Immunohistochemical analysis of B7-H3 expression in patients with lung cancer following various anti-cancer treatments.

B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0-3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3.

Utility of needle biopsy in centrally located lung cancer for genome analysis: a retrospective cohort study.

BACKGROUND: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. METHODS: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. RESULTS: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. CONCLUSIONS: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

Dacomitinib overcomes afatinib-refractory carcinomatous meningitis in a lung cancer patient harbouring EGFR Ex.19 deletion and G724S mutation; a case report.

It has been reported that the efficacy of EGFR-TKI is predicted, not by which exon of the EGFR gene is mutated, but by the structural change in the EGFR protein due to the mutation. Here, we present an EGFR-mutated lung cancer patient with a 13-year history of anticancer treatment, in which EGFR ex.19 deletion (E746_S752 > V) and G724S mutations were detected by liquid biopsy during 12th line afatinib treatment, and switching to dacomitinib showed improvement of cancerous meningitis. We choose dacomitinib as 14th line chemotherapy based on ex.19 deletion and G724S mutant EGFR structure and its penetration rate to cerebral fluid, which successfully prolonged her life by 6 months. The optimal EGFR-TKI may be selected by understanding the EGFR compound mutation profile by next generation sequencing and predicting the effect based on the structure. Dacomitinib may be effective choice in afatinib-refractory carcinomatous meningitis harboring G724S mutation. This is the first case report showing that a change to dacomitinib responded to afatinib refractory cancerous meningitis.

Retrospective analysis of osimertinib re-challenge after osimertinib-induced interstitial lung disease in patients with EGFR-mutant non-small cell lung carcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0-80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.

Clinical impact of walking capacity on the risk of disability and hospitalizations among elderly patients with advanced lung cancer.

PURPOSE: Little is known about the impact of decreased walking capacity on clinical outcomes in elderly patients with cancer. This prospective observational study aimed to investigate the impact of walking capacity on the risk of disability and hospitalization in elderly patients with advanced lung cancer. METHOD: This study prospectively enrolled 60 patients aged ≥ 70 years with advanced non-small-cell lung cancer (NSCLC) scheduled to receive first-line chemotherapy or radical radiotherapy between January 2013 and December 2014 (trial registration number: UMIN000009768). Patients were classified into the mobile or less mobile group based on the median incremental shuttle walking distance (ISWD) before initial treatment. Assessments included the Barthel index, disability-free survival time, mean cumulative lengths of hospital stay, and inpatient medical costs. RESULTS: The median ISWD was 290 m (interquartile range, 245-357.5 m). The mobile group (ISWD ≥ 290 m) had a longer disability-free survival time than the less mobile group (ISWD < 290 m, 24.6 months vs. 8.4 months, p < 0.05). During the first year from study entry, the mobile group had shorter cumulative lengths of hospital stay (41.3 vs. 72.9 days/person, p < 0.05) and lower inpatient medical costs (¥1.9 vs. ¥2.9 million/person, p < 0.05) than the less mobile group. CONCLUSION: Elderly NSCLC patients with adequate walking capacity showed lower risks of disability, shorter hospitalizations, and lower inpatient medical costs than patients with reduced walking capacity. Further prospective research is needed to validate these findings. The trial was registered with the University Hospital Medical Information Network as trial number UMIN000009768 on January 13, 2013. TRIAL REGISTRATION: UMIN000009768.

Osimertinib for patients with poor performance status and EGFR T790M mutation-positive advanced non-small cell lung cancer: a phase II clinical trial.

Osimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status (PS) is unknown. Therefore, we conducted an open-label, multi-center, single-arm phase II study to evaluate its efficacy and safety in EGFR T790M mutation-positive NSCLC patients with Eastern Cooperative Oncology Group PS scores of between 2 and 4. Patients received 80 mg of osimertinib once daily. Our primary endpoint was progression-free survival. Eighteen patients were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55-85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and had been treated with first- or second-generation EGFR- tyrosine kinase inhibitors previously. The overall median progression-free survival was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate and median overall survival were 53% and 12.7 months, respectively. Moreover, improved PS scores were observed in 72% of the patients. Although the incidence of grade 3 adverse events was low, with no grade 4 or 5 events observed, three patients required treatment cessation due to the development of interstitial lung disease. Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced NSCLC patients with poor PS. This trial was registered with the Japan Registry of Clinical Trials on March 12, 2019 (trial no. jRCT1041180081).

Negative impact of malignant effusion on osimertinib treatment for non-small cell lung cancer harboring EGFR mutation.

3rd-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, have reasonable efficacy in non-small-cell lung cancers (NSCLC) with EGFR mutations. However, the efficacy of osimertinib in NSCLC patients with fluids, such as pleural, pericardial and abdominal effusions, is unclear. We evaluated the efficacy of osimertinib in this specific setting. NSCLC patients harboring EGFR T790 M mutations who experienced progressive disease after first EGFR-TKI treatment and started osimertinib treatment between April 2016 and August 2018 were retrospectively screened. In particular, we assessed the efficacy of osimertinib for NSCLC with EGFR T790 M mutations in patients who were diagnosed with EGFR T790 M mutation by malignant effusion. Among 90 patients with EGFR T790 M mutation who started osimertinib treatment after EGFR-TKI failure, 21 were diagnosed from malignant effusions excluding cerebrospinal fluid (F group) and 69 using other methods including tissue biopsies (NF group). Patient characteristics were well-balanced between the two groups. Overall response was 50%, and significantly worse in the F group (29%) than the NF group (57%; P = 0.025). Median progression-free survival with osimertinib treatment in the F group (7.1 months, 95% confidence interval [CI]: 2.3-14.0) was significantly shorter than that in the NF group (11.9 months, 95% CI: 9.5-16.0; P = 0.046)). Median drainage-free time was 10.9 months (95% CI: 1.4 months- not reached). The present study showed that the efficacy of osimertinib for NSCLC in which EGFR T790 M mutation is detected by malignant effusion may be less than in EGFR T790 M-mutated NSCLC detected by other methods.

Clinical and radiation dose-volume factors related to pneumonitis after treatment with radiation and durvalumab in locally advanced non-small cell lung cancer.

Introduction Durvalumab has been shown to confer a survival benefit after definitive chemoradiotherapy in the patients with locally advanced non-small cell lung cancer, but no studies have attempted to identify risk factors for pneumonitis after durvalumab therapy. The purpose of this study was to investigate associations between clinical and radiation dose-volume factors, and the severity of pneumonitis. Methods We retrospectively assessed the cases of 30 patients who had been started on durvalumab therapy between July 2018 and February 2019. In this study we evaluated the percentage of lung volume receiving radiation dose in excess of 20 Gy (V20) as radiation dose-volume factor. We compared V20 and some baseline factors between a grade 0 or 1 (Gr 0/1) pneumonitis group and a grade 2 or more (≥Gr 2) pneumonitis group, and we performed a logistic regression analysis to establish the associations between variables and ≥ Gr 2 pneumonitis. Results Pneumonitis had developed in 22 patients (73.3%): Gr 1/2/3-5 in 8 (26.7%)/14 (46.7%) /0 (0%), respectively. The difference in V20 between the Gr 0/1 group and Gr 2 group (median: 20.5% vs. 23.5%, p = 0.505) was not statistically significant, and thus V20 was not a risk factor for Gr 2 pneumonitis (odds ratio: 1.047, p = 0.303). None of the clinical factors, including sex, age, smoking history, presence of baseline pneumonitis, type of radiation therapy, location of lesion and facility, were risk factors. Conclusions Our study suggest that the severity of pneumonitis after durvalumab is unrelated to V20 or any of the clinical factors assessed in this study.

Improvement strategies for successful next-generation sequencing analysis of lung cancer.

Aim: We aimed to improve the success rate of NGS (next-generation sequencing) analysis through improved strategies of lung cancer sampling. Materials & methods: The improvement strategies are as follows. Surgically resected specimens were preferentially submitted in cooperation with pathologists and surgeons. In bronchoscopic samples, the size of the sample collection device and the number of samples collected was increased. Results: The strategies increased the success rate of NGS analysis of DNA from 69.3 to 91.1%, and that of RNA from 64.6 to 90.0%. Discussion: The introduction of strategies aimed at improving the success of NGS analysis resulted in an improvement in the success rate and brought us closer to the delivery of effective precision medicine in cancer therapy.

PD-L1 expression and response to pembrolizumab in patients with EGFR-mutant non-small cell lung cancer.

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is less likely to express programmed death-ligand 1 (PD-L1) than tumors with wild-type EGFR and is associated with poor response to pembrolizumab. To understand the relationship between EGFR mutation and PD-L1 expression in pembrolizumab response, we retrospectively evaluated the factors contributing to the high tumor proportion score in 155 EGFR-mutant non-small cell lung cancer cases and their associated response to pembrolizumab. Uncommon EGFR mutations were significantly associated with a PD-L1 tumor proportion score ≥ 50% compared to common EGFR mutations. The objective response rate to pembrolizumab of 14 patients was 36%, including 22% in patients with common EGFR mutations, 60% in patients with uncommon EGFR mutations and 75% in patients with both uncommon mutations and a PD-L1 tumor proportion score ≥ 50%. A PD-L1 tumor proportion score ≥ 50% was more frequent in non-small cell lung cancer patients harboring uncommon EGFR mutations and was associated with pembrolizumab efficacy.

Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein.

The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5 years with marked efficacy. However, he experienced recurrence of a bulbar metastasis after discontinuation of alectinib. Reintroduction of standard-dose alectinib therapy resolved the lesion again. Our findings suggest that ALK-tyrosine kinase inhibitor therapy should be continued in patients showing a long-term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases.

Acquired immunodeficiency associated with thymoma: a case report.

BACKGROUND: Acquired immunodeficiency associated with thymoma is a rare disorder. Here we reported a case of acquired immunodeficiency with thymoma, with an unusual pattern of low CD4+ count with normal gammaglobulin levels. CASE PRESENTATION: A 70-year-old man presented to the emergency room of our hospital with a high-grade fever, headache, and nausea. He had a five-year history of unresectable thymoma treatment, including several cytotoxic regimens. He had received thoracic palliative radiotherapy 2 months prior to the emergent visit. During the previous month, he had experienced multiple febrile episodes, dry cough, fatigue, weight loss, and watery diarrhea. Upon admission, he had a high-grade fever, nausea, and immobility. Physical examination revealed indistinct consciousness, neck stiffness, and oropharyngeal candidiasis. Both cerebrospinal fluid and blood cultures yielded multiple short chains of Gram-positive rods later identified as Listeria monocytogenes, so he was diagnosed with Listeria meningitis. Intravenous administration of antibiotics was initiated, and the patient fully recovered and was discharged. Additional examination found normal immunoglobulin levels. Peripheral-blood cell counts revealed low CD4+ cell count (108 CD4+ cells/µl). His CD4+ cell count remained low after discharge. CONCLUSIONS: Our findings suggest that physicians need to be aware of severe infections due to immunodeficiency with thymoma.

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data.

Postmarketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we applied postmarketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin-treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony-stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h-1 , neutrophil elimination rate constant = 0.0295 h-1 , and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.

Crizotinib-induced simultaneous multiple cardiac toxicities.

Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.

Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure.

Although third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) can overcome T790M-mediated resistance in non-small-cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR-TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)-guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR-TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.

Exceptionally long-lasting response to dabrafenib plus trametinib treatment in a patient with lung adenocarcinoma harboring the BRAF V600E mutation with high expression of PD-L1: A case report.

We present a patient with lung adenocarcinoma showing high PD-L1 expression and BRAF V600E mutation, who achieved a remarkable long-term response to the combination therapy of dabrafenib and trametinib (DT treatment) after disease progression on immunotherapy. This case may provide an opportunity for clinicians to consider the order of administration of immunotherapy and molecular targeted therapy for BRAF V600E-positive lung cancer.

Clinical application of the Lung Cancer Compact PanelTM using various types of cytological specimens in patients with lung cancer.

BACKGROUND: The Lung Cancer Compact PanelTM (compact panel) is a gene panel that can detect driver alterations with high sensitivity in liquid samples, including tumor cells. This study examined the ability of a compact panel to detect genetic mutations in liquid specimens used in clinical practice. METHODS: Three cohorts, bronchoscopic biopsy forceps washing (washing cohort), pleural effusion (pleural cohort), and spinal fluid (spinal cohort), were analyzed using the compact panel. Liquid samples were added into the GM (Genemetrics) tubes and analyzed. The washing cohort assessed the concordance rate of gene panel analysis outcomes in tissue specimens derived from the primary tumor. Meanwhile, the pleural cohort investigated the impact of storing specimens for 8 weeks and more on nucleic acid and mutation detection rates. RESULTS: In the washing cohort (n = 79), the concordance rate with mutations detected in tissues was 75/79 (94.9 %). This rate reached 100 % when focusing solely on driver alterations for treatment. The pleural cohort (n = 8) showed no deterioration in nucleic acid quality or quantity after 8 weeks of storage in GM tubes. Similarly, in the spinal cohort (n = 9), spinal fluid with malignant cells exhibited driver alterations similar to those in the primary tumor. These findings underscore the efficacy of the compact panel in accurately identifying genetic mutations in different liquid specimens. CONCLUSIONS: The compact panel is a reliable tool for detecting driver alterations in various cytological specimens. Its consistent performance across diverse sample types emphasizes its potential for guiding targeted therapies for patients with lung cancer and enhancing precision medicine approaches.

Feasibility of atezolizumab and bevacizumab combination regimens in patients with hepatocellular carcinoma and lung cancer taking direct oral anticoagulants.

AIM: Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs. METHODS: This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed. RESULTS: The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039). CONCLUSIONS: DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.