Drug-Related Pneumonitis Induced by Osimertinib as First-Line Treatment for Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Real-World Setting

doi:10.1016/j.chest.2022.05.035

CHEST

Volume 162, Issue 5, November 2022, Pages 1188-1198

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https://doi.org/10.1016/j.chest.2022.05.035 Get rights and content

Background

Osimertinib has demonstrated impressive efficacy as a first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive (m+) lung cancer. Drug-related pneumonitis (DRP) is a potentially lethal complication of osimertinib treatment, but reliable real-world data currently are lacking.

Research Question

What is the prevalence of osimertinib-induced DRP in first-line settings? What are the characteristics, clinical impact, and risk factors of osimertinib-induced DRP?

Study Design and Methods

We conducted a retrospective multicenter cohort study of patients who received osimertinib as a first-line treatment for advanced EGFR m+ non-small cell lung cancer (NSCLC) between August 2018 and December 2019. All chest CT scans and clinical information during osimertinib exposure were collected until June 2020. The primary end point was DRP incidence identified through central review.

Results

A total of 452 patients from 18 institutions were evaluated. Eighty patients (18%) had a diagnosis of DRP (all grades), and 21 patients (4.6%) had a diagnosis of grade 3 or more DRP. Among the patients with DRP, 46% were identified as having transient asymptomatic pulmonary opacity (TAPO). Regarding the CT scan patterns, organizing pneumonia, simple pulmonary eosinophilia, hypersensitivity pneumonia, diffuse alveolar damage, and nonspecific interstitial pneumonia were found in 30, 21, 18, 9, and two patients (38%, 26%, 23%, 11%, and 3%), respectively. In multivariate analysis, smoking history was identified as an independent risk factor for DRP (hazard ratio, 1.72; 95% CI, 1.01-2.89; P = .046). In the 3-month landmark analysis, DRP was associated with poor treatment efficacy; however, the presence of TAPO did not affect treatment efficacy negatively.

Interpretation

For osimertinib treatment in first-line settings, the frequency of DRP was considerably elevated to 18 %, and half of these patients exhibited TAPO features.

Graphical Abstract

Section snippets

Participants and Study Design

This study was a cohort analysis of Osimertinib for Advanced non-small cell lung cancer as first-line Treatment in real world setting (Osi-FACT)/Hanshin Oncology Clinical Problem Evaluation Group (HOPE 006).¹⁵ Consecutive patients with advanced EGFR m+ NSCLC who initially were treated with osimertinib between August 2018 and December 2019 at the Hanshin Oncology Clinical Problem Evaluation Group were included. We excluded patients concurrently using other anticancer agents, undergoing thoracic

Patient Characteristics

From the main study, 86 patients were excluded (54 patients did not participate, nine patients did not provide consent, 19 patients did not have available pretreatment CT scans for technical reasons, and four patients had low-dose pretreatment CT scans that were inadequate for radiologic analysis). Thus, this study included 452 patients with histologically confirmed EGFR m+ NSCLC, with pretreatment baseline chest CT scans available for radiographic review (e-Fig 1). A total of 2,425 CT scans

Discussion

To the best of our knowledge, this is the largest cohort study to evaluate osimertinib-induced DRP and its clinical impact in a first-line setting. One strength of our study is that we evaluated all chest CT scan data at baseline and during osimertinib exposure. To understand the precise disease course of DRP, we should minimize reporting bias, which has existed in postmarketing surveillance-based articles.¹³ Specifically, when attending physicians encounter asymptomatic pneumonic shadows with

Interpretation

DRP associated with first-line osimertinib treatment occurred at a higher rate in the real-world population than in previous study cohorts. Half of the patients demonstrated TAPO features, and TAPO did not negatively impact prognosis. Osimertinib-related DRP has some characteristics that differ from those of other TKIs. Osimertinib therapy requires that clinicians carefully monitor pneumonitis risks in real-world settings.

Acknowledgments

Author contributions: Y. Sato takes responsibility for the content of manuscript data and analysis. Y. Sato contributed to data collection, methodology, formal analysis, funding acquisition, investigation, resource allocation, visualization, project administration, writing the original draft, and reviewing and editing the final draft. H. Sumikawa contributed to investigation, validation, writing the original draft, and reviewing and editing the final draft. R. S. contributed to data collection,

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Cited by (19)

Risk factors for interstitial lung disease in patients with non-small cell lung cancer with epidermal growth factor receptor-tyrosine kinase inhibitors: A systematic review and meta-analysis
2024, Respiratory Investigation
The use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) can potentially result in interstitial lung disease (ILD), which can substantially impact a patient's quality of life, subsequently leading to the interruption or discontinuation of EGRF-TKI treatment. Clinicians, therefore, need to thoroughly assess patients to determine if they are at risk for ILD.
We searched for observational study in the following databases: MEDLINE via the PubMed, CENTRAL, and IchushiWeb. The primary outcome was risk factors for the development of ILD, while the secondary outcome was risk factors for the severity of ILD. Of the 1602 studies returned, we selected 11 for meta-analysis, performed using a random-effects model.
Risk factors for developing ILD were sex (odds ratio (OR), 1.87; 95% confidence interval (CI), 1.08–3.22; I² = 0%; P = 0.02), smoking history (OR, 2.13; 95% CI, 1.51–3.00; I² = 3 4%; P = 0.0001), and history of ILD (OR = 5.95; 95% CI, 3.34–10.59; I² = 67%; P = 0.0009). Age, previous thoracic surgery or radiotherapy, performance status, histological type of lung cancer, and treatment line were not statistically significant risk factors for ILD. Risk factors identified in one study were serum albumin level, history of nivolumab use, radiographic residual lung volume, and history of pulmonary infection.
We identified risk factors for developing ILD in patients with non-small cell lung cancer treated with EGFR-TKIs.
EGFR-TKI rechallenge in patients with EGFR-mutated non-small-cell lung cancer who progressed after first-line osimertinib treatment: A multicenter retrospective observational study
2024, Respiratory Investigation
Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting.
Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis.
Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade ≥3.
Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity.
Treatment-Related Pneumonitis of EGFR Tyrosine Kinase Inhibitors Plus Thoracic Radiation Therapy in Patients With Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
2024, International Journal of Radiation Oncology Biology Physics
Thoracic radiation therapy (RT) for non-small cell lung cancers may overcome resistance to tyrosine kinase inhibitors (TKIs). However, the risk of severe treatment-related pneumonitis (TRP) is a major concern, and the results of the combined treatment remain controversial. Therefore, we aimed to systematically review existing publications and provide a meta-analysis of TRP from a combined therapy of thoracic RT and TKIs. A systematic literature review was performed using the PubMed-MEDLINE and Embase databases to identify eligible publications. The number of severe TRP cases of grade 3 or higher was extracted and then analyzed by fixed or randomized model meta-analysis. Heterogeneity tests were performed using the I² and τ² statistics. Subgroup analyses were conducted on the types of RT and the sequence of the combined treatment. Our literature search identified 37 eligible studies with 1143 patients. Severe TRP occurred in 3.8% (95% CI, 1.8%-6.5%) of patients overall, and fatal pneumonitis occurred rarely in 0.1% (95% CI, 0.0%-0.3%). In the subgroup analysis, the severe TRP proportion was 2.3% (95% CI, 1.0%-4.1%) for patients under definitive (chemo)RT (19 studies, n = 702) versus 2.9% (95% CI, 1.3%-5.1%) for patients who received local stereotactic body RT or palliative RT (15 studies, n = 361). The severe TRP rate was 4.9% (95% CI, 2.4%-8.1%) for concurrent TKI and RT (26 studies, n = 765), which was significantly higher than TRP of 0.4% (95% CI, 0.0%-3.1%) for sequential therapy (6 studies, n = 200).
Our meta-analysis showed that combined thoracic RT and epidermal growth factor receptor–TKI therapy has an acceptable risk of severe TRP and rare mortality in patients with non-small cell lung cancers. Concurrent treatment is less tolerable and should be administered with caution. Further investigations using osimertinib are required as the data on its effects are limited.
Pneumonitis in Patients Receiving Thoracic Radiotherapy and Osimertinib: A Multi-Institutional Study
2023, JTO Clinical and Research Reports
Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population.
We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis.
The median follow-up was 10.2 months (range: 1.9–53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5–6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021).
Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.
Regulation of dendritic cell maturation in osimertinib-treated lung adenocarcinoma patients
2023, Journal of the Formosan Medical Association
Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N = 10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.
Safety and efficacy of osimertinib rechallenge or continuation after pneumonitis: A multicentre retrospective cohort study
2023, European Journal of Cancer
Citation Excerpt :
In this multicentre, retrospective, hospital-based cohort study, we included patients who met the following criteria: (1) patients with advanced NSCLC with EGFR mutation; (2) patients who had computed tomography (CT) images before osimertinib therapy; (3) patients who started osimertinib as a first-line treatment between 1 August 2018 and 31 December 2019; (4) patients who developed osimertinib-associated pneumonitis by 31 October 2020; (5) patients who received osimertinib rechallenge by 31 October 2020; (6) patients who did not show disease progression with any EGFR-TKIs before the start of osimertinib rechallenge. These data were from patients who were included in an existing cohort [13,14]. The cut-off date for data collection was 30 April 2021.
Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis.
We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge.
In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1–21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months – not reached).
Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis.

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CHEST

Thoracic Oncology: Original ResearchDrug-Related Pneumonitis Induced by Osimertinib as First-Line Treatment for Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Real-World Setting

Background

Research Question

Study Design and Methods

Results

Interpretation

Graphical Abstract

Section snippets

Participants and Study Design

Patient Characteristics

Discussion

Interpretation

Acknowledgments

National Institutes of Health Clinical Center. AZD9291 versus gefitinib or erlotinib in patients with locally advanced or metastatic non-small cell lung cancer (FLAURA). NCT02296125. ClinicalTrials.gov. National Institutes of Health; 2014. Updated August 26, 2022

Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer

N Engl J Med

Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC

N Engl J Med

Japanese Lung Cancer Society guidelines for stage IV NSCLC with EGFR mutations

JTO Clin Res Rep

Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update

J Clin Oncol

NCCN guidelines, version 7.2021. National Comprehensive Cancer Network website

Characteristics and prognostic impact of pneumonitis during systemic anti-cancer therapy in patients with advanced non-small-cell lung cancer

PloS One

Pembrolizumab plus chemotherapy-induced pneumonitis in chemo-naive patients with non-squamous non-small cell lung cancer: a multicentre, retrospective cohort study

Eur J Cancer

Basis of acute exacerbation of idiopathic pulmonary fibrosis in Japanese patients

Am J Respir Crit Care Med

Impact of checkpoint inhibitor pneumonitis on survival in NSCLC patients receiving immune checkpoint immunotherapy

J Thorac Oncol

Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: meta-analysis of 153 cohorts with 15,713 patients: meta-analysis of incidence and risk factors of EGFR-TKI pneumonitis in NSCLC

Lung Cancer

Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset

Jpn J Clin Oncol

Real-world evaluation of factors for interstitial lung disease incidence and radiologic characteristics in patients with EGFR T790M-positive NSCLC treated with Osimertinib in Japan

J Thorac Oncol

Osimertinib as first-line treatment for advanced EGFR mutation-positive non-small cell lung cancer in a real-world setting (OSI-FACT)

Eur J Cancer

Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non-small-cell lung cancer

Cancer Sci

Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: a position paper from the Fleischner Society

Radiology

Transient asymptomatic pulmonary opacities during osimertinib treatment and its clinical implication

J Thorac Oncol

Transient asymptomatic pulmonary opacities occurring during osimertinib treatment

J Thorac Oncol

Severe acute interstitial pneumonia and gefitinib

Lancet

Thoracic Oncology: Original Research
Drug-Related Pneumonitis Induced by Osimertinib as First-Line Treatment for Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Real-World Setting