCLC cases in the FAERS database? Findings: In this pharmacovigilance analysis of 67,818 FAERS reports, combination therapy was associated with a markedly higher proportion of IP reports (15.64%) than EGFR-TKI (4.88%) or PD-1/PD-L1 inhibitor monotherapy (10.59%), with correspondingly higher adjusted reporting odds. Durvalumab- and nivolumab-based regimens showed the greatest excess reporting, whereas pembrolizumab- and atezolizumab-based combinations showed no significant increase; these agent-specific combination findings are exploratory given small subgroup numbers. Meaning: Combining EGFR-TKIs with PD-1/PD-L1 inhibitors is associated with disproportionately increased reporting of IP, with apparent agent-specific variation. These findings represent a pharmacovigilance signal rather than a confirmed causal risk estimate and warrant vigilant clinical monitoring and further prospective study. Introduction Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide ( 1 , 2 ). In recent years, the treatment landscape for NSCLC has undergone a paradigm shift with the advent of molecular targeted therapies and immune checkpoint inhibitors (ICIs) ( 3 , 4 ). Among targeted agents, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib, afatinib, and osimertinib, have significantly improved outcomes in patients harboring EGFR mutations ( 5 ). Concurrently, ICIs (such as nivolumab, pembrolizumab, and atezolizumab) targeting the programmed cell death 1 (PD-1) or its ligand (PD-L1) have demonstrated durable clinical benefits in a broad range of NSCLC patients, regardless of the presence of driver mutations ( 6 ). Given their distinct mechanisms of action and non-overlapping indications, there has been growing interest in combining or sequencing EGFR-TKIs with ICIs to overcome resistance and broaden therapeutic efficacy ( 7 ). However, accumulating evidence suggests that such combinations may carry unexpected toxicities. One particularly severe and potentially fatal complication is interstitial pneumonitis (IP), an inflammatory lung condition characterized by alveolar and interstitial infiltration, often leading to respiratory failure ( 8 ). IP is a known adverse event associated with both EGFR-TKIs and ICIs at varying frequencies. The incidence of EGFR-TKI-induced IP ranges from 0.3% to 4.3%, with higher rates observed in East Asian populations ( 9 , 10 ). Similarly, ICI-associated pneumonitis has been reported in approximately 3%-5% of patients in clinical trials, although the rates may be higher in real-world settings ( 11 , 12 ). While these risks are manageable when the drugs are used independently, the safety of combination or sequential therapy involving EGFR-TKIs and PD-1/PD-L1 inhibitors remains insufficiently understood; concurrent combination and sequential administration may carry distinct mechanisms and risks and, where possible, should be considered separately. Several case series and early-phase trials have reported a heightened risk of severe pneumonitis in patients receiving both EGFR-TKIs and ICIs, particularly when EGFR-TKIs are administered shortly after immunotherapy. For example, the TATTON trial, which evaluated osimertinib in combination with durvalumab, was prematurely halted due to unacceptably high rates of pneumonitis ( 13 ). Consistent with this, a retrospective cohort study of patients with EGFR-mutant NSCLC found that severe immune-related adverse events, including pneumonitis, were common when osimertinib was started shortly after prior PD-(L)1 blockade, whereas no such events were observed when osimertinib preceded PD-(L)1 inhibitor therapy, highlighting that treatment sequence may be an important determinant of risk ( 14 ). Moreover, post-marketing surveillance in Japan has identified fatal cases of interstitial lung disease in patients who received EGFR-TKIs following prior treatment with ICIs such as nivolumab ( 15 ). Despite these alarming signals, comprehensive real-world data on the occurrence and risk of IP associated with EGFR-TKI, when combined with PD-1/PD-L1 inhibitors, remain scarce. Most existing studies are limited by small sample sizes, single-center designs, or a lack of control groups. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) provides a comprehensive, publicly accessible pharmacovigilance database that captures real-world toxicity signals across diverse populations and treatment regimens ( 16 , 17 ). In this study, we used the FAERS database to conduct a retrospective pharmacovigilance analysis of 67,818 NSCLC-related reports. We aimed to describe the reporting proportion and reporting odds of IP among cases treated with EGFR-TKIs, PD-1/PD-L1 inhibitors, or both, and to evaluate whether combination therapy was associated with disproportionately increased reporting of IP. Methods Study design and data source This retrospective observational study was conducted using data from the FAERS database, a publicly available post-marketing safety surveillance database. FAERS collects spontaneous reports of adverse drug events from healthcare professionals, patients, and pharmaceutical manufacturers worldwide through the FDA MedWatch program ( 18 ). This study included data collected between January 1, 2015, and December 31, 2024. The study protocol for our observational, retrospective, cross-sectional pharmacovigilance study of the FAERS database was registered on ClinicalTrials.gov (No. NCT07036016) and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The institutional review board approval and informed consent were exempt since data in FAERS are anonymized and publicly available. Study population and case identification We identified NSCLC reports using the following MedDRA preferred terms (PTs): “Non-small cell lung cancer”, “Lung neoplasm malignant”, “Adenocarcinoma of lung”, “Squamous cell carcinoma of lung”, “Lung cancer metastatic”, and related NSCLC indication terms. Study drugs were searched using generic names, brand names, and common spelling variants: gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif), osimertinib (Tagrisso), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), and durvalumab (Imfinzi). Drug involvement was determined from the FAERS drug file using the role codes Primary Suspect (PS), Secondary Suspect (SS), Concomitant (C), and Interacting (I); PS and SS roles were used to define exposure. Reports were categorized into mutually exclusive groups based on treatment exposure: EGFR-TKI monotherapy, PD-1/PD-L1 inhibitor monotherapy, or combination therapy, the last defined as co-reporting of both an EGFR-TKI and a PD-1/PD-L1 inhibitor on the same FAERS case. Reports were considered not classifiable if they contained incomplete drug information, multiple drugs within the same therapeutic class precluding unique assignment, or non-suspect drug roles only. These reports were excluded from treatment-group comparisons. Because FAERS does not capture treatment timing or dosing schedules, this combination category cannot reliably distinguish concurrent (simultaneous) administration from closely sequential use (e.g., an EGFR-TKI initiated shortly before or after an immune checkpoint inhibitor); we therefore use “combination” to denote co-reported exposure rather than confirmed concurrent dosing, and we discuss this limitation further below. Duplicate case reports were removed by retaining the latest record for each CASEID according to FDA_DT and, when necessary, the highest PRIMARYID. Outcome measure The primary outcome was the reporting proportion of IP in the NSCLC cases reported to the FAERS database, defined by the presence of at least one preferred term related to pneumonitis in the MedDRA preferred term, including: “Interstitial lung disease”, “Pneumonitis”, “Pulmonary fibrosis”, “Organizing pneumonia”, “Diffuse alveolar damage”. Reports containing more than one of these preferred terms were counted once as a single IP case rather than multiple times. All candidate IP reports were independently reviewed by two investigators (J.T. and Z.F.) for consistency in event coding and for plausibility of the NSCLC indication; discordant cases were resolved by consensus discussion. Statistical analysis Descriptive statistics were used to summarize patient demographics, including age, sex, and country of origin. Because FAERS is a spontaneous reporting system without a defined population denominator, all percentages in this study represent reporting proportions among included cases rather than true clinical incidence or absolute risk. The reporting proportion of IP was calculated for each treatment group. Categorical variables were reported as frequencies and percentages, whereas continuous variables were expressed as mean (standard deviation). Multivariable logistic regression was performed to estimate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the association between the treatment group and the reporting of IP. Covariates included in the model were age, sex, and treatment category (EGFR-TKI monotherapy, PD-1/PD-L1 inhibitor monotherapy, or combination therapy); reporting country, reporting year, and reporter type were not included in this primary model. We also did not additionally perform formal disproportionality (signal-detection) analyses, such as the reporting odds ratio or proportional reporting ratio, in this version of the manuscript; our primary aim was to compare reporting patterns between prespecified, clinically defined exposure groups using multivariable-adjusted logistic regression rather than to screen broadly for signals across the FAERS database. All analyses were performed using R software (version 4.3.3, R Foundation for Statistical Computing). A two-sided P-value < 0.05 was considered statistically significant, and odds ratios from this analysis should be interpreted as measures of reporting association rather than clinical risk. Results A total of 67,818 NSCLC-related reports were identified in the FAERS database from the first quarter of 2015 to the fourth quarter of 2024. Among these, 13,678 (20.17%) reports involved EGFR-TKI monotherapy, 30,722 (45.30%) involved PD-1/PD-L1 inhibitor monotherapy, and 307 (0.45%) reports involved combination therapy with an EGFR-TKI and a PD-1/PD-L1 inhibitor, whereas 23,111 reports were not classifiable under the prespecified study-drug criteria and were excluded from exposure comparisons because of incomplete drug information, multiple drugs within the same therapeutic class precluding unique assignment, or non-suspect drug roles only ( Figure 1 ). Patient demographics and baseline characteristics are summarized in Table 1 . The mean (SD) age across the study population was 65.6 (11.40) years, and predominantly male (47.91%). Geographically, the top five countries with the largest number were Japan (18,443 cases, 27.19%), the United States (14,201 cases, 20.94%), China (4,316 cases, 6.36%), Germany (4,282 cases, 6.31%), and France (3,295 cases, 4.86%). Figure 1 Detailed report-selection flow diagram. In this study, 13,880,870 reports were retrieved from the FAERS database from the first quarter of 2015 to the fourth quarter of 2024. By using NSCLC-related MedDRA preferred terms, 67,818 NSCLC-related reports remained after excluding duplicate reports and reports not meeting drug-exposure criteria. Of 67,818 NSCLC reports, 44,707 were classifiable as EGFR-TKI-only (n = 13,678), PD-1/PD-L1 inhibitor-only (n = 30,722), or dual-class exposure (n = 307), whereas 23,111 reports were not classifiable under the prespecified study-drug criteria and were excluded from exposure comparisons. Among these, 3,970 cases were reported to have interstitial pneumonitis and were ultimately enrolled. Table 1 Characteristic All NSCLC cases (N = 67,818) IP-coded reports (N = 3,970) Age, mean (SD), y 65.6 (11.40) (age not reported, n=19,445) 68.8 (9.78) (age not reported, n=755) Sex, no. (%) Female 25,181 (37.10) 1,065 (26.80) Male 32,475 (47.91) 2,449 (61.70) Not reported 10,162 (15.01) 456 (11.50) Reporters, no. (%) Healthcare professional 50,131 (73.95) 3,121 (78.62) Non-healthcare professional 15,639 (23.03) 645 (16.24) Not reported 2,048 (3.02) 204 (5.14) Reporting countries (top 5), no. (%) Japan 18,443 (27.19) 2,318 (58.39) United States 14,201 (20.94) 601 (15.14) China 4,316 (6.36) 202 (5.09) Germany 4,282 (6.31) 127 (3.20) France 3,295 (4.86) 106 (2.67) Reporting year, no. (%) 2015 3,674 (5.42) 84 (2.12) 2016 5,267 (7.77) 293 (7.38) 2017 6,279 (9.26) 330 (8.31) 2018 6,869 (10.13) 495 (12.51) 2019 7,970 (11.75) 881 (22.23) 2020 7,453 (10.99) 562 (14.22) 2021 7,397 (10.91) 427 (10.81) 2022 8,373 (12.35) 374 (9.45) 2023 6,729 (9.92) 243 (6.12) 2024 7,807 (11.51) 280 (7.05) Treatments, no. (%) EGFR-TKIs 13,678 (20.17) 668 (16.83) PD-1/PD-L1 inhibitor 30,722 (45.30) 3,254 (81.96) Combination therapy 307 (0.45) 48 (1.21) Characteristics of 67,818 NSCLC-related FAERS reports and 3,970 reports with interstitial pneumonitis. NSCLC, non–small cell lung cancer; EGFR-TKI, epidermal growth factor receptor–tyrosine kinase inhibitor; PD-1/PD-L1, programmed death-1/programmed death-ligand 1; SD, standard deviation. Among these NSCLC-related reports, 3,970 cases included IP, corresponding to an overall crude reporting proportion of 5.85%. The number of reports that included IP-related preferred terms increased during the 2015–2024 period, with 881 (22.23%) cases reported in 2019. Among reports involving EGFR-TKI monotherapy, 668 of 13,678 (4.88%) included IP. In the PD-1/PD-L1 inhibitor monotherapy group, 3,254 of 30,722 (10.59%) included IP. In contrast, 48 of 307 reports involving both drug classes included IP-related preferred terms, resulting in a significantly higher reporting proportion of 15.64% (95% CI, 11.76%-20.19%; P <.001) compared with either monotherapy group. To confirm this observation, we conducted a multivariable logistic regression analysis of the interaction between PD-1/PD-L1 inhibitor and EGFR-TKI. The multivariable logistic regression adjusting for age, sex, and treatment category demonstrated increased adjusted reporting odds of IP associated with PD-1/PD-L1 inhibitor and combination therapy reports (EGFR-TKI monotherapy as the reference) ( Table 2 ). As shown in Figure 2 , the forest plot illustrates the adjusted odds ratios (aOR) for IP across demographic and treatment subgroups. Male patients had significantly higher adjusted reporting odds than female patients (aOR, 1.49; 95% CI, 1.37–1.62; P <0.001). Age was also associated with higher adjusted reporting odds: patients aged 45–70 years had an aOR of 1.44 (95% CI, 1.08–1.92; P = 0.012), whereas those older than 70 years had an aOR of 1.95 (95% CI, 1.46–2.59; P <0.001) relative to those younger than 45 years. Treatment category showed the strongest association: PD-1/PD-L1 inhibitor monotherapy was associated with 1.77-fold higher adjusted reporting odds (
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