Non–small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases and treatment has increasingly relied on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors targeting PD-1/PD-L1. Both drug classes are individually associated with interstitial pneumonitis (IP), an inflammatory lung injury that can be severe or fatal. Prior reports and early trials suggested enhanced risk of pneumonitis when EGFR-TKIs and PD-1/PD-L1 inhibitors are combined or administered in close sequence; however, real-world, comparative data on reporting patterns remain limited. This study used the US FDA Adverse Event Reporting System (FAERS) to evaluate IP reporting among NSCLC cases exposed to EGFR-TKIs, PD-1/PD-L1 inhibitors, or both.
The analysis included FAERS reports submitted from January 1, 2015, to December 31, 2024. NSCLC reports were identified using prespecified MedDRA preferred terms for lung cancer indications. IP was defined by specific MedDRA preferred terms including “Interstitial lung disease,” “Pneumonitis,” “Pulmonary fibrosis,” “Organizing pneumonia,” and “Diffuse alveolar damage.” Two investigators independently reviewed candidate IP reports for coding consistency and plausibility of the NSCLC indication, resolving discordances by consensus.
Study drugs searched included gefitinib, erlotinib, afatinib, osimertinib, nivolumab, pembrolizumab, atezolizumab, and durvalumab by generic and brand names. Drug role codes PS (primary suspect) and SS (secondary suspect) were used to define exposure. Reports were assigned to mutually exclusive groups: EGFR-TKI monotherapy, PD-1/PD-L1 inhibitor monotherapy, or combination therapy (co-reporting of an EGFR-TKI and a PD-1/PD-L1 inhibitor on the same FAERS case). The combination category denotes co-reported exposure and cannot determine whether agents were administered concurrently or sequentially.
Descriptive statistics summarized demographics and reporting patterns. Reporting proportions of IP were calculated within each exposure group. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals for the association between treatment category and IP reporting, adjusting for age and sex. Reporting year, country, and reporter type were not included in the primary regression model. The authors did not perform formal disproportionality analyses in this manuscript; odds ratios are measures of reporting association rather than incidence or causation.
After deduplication and exclusions, 67,818 NSCLC-related FAERS reports remained. Of these, 13,678 (20.17%) were classified as EGFR-TKI monotherapy, 30,722 (45.30%) as PD-1/PD-L1 inhibitor monotherapy, and 307 (0.45%) as co-reported combination therapy; 23,111 reports were not classifiable under prespecified drug criteria and were excluded from exposure comparisons. Across all NSCLC reports, 3,970 cases contained IP-related preferred terms, yielding an overall reporting proportion of 5.85%.
Reporting proportions by exposure group were as follows: 4.88% (668/13,678) for EGFR-TKI monotherapy, 10.59% (3,254/30,722) for PD-1/PD-L1 inhibitor monotherapy, and 15.64% (48/307) for co-reported combination therapy. The number of IP reports increased across the 2015–2024 interval with a notable peak in 2019.
In multivariable logistic regression adjusted for age and sex and using EGFR-TKI monotherapy as the reference, PD-1/PD-L1 inhibitor monotherapy had higher adjusted reporting odds for IP (aOR 1.77; 95% CI 1.60–1.96). Co-reported combination therapy demonstrated the largest adjusted association with IP reporting (aOR 3.46; 95% CI 2.46–4.88).
Demographic factors were also associated with adjusted reporting odds. Male patients had higher adjusted odds compared with female patients (aOR 1.49; 95% CI 1.37–1.62). Older age was associated with increased adjusted reporting odds: ages 45–70 years (aOR 1.44; 95% CI 1.08–1.92) and >70 years (aOR 1.95; 95% CI 1.46–2.59) versus <45 years.
The analysis explored agent-specific combinations though subgroup sizes were small and described as exploratory. Notable findings included markedly elevated reporting proportions and aORs for certain PD-1/PD-L1 plus EGFR-TKI pairings: durvalumab combined with an EGFR-TKI had an IP reporting proportion of 47.22% and an aOR of 16.58 (95% CI 7.89–35.51), and nivolumab plus an EGFR-TKI had a reporting proportion of 21.05% with an aOR of 4.26 (95% CI 2.57–6.79). Pembrolizumab- and atezolizumab-based combinations did not show statistically significant increases in reporting odds in these small subgroups. The authors emphasize that these agent-level findings are exploratory given small numbers.
These FAERS-based results identify a pharmacovigilance signal: co-reported exposure to EGFR-TKIs and PD-1/PD-L1 inhibitors is associated with a higher proportion and higher adjusted reporting odds of interstitial pneumonitis compared with either class alone. Important limitations inherent to FAERS apply: absence of a true denominator of exposed patients, inability to determine causality, potential reporting bias, and lack of precise treatment timing or dosing information. The co-reported “combination” category cannot distinguish concurrent administration from closely sequential use, which may carry different risks. Additionally, 23,111 reports could not be classified for exposure and were excluded from comparative models.
Clinically, these findings support vigilant monitoring for pulmonary symptoms when patients receive or recently received both drug classes, and suggest safety concerns warranting prospective investigation. The authors call for continued pharmacovigilance and controlled, prospective studies to quantify clinical risk and to evaluate the influence of treatment sequence and specific agent pairings.
In this retrospective pharmacovigilance analysis of 67,818 NSCLC FAERS reports, PD-1/PD-L1 inhibitors had higher reporting of IP than EGFR-TKIs, and co-reported EGFR-TKI plus PD-1/PD-L1 exposure was associated with the highest reporting proportion and adjusted reporting odds of IP. Findings constitute a reporting association and safety signal rather than a validated incidence or causal estimate. The study recommends heightened clinical vigilance, careful consideration of sequencing when combining these therapies, and further prospective research to define true risk and guide safe use.