Afatinib is the second generation EGFR-TKI. Recently, transient asymptomatic pulmonary opacity (TAPO) was reported in EGFR-mutation harboring NSCLC receiving osimertinib. However, TAPO related to other EGFR-TKI has not been reported. Here, we reported a case of TAPO related to afatinib in lung adenocarcinoma harboring EGFR mutation. A 64-year-old male had the diagnosis of stage IV (The 7th edition of the staging system by the Union for International Cancer Control) lung adenocarcinoma harboring EGFR del 19 mutation. He received afatinib 40 mg per day from May 2015. Partial response was achieved, though the dose was reduced to 30 mg per day due to grade 3 rash. In January 2016, CT showed ground glass opacity in the right middle lobe, which resolved spontaneously 2 weeks later. He had no symptom and laboratory findings were not remarkable. Thereafter, recurrent GGO was revealed with chest CT, but all opacity improved without any medication (i.e., corticosteroids) or stopping afatinib. Therefore, we diagnosed a series of opacity as recurrent TAPO with afatinib. TAPO could occur with EGFR-TKI other than osimertinib. Further study is needed to establish the management of new opacity suggesting TAPO under EGFR-TKI treatment.

© 2023 The Author(s). Published by S. Karger AG, Basel

Epidermal growth factor receptor (EGFR)-TKI is the key drug for EGFR-mutation harboring non-small cell lung cancer (NSCLC). EGFR-TKI could cause some adverse events, such as rash, liver dysfunction, and lung injury [1]. Especially, lung injury is fatal in some cases and needs attention. Recently, transient asymptomatic pulmonary opacity (TAPO) was reported in EGFR-mutation harboring NSCLC receiving osimertinib [2–4]. However, TAPO related to other EGFR-TKI has not been reported. Here, we reported a case of TAPO related to afatinib in lung adenocarcinoma harboring EGFR mutation. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529894).

In April 2015, a 64-year-old male had the diagnosis of stage IV (The 7th edition of the staging system by the Union for International Cancer Control) lung adenocarcinoma harboring EGFR del 19 mutation (Fig. 1a). He was an ex-smoker with 20 pack-year and had unremarkable medical history. CT showed no pulmonary fibrosis. He received afatinib 40 mg per day from May 2015. Partial response was achieved, though the dose was reduced to 30 mg per day due to grade 3 rash (Fig. 1b). In January 2016, CT showed ground glass opacity with bronchiectasis in right middle lobe (irregular boundary with diameter of 16 mm), which resolved spontaneously 2 weeks later (Fig. 2). He had no symptom and physical examination showed no significant findings including normal vesicular sound without crackles. Laboratory findings were not remarkable. We continued afatinib because his physical and laboratory findings and clinical course were not consistent with EGFR-TKI-induced lung injury.

Efficacy of EGFR-TKIs. a Chest CT shows primary lesion in right upper lobe. b Partial response was achieved with afatinib. c Re-growth of primary lesion was detected in 2020 and lobectomy of right upper lobe was performed. d Malignant pleural effusion appeared in December 2021 but disappeared with osimertinib.

Repeated TAPO with afatinib. Representative episode of repeated TAPO. All opacities improved spontaneously.

Thereafter, recurrent GGO was revealed with chest CT, but all opacity improved without any medication (i.e., corticosteroids) or stopping afatinib (Fig. 2). Therefore, we diagnosed a series of opacity as recurrent TAPO with afatinib.

In August 2021, he underwent right upper lobe lobectomy because of oligo-progression (Fig. 1c). Preoperative lung function was normal (predicted vital capacity of 110.9% and forced expiratory volume in 1 s/forced vital capacity of 78.5%). Pathological findings showed lung adenocarcinoma (T790M mutation was detected with surgical specimen). Underlying lung condition was emphysema. Fibrosis and evidence of inflammation and infection were not detected. In November 2021, pleural effusion was detected and cytology with pleural effusion revealed adenocarcinoma (Fig. 1d). Afatinib stopped and osimertinib started. PR was obtained with osimertinib. TAPO was not detected with osimertinib.

Afatinib is the second generation EGFR-TKI. The efficacy of afatinib was reported in phase IIb study with median progression-free survival of 11.0 months and overall survival of 27.9 months [1]. Recently, TAPO was reported in EGFR-mutation harboring NSCLC receiving osimertinib [2–4]. However, TAPO related to other EGFR-TKI has not been reported. Here, we reported a case of TAPO related to afatinib in lung adenocarcinoma harboring EGFR mutation.

Noonan et al. [2] reported 7 TAPO cases out of 20 NSCLC subjects receiving osimertinib. Since then, some other studies reported TAPO with osimertinib and its incidence of 19.6–20.3% [3, 4]. But, considering the unresolved etiology of TAPO, it could occur in other EGFR-TKI. EGFR-TKI causes interstitial lung disease and this adverse event is life-threating [1]. Thus, it is challenging to manage when the clinicians detected opacity in NSCLC receiving EGFR-TKI. In fact, about half of drug-related pneumonitis related to osimertinib were TAPO in one report [5]. TAPO resolved spontaneously and ILD induced by EGFR-TKI requires discontinuation of EGFR-TKI and corticosteroids. Kobayashi et al. [6] reported NSCLC with TAPO successfully managed by stop-and-go osimertinib. Further study is needed to establish the management of new opacity suggesting TAPO under EGFR-TKI treatment.

Clinical meanings of TAPO remain unknown. Lee et al. [3] reported that the duration of exposure to osimertinib in EGFR-harboring NSCLC with TAPO was longer than those without TAPO. In this case, PFS was longer compared to that reported in clinical trial. TAPO might relate to long-term exposure to EGFR-TKI. On the other hand, Taronna et al. [4] reported no difference of OS and time to treatment failure between TAPO positive and TAPO negative NSCLC receiving osimertinib. Further study is needed to reveal the clinical meaning of TAPO.

In conclusion, TAPO could occur with EGFR-TKI other than osimertinib. Further study is needed to establish the management of new opacity suggesting TAPO under EGFR-TKI treatment.

Written informed consent was obtained from the participant for publication of the details of their medical case and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

Keisuke Watanabe has received research grants and/or personal fees from AstraZeneca, Novartis, Ono Pharmaceutical, Boehringer Ingelheim, and Daiichi Sankyo outside of the present work. Nobuaki Kobayashi has received research grants and/or personal fees from Chugai Pharmaceutical, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Sanofi, Ono Pharmaceutical, MSD, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, and Kyowa Kirin outside of the present work. Takeshi Kaneko has received research grants and/or personal fees from Chugai Pharmaceutical, AstraZeneca, Novartis, GlaxoSmithKline, Boehringer Ingelheim, KYORIN Pharmaceutical, Otsuka Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Sanofi, Pfizer, Shionogi, and Teijin Pharma outside of the present work.

No funding received.

Keisuke Watanabe collected clinical data and wrote the initial draft of the manuscript. Nobuaki Kobayashi and Takeshi Kaneko supervised and edited the manuscript. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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