Case report: EGFR-TKI rechallenge after osimertinib-induced interstitial lung disease: a case report and literature review.

Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), has demonstrated significant efficacy in treating non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, EGFR-TKI-induced interstitial lung disease (ILD), a well-known adverse effect, can seriously affect the treatment outcome. There is currently no international consensus on the efficacy and safety of re-administration of EGFR-TKI after EGFR-TKI-induced ILD. We report a case of a 62-year-old male with stage IV lung adenocarcinoma and EGFR L858R mutation who was treated with osimertinib at a dose of 80 mg/day as first-line therapy. On the sixth day of treatment, the patient developed grade 4 ILD, chest tightness, shortness of breath, and paroxysmal dry cough. Arterial blood gas analysis indicated the presence of type I respiratory failure, while the chest CT scan revealed newly developed ground-glass opacities in both lungs and a considerable amount of pleural effusion on the left side. Subsequently, the patient was administered methylprednisolone for anti-inflammatory therapy, in conjunction with oxygen therapy, anti-infection treatment, and closed thoracic drainage, which resulted in a favourable recovery and discharge after 18 days. During this period, the patient adhered to third-generation EGFR-TKI oral targeted therapy. Nevertheless, within a week of discharge, the patient was readmitted due to the recurrence of chest tightness and shortness of breath. A chest CT scan indicated a recurrent ILD. Despite the administration of high-dose methylprednisolone for 9 days, the patient's condition continued to deteriorate, ultimately resulting in death. It is of the utmost importance to conduct a meticulous evaluation of the severity of osimertinib-induced ILD in order to ascertain the potential risks and benefits of EGFR-TKI rechallenge. Particularly, for patients with grade 4 ILD, firm drug discontinuation should be considered.

Gu X ，Zhong Y ，Huang H 《Frontiers in Pharmacology》

Successful treatment of EGFR T790M-mutant non-small cell lung cancer with almonertinib after osimertinib-induced interstitial lung disease: a case report and literature review.

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the standard treatment for EGFR T790M-positive non-small cell lung cancer (NSCLC). Osimertinib is one of the third-generation EGFR-TKIs and is currently the most advanced in clinical development. Interstitial lung disease (ILD) is a potentially fatal side effect of osimertinib use. Successful rechallenge with the second-generation TKI afatinib following osimertinib-induced ILD has been reported. However, few reports have discussed the safety and efficacy of third-generation TKI rechallenge in this patient population. In this paper, a case of lung adenocarcinoma is retrospectively analyzed, and the relevant literature is reviewed. The patient was initially diagnosed with early lung cancer, for which surgical treatment was performed. The postoperative diagnosis indicated stage IB (pT2N0M0) right lung adenocarcinoma. Genetic testing (amplification-refractory mutation system) revealed EGFR exon 19 deletion. More than 2 years after surgery, multiple metastases occurred in both lungs, so gefitinib (250 mg per day) was administered. However, 6 months after the start of gefitinib treatment, the tumor progressed. Lung tumor biopsy was performed for genetic testing (NGS) and an EGFR T790M mutation was observed. Subsequently, second-line treatment with osimertinib (80 mg per day) was given for 3 months. The evaluated response suggested a partial response (PR) with the occurrence of grade 3 ILD. Pemetrexed plus bevacizumab chemotherapy was subsequently administered, resulting in stable disease. However, following a severe drug reaction after six courses, the patient's chemotherapy was discontinued. Another third-generation TKI, almonertinib (110 mg per day), was rechallenged based on no ILD having been reported in a phase I/II study of this drug. After 4 months of almonertinib administration and 6 months without ILD recurrence, partial remission was attained. This is the first report of successful treatment with almonertinib after osimertinib-induced ILD. The results suggested that almonertinib had a significant effect in patients with EGFR T790M mutation, with fewer side effects and better survival benefits for patients with advanced lung cancer.

Wu L ，Zhong W ，Li A ，Qiu Z ，Xie R ，Shi H ，Lu S ... -  《-》

Outcome in advanced non-small cell lung cancer patients with successful rechallenge after recovery from epidermal growth factor receptor tyrosine kinase inhibitor-induced interstitial lung disease.

Kashiwabara K ，Semba H ，Fujii S ，Tsumura S ... -  《-》

Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

Kanaji N ，Ichihara E ，Tanaka T ，Ninomiya T ，Kozuki T ，Ishikawa N ，Nishii K ，Shoda H ，Yamaguchi K ，Kawakado K ，Toyoda Y ，Inoue M ，Miyatake N ，Watanabe N ，Inoue T ，Mizoguchi H ，Komori Y ，Kojima K ，Kadowaki N ... -  《-》

Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

Li MSC ，Lee KWC ，Mok KKS ，Loong HHF ，Lam KC ，Mok FST ，Chan LL ，Lau YM ，Chan KP ，Ng JTY ，Wong WKY ，Lam BHW ，Chen ACC ，Lee MMP ，Chen OH ，Mok TSK ... -  《-》