Successful rechallenge twice with different EGFR-TKIs in a patient with lung adenocarcinoma after EGFR- TKI-induced grade 3 stomatitis and interstitial lung disease: a case report

Successful rechallenge twice with different EGFR-TKIs in a patient with lung adenocarcinoma after EGFR- TKI-induced grade 3 stomatitis and interstitial lung disease: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Successful rechallenge twice with different EGFR-TKIs in a patient with lung adenocarcinoma after EGFR- TKI-induced grade 3 stomatitis and interstitial lung disease: a case report Xueni Liu, Kejun Zhu, Yanru Xie, Jianhui Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3812219/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Rechallenge with EGFR tyrosine kinase inhibitors (TKIs) can be successful as a result of different TKI adverse event profiles. Grade 3 stomatitis seriously affects a patient’s life and leads to drug discontinuation, which can affect survival. Serious adverse effects caused by EGFR-TKIs, such as interstitial lung disease (ILD), can be fatal. This study provides new treatment options for patients who develop grade 3 stomatitis or ILD following EGFR-TKI therapy. Case Description: We present the case of a 67-year-old female patient with stage IV adenocarcinoma involving an EGFR exon 19 deletion mutation who received gefitinib for three months and then discontinued treatment due to grade 3 stomatitis. Icotinib was readministered without any adverse events (AEs). After stable control for 14 months, new liver metastases appeared, and three cycles of pemetrexed and carboplatin plus bevacizumab were administered. Subsequent next-generation sequencing of plasma indicated an EGFR T790M mutation, and the patient subsequently received osimertinib for three months. However, as the patient developed osimertinib-induced grade 3 ILD, the TKIs were discontinued, and high-dose methylprednisolone was administered. After symptomatic remission, half-dose aumolertinib and steroid protection were administered. As there was no ILD recurrence, aumolertinib was increased to the standard dose in 1 month, and the tumor achieved a partial response (PR) .The progression-free survival (PFS) with aumolertinib was more than 17 months without obvious AEs. Conclusions: We report a case of successful rechallenge with two different EGFR-TKIs. Faced with serious adverse effects such as ILD, the rechallenge can be attempted after a thorough assessment of clinical benefits and potential risks. EGFR-TKI rechallenge aumolertinib stomatitis grade 3 interstitial lung disease Figures Figure 1 Figure 2 Highlight Key findings We report a case of successful rechallenge with two different EGFR-TKIs when faced with serious adverse effects such as grade 3 stomatitis and ILD. What is known and what is new? EGFR-TKIs are used as the first-line therapies for patients with advanced NSCLC with sensitive EGFR mutations. When faced with serious adverse effects such as ILD, there are no uniform standards for the principles and methods of EGFR-TKI rechallenge. The successful rechallenge in this case can provide a promising therapeutic strategy. What is the implication, and what should change now? Clinicians may consider this therapy for EGFR-TKI rechallenge. 1. Introduction Primary lung cancer has the highest incidence and mortality rate in China ( 1 ), and non-small cell lung cancer(NSCLC) is the most common pathology, among which EGFR exon 19 deletion (19del) and exon 21 L858R mutation are the two major sensitive mutations. EGFR tyrosine kinase inhibitors (TKIs) are used as the first-line therapies for patients with advanced NSCLC with sensitive EGFR mutations. However, this therapy presents new challenges for clinicians owing to its adverse effects. Grade 3 stomatitis seriously affects the quality of daily life and leads to discontinuation of medication. Serious adverse effects such as ILD caused by EGFR-TKIs cannot be ignored and can sometimes be fatal. Case studies on the onset of osimertinib-induced ILD are scarce, and no standard treatment is available. We report the case of a patient with advanced EGFR T790M-positive NSCLC who developed grade 3 ILD after osimertinib treatment, which was successfully treated with low-dose aumolertinib transition to a standard dose after the ILD subsided. 2. Case Description A 67-year-old female patient with no history of smoking or family history of tumors was diagnosed with stage IV left lung adenocarcinoma (metastatic pattern: multiple bone and lymph node metastases) in March 2020. Genetic analysis of the lung needle biopsy confirmed that the tumor harbored an EGFR exon 19 deletion mutation (Fig. 1 ). Gefitinib (250 mg/day) was administered as first-line therapy starting on 2 April 2020. Palliative radiotherapy for thoracolumbar metastases was used to alleviate pain. The patient achieved a PR according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 but developed grade 3 stomatitis. Due to stomatitis, patients require repeated discontinuation. Icotinib (125 mg three times per day) was administered orally starting on 8 July 8 2020 without adverse events. The tumor lesions remained stable. However, new liver metastases were noted on 2 September 2021, and first-generation EGFR-TKI drug resistance was considered to have occurred. The patient refused liver needle biopsy and genetic testing because of financial constraints. Three courses of pemetrexed and carboplatin plus bevacizumab (PCB) were administered on 4 September, 29 September, and 24 October 2021. Imaging indicated that the liver metastases had decreased slightly in size; However, the lesion in the right lung had become larger, and the patient agreed to undergo genetic testing.The genomic information was obtained from NGS-based 340 gene panel (OrigiMed, Shanghai, China),which encompasses 58 Germline Gene(Supplementary Table 1) .The result showed EGFR T790M mutation and then she received osimertinib (80 mg/day) starting on 25 November 2021. Compared with the CT in July of 2021(Fig. 2 A), a PR was achieved after osimertinib administration for one month (Fig. 2 B). Unfortunately, three months after osimertinib initiation, the patient developed chest tightness after exercise, which did not, however, seriously affect their daily life. The patient did not have a cough, sputum, fever, or chills. A chest CT on 28 February 2022 revealed no significant changes in the tumor lesions; however, new diffuse ground-glass opacities developed in both lungs (Fig. 2 C). To further clarify the diagnosis, electronic bronchoscopy was performed, which revealed no obvious abnormalities. Bronchoalveolar lavage fluid was sent for pathogenic microorganism culture, and no pathogens were detected by routine laboratory tests. The levels of inflammatory markers such as CRP, leukocytes, neutrophils, and calcitonin were within the normal ranges. Based on the patient’s symptoms, imaging, and laboratory tests, osimertinib was identified as the cause of grade 3 ILD. Osimertinib was immediately discontinued, and oxygen and methylprednisolone (40 mg/day) were administered. The patient’s chest tightness improved significantly, and chest CT revealed diffuse ground-glass shadows in both lungs, which were reduced after 3 days (Fig. 2 D). The methylprednisolone tablets were reduced to 32 mg orally daily after one week and then further reduced to 4–8 mg weekly until discontinuation. CT on 20 April 2022 revealed that these diffuse ground glass shadows in both lungs were significantly reduced (Fig. 2 E). The MRI suggested that the liver metastases were smaller than in the MRI findings of 4 January 2022. Combined with adverse reaction regression and drug efficacy, low-dose aumolertinib (55 mg/day) was administered to control tumor progression, with the patient’s consent, on 21 April 2022, and oral methylprednisolone (4 mg/day) was administered to prevent the occurrence of ILD. The scattered ground-glass shadows in both lungs continued to decrease after treatment with aumolertinib for one month. The aumolertinib dose was increased to 110 mg/day under steroid protection (4 mg methylprednisolone daily) on 19 May 2022. Chest CT indicated that the scattered ground-glass shadows were largely absorbed, and the patient continued to receive aumolertinib without steroid protection as of 2 June 2022. The patient did not exhibit signs of worsening of the respiratory symptoms. Chest CT performed in August and December 2022 showed that the lung lesions were stable and there were no interstitial pneumonia changes (Fig. 2 F). The liver metastases continued to shrink. The patient achieved a partial response (PR). To date, the patient has experienced no obvious adverse drug reactions to aumolertinib, and ILD has not recurred. 3. Discussion Lung cancer is the second most commonly diagnosed cancer worldwide, and it remains the leading cause of cancer death ( 2 ). The five-year overall survival rate remains below 5% for patients with metastatic NSCLC treated with chemotherapy. IPASS research has established the potential of targeted therapy in the field of advanced NSCLC treatment; The PFS has been reported to be significantly longer for gefitinib than for carboplatin/paclitaxel (median PFS 9.6 months vs. 6.3 months, respectively) ( 3 ). New TKIs are constantly being developed to further improve PFS and OS. The FLAURA trial showed that osimertinib significantly prolonged the median OS compared with the control group (38.6 months vs. 31.8 months, respectively; HR = 0.80, P = 0.046) ( 4 ). However, this therapy presents new challenges to clinicians because of its inherently different spectrum of toxicity, which is unique to the pharmacodynamic profile of each drug. Rashes, paronychia, diarrhea, stomatitis, liver dysfunction, and pulmonary toxicity are frequently observed in patients treated with EGFR-TKIs. The treatment-related AEs are usually tolerable. However, among the adverse effects of TKIs, interstitial lung disease is a rare but serious off-target adverse reaction that has been reported to be fatal even after intensive supportive therapy ( 5 , 6 ). The patient was a 67-year-old woman who developed recurrent stomatitis after first-line use of gefitinib, which not only affected their quality of life but also prevented them from undergoing normal treatment owing to repeated discontinuation. Given the differences in the incidence and severity of adverse events associated with EGFR-TKIs, substitution between different TKIs has become a direction to be explored. The incidence of all-grade stomatitis caused by gefitinib is approximately 17%, and that of grade 3 or higher stomatitis is < 1% ( 7 ). In the CONVINCE study, stomatitis was not reported following icotinib ( 8 ). Icotinib is associated with fewer treatment-related adverse events than gefitinib, suggesting that icotinib may have a better safety profile ( 9 ). In this patient, their stomatitis resolved after treatment replacement with icotinib, which was well tolerated. Third-generation EGFR TKIs are used to treat patients with EGFR T790M-positive NSCLC who experience secondary drug resistance following first- or second-generation EGFR-TKI therapy ( 10 , 11 ). Additionally, since third-generation EGFR-TKIs significantly prolong the median PFS ( 12 – 14 ) and improve overall survival (OS) ( 4 ) compared to first-generation EGFR-TKIs, they are also the first-line standard treatment for patients with advanced NSCLC. However, the patient developed drug resistance (EGFR T790M mutation) after 17 months of treatment. Unfortunately, although the tumor achieved PR, this was associated with grade 3 ILD after receiving osimertinib for three months. Although the clinical recognition of ILD is increasing, the molecular mechanisms mediating the association between EGFR-TKIs and lung injury remain unknown. This may be due to the following reasons. Alveolar type II epithelial cells express EGFR, which plays an essential role in maintaining epithelial cells. EGFR-TKIs inhibit tumor growth but may also impair epithelial cell growth and repair of damage, thereby leading to tissue injury ( 15 , 16 ). Interleukin 6 (IL-6) is also known to induce interstitial pneumonia. EGFR-TKIs activate activating protein-1 (AP-1) in cancer cells and induce the production of large amounts of IL-6, which increases the risk of chemoresistance and acute interstitial pneumonia ( 17 ). However, ILD may also be the result of immune-mediated allergic reactions to EGFR-TKIs ( 18 ). According to previous studies, the risk of ILD needs to be assessed in patients receiving EGFR-TKIs. To date, the listed risk factors of ILD include being male, a history of smoking, age ≥ 55 years, Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) ≥ 2, presence of contralateral lung metastases, a history of radiation therapy within one year, early treatment initiation after diagnosis, pre-existing interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), lung infectious disease, previous treatment with anti-programmed cell death protein-1 monoclonal antibodies (PD-1), coexisting heart disease, and normal lung area < 50% ( 6 , 19 , 20 ). Combined with the medical history, the patient had no other high-risk factors for ILD except for advanced age. Additionally, previous TKIs such as gefitinib and icotinib had been used without the adverse events of ILD. After remission of osi-ILD, it is necessary to choose appropriate drugs to control tumor progression and prolong patient survival. In principle, patients who develop grade 3 or greater ILD usually discontinue their treatment permanently. Since the patients discontinue the effective drug because of ILD, the subsequent antitumor treatment options are limited. Kosuke et al. ( 21 ) reported a total of 11 cases of successful EGFR-TKI rechallenge after recovery from gefitinib- or erlotinib-induced ILD, and the OS of patients with EGFR-TKI rechallenge was longer than that in patients without EGFR-TKI rechallenge (15.5 vs. 3.5 months, respectively; p = 0.029). Combined with imaging changes and routine laboratory tests, the patient exhibited grade 3 ILD, albeit without severe symptoms. The patient had only slight chest tightness after activity, without hypoxemia. After administering methylprednisolone (40 mg/day) for 3 days, the patient’s symptoms improved significantly, and chest CT revealed that the ground-glass opacity was significantly reduced. These findings indicate that the patient was sensitive to steroid therapy. For this patient, based on successful treatment with icotinib after gefitinib-induced stomatitis, we believe that other third-generation EGFR-TKIs can also be considered after rapid control of ILD. ILD adverse reactions occur in 2–3% of osimertinib treatments ( 14 , 22 , 23 ). There is a high prevalence of ILD in Japanese patients, and pneumonitis occurred in 12.3% of patients treated with osimertinib ( 24 ). Aumolertinib is a novel, irreversible, small-molecule, third-generation EGFR TKI with high selectivity for EGFR-sensitizing and T790M resistance mutations. The structure of aumolertinib was innovatively optimized based on osimertinib, but with the replacement of a cyclopropyl group on the indole nitrogen. As a result, some non-selective metabolites that inhibit the WT EGFR may not be generated during drug metabolism in order to reduce wild-type EGFR-related adverse reactions caused by non-selective metabolites while still ensuring antitumor activity. The most common adverse reactions of aumolertinib are CPK elevation, mild skin rash, and diarrhea, while associated ILD was extremely rare ( 10 , 25 ). Almost two months after the discontinuation of Osimertinib, imaging showed that the tumor continued to shrink. The patient was evaluated as having a PR, indicating that she was sensitive to third-generation TKIs. According to some reported cases, continued use of osimertinib to control tumor progression may be an option after ILD has been controlled ( 23 , 26 – 28 ). However, the same-drug rechallenge is not recommended when other drugs are available. Owing to the low incidence of aumolertinib-associated ILD, the patient received an EGFR-TKI rechallenge. Under close monitoring, low-dose aumolertinib (55 mg/day) was administered along with corticosteroids. After one month, CTs showed no ILD aggravation; therefore, aumolertinib was added at the normal dose (110 mg per day). The CT was repeated after 15 days, and no ILD occurred. The patient consequently discontinued the corticosteroid therapy. To date, the tumor has been successfully controlled for more than 17 months, with no adverse drug reactions such as ILD. Third-generation EGFR-TKIs differ in the incidence or severity of adverse events, and replacement with different third-generation EGFR-TKIs has become a direction of exploration. Careful use of EGFR-TKIs should be considered after a thorough assessment of their clinical benefits and potential risks. First, patients with advanced NSCLC can achieve partial or complete responses to previous EGFR-TKI treatments. Second, ILD subsides or heals in grade 1–2 patients. In principle, patients who develop grade 3 ILD usually stop treatment permanently; however, if the patient has no serious symptoms and is sensitive to corticosteroid therapy, the inflammation can subside within a short period, and TKI can be considered for reactivation. Most importantly, the patients have no other treatment options. The condition needs to be closely monitored during rechallenge, and TKI should be permanently discontinued if ILD recurs. In conclusion, we report on a case of successful aumolertinib rechallenge with corticosteroids after osimertinib-induced ILD. In the case of a high fatal risk of ILD or a rechallenge strategy after ILD, aumolertinib can be considered to control tumor progression by balancing the risks and benefits. 4. Conclusions We report a case of successful rechallenge with two different EGFR-TKIs. Faced with serious adverse effects such as ILD, the rechallenge can be attempted after a thorough assessment of clinical benefits and potential risks. Aumolertinib is an effective and well-tolerated third-generation EGFR-TKI that can be used to control tumor progression after ILD remission. Declarations Ethics approval and consent to participate ： The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient. Consent for publication: Informed consent was obtained from all patients for publication of the information/images prior to the study. Availability of data and materials: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: There are no conflicts of interests. Funding: This work was not been supported by fundings. Author Contributions: (I) Conception and design: XN Liu,YR Xie; (II) Administrative support: YR Xie,KJ Zhu; (III) Provision of study materials or patients: XN Liu, JH Huang; (IV) Collection and assembly of data: XN Liu; (V) Data analysis and interpretation: XN Liu,YR Xie; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Acknowledgements: The authors thank the patient who participated in this study.This study was supported by the Lishui Municipal Central Hospital. References Qiu H, Cao S, Xu R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond). 2021;41(10):1037–48. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3812219","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":286311079,"identity":"b9838684-415e-4dfd-9579-e72dec485a17","order_by":0,"name":"Xueni Liu","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xueni","middleName":"","lastName":"Liu","suffix":""},{"id":286311080,"identity":"42893a84-8e26-4b95-9579-4301b47ae441","order_by":1,"name":"Kejun Zhu","email":"","orcid":"","institution":"Lishui Municipal Central Hoslital","correspondingAuthor":false,"prefix":"","firstName":"Kejun","middleName":"","lastName":"Zhu","suffix":""},{"id":286311081,"identity":"e8b5d7a7-0096-4f63-a4c3-88cc0887dd8a","order_by":2,"name":"Yanru Xie","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBACxv6G5Md/Kv7X9xOthXnGgWcGPGeYGWc2EKuFvSHxgQRvCzPjhgPEauFtOJxgINnAxmx8PHkDw4+KbYS1SDa3JTww3MHDZnbmWQFjz5nbhLUYNpxJMEg8I8FjdiPHgJmxjQgt9gfyP0gcbDOQMJ5BrBbGhoQEyca2BAMDCaK1zDiQZsxw5kCCBNAvB4nyCzgqGSoOJPC3J2988KOCCC1IIMHgAEnqwVpI1TEKRsEoGAUjBAAAGzRC6NYGwRQAAAAASUVORK5CYII=","orcid":"","institution":"Lishui Municipal Central Hoslital","correspondingAuthor":true,"prefix":"","firstName":"Yanru","middleName":"","lastName":"Xie","suffix":""},{"id":286311082,"identity":"b47653f1-dbcb-4b4b-bf55-bbd056d7b2da","order_by":3,"name":"Jianhui Huang","email":"","orcid":"","institution":"Lishui Municipal Central Hoslital","correspondingAuthor":false,"prefix":"","firstName":"Jianhui","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2023-12-27 12:29:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3812219/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3812219/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54036670,"identity":"b9f02fa3-680d-402f-9a54-307361ea409f","added_by":"auto","created_at":"2024-04-03 17:03:29","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44615,"visible":true,"origin":"","legend":"\u003cp\u003eDiagnosis and treatment timeline. ADC: adenocarcinoma, 19Del, EGFR exon 19 deletion; AEs, adverse events;PCB, pemetrexed and carboplatin plus bevacizumab; MPA, methylprednisolone\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3812219/v1/5c9f3c490e447f8726545e6e.jpg"},{"id":54036671,"identity":"6eafd2dc-f2d0-450e-a664-25b2b3ab6161","added_by":"auto","created_at":"2024-04-03 17:03:29","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":439530,"visible":true,"origin":"","legend":"\u003cp\u003eThe clinical course according to CT scan findings. (A) Baseline CT scan at diagnosis in July, 2021. (B) PR on Osimertinib in Jan, 2022.(C) CT revealed the diffuse ground glass opacities to developed in Feb, 2022. (D)Diffuse ground glass shadow in both lungs reduced than before after 3 days (E) Ground glass shadow in both lungs Significantly reduced in Apr,2022. (F) Lung lesions was stable with no interstitial pneumonia change in Dec,2022.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3812219/v1/5ad938b4b8bca1a9de4fd9ea.jpg"},{"id":58731982,"identity":"70dd0957-7f6d-4a1b-bc3f-9685b63fb762","added_by":"auto","created_at":"2024-06-20 11:29:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":817726,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3812219/v1/61c9dec5-2c67-45d7-b151-6f6e00a7d2d0.pdf"},{"id":54036674,"identity":"9dbcc1ee-958d-469e-a014-c57009e94fcd","added_by":"auto","created_at":"2024-04-03 17:03:30","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":220826,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklistEnglish.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3812219/v1/f86e0d1867e339b4c27cbc91.pdf"},{"id":54036672,"identity":"3ccb9926-efcd-4862-bf7d-0af9c6422b67","added_by":"auto","created_at":"2024-04-03 17:03:29","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":17551,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3812219/v1/31e55162c73af4e60a6cf3f8.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful rechallenge twice with different EGFR-TKIs in a patient with lung adenocarcinoma after EGFR- TKI-induced grade 3 stomatitis and interstitial lung disease: a case report","fulltext":[{"header":"Highlight","content":"\u003cp\u003e\u003cstrong\u003eKey findings\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eWe report a case of successful rechallenge with two different EGFR-TKIs when faced with serious adverse effects such as grade 3 stomatitis and ILD.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is known and what is new? \u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eEGFR-TKIs are used as the first-line therapies for patients with advanced NSCLC with sensitive EGFR mutations. When faced with serious adverse effects such as ILD, there are no uniform standards for the principles and methods of EGFR-TKI rechallenge.\u003c/li\u003e\n\u003cli\u003eThe successful rechallenge in this case can provide a promising therapeutic strategy.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is the implication, and what should change now? \u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eClinicians may consider this therapy for EGFR-TKI rechallenge.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"1. Introduction","content":"\u003cp\u003ePrimary lung cancer has the highest incidence and mortality rate in China (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), and non-small cell lung cancer(NSCLC) is the most common pathology, among which EGFR exon 19 deletion (19del) and exon 21 L858R mutation are the two major sensitive mutations. EGFR tyrosine kinase inhibitors (TKIs) are used as the first-line therapies for patients with advanced NSCLC with sensitive EGFR mutations. However, this therapy presents new challenges for clinicians owing to its adverse effects. Grade 3 stomatitis seriously affects the quality of daily life and leads to discontinuation of medication. Serious adverse effects such as ILD caused by EGFR-TKIs cannot be ignored and can sometimes be fatal. Case studies on the onset of osimertinib-induced ILD are scarce, and no standard treatment is available. We report the case of a patient with advanced EGFR T790M-positive NSCLC who developed grade 3 ILD after osimertinib treatment, which was successfully treated with low-dose aumolertinib transition to a standard dose after the ILD subsided.\u003c/p\u003e"},{"header":"2. Case Description","content":"\u003cp\u003eA 67-year-old female patient with no history of smoking or family history of tumors was diagnosed with stage IV left lung adenocarcinoma (metastatic pattern: multiple bone and lymph node metastases) in March 2020. Genetic analysis of the lung needle biopsy confirmed that the tumor harbored an EGFR exon 19 deletion mutation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Gefitinib (250 mg/day) was administered as first-line therapy starting on 2 April 2020. Palliative radiotherapy for thoracolumbar metastases was used to alleviate pain. The patient achieved a PR according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 but developed grade 3 stomatitis. Due to stomatitis, patients require repeated discontinuation. Icotinib (125 mg three times per day) was administered orally starting on 8 July 8 2020 without adverse events. The tumor lesions remained stable.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHowever, new liver metastases were noted on 2 September 2021, and first-generation EGFR-TKI drug resistance was considered to have occurred. The patient refused liver needle biopsy and genetic testing because of financial constraints. Three courses of pemetrexed and carboplatin plus bevacizumab (PCB) were administered on 4 September, 29 September, and 24 October 2021. Imaging indicated that the liver metastases had decreased slightly in size; However, the lesion in the right lung had become larger, and the patient agreed to undergo genetic testing.The genomic information was obtained from NGS-based 340 gene panel (OrigiMed, Shanghai, China),which encompasses 58 Germline Gene(Supplementary Table\u0026nbsp;1) .The result showed EGFR T790M mutation and then she received osimertinib (80 mg/day) starting on 25 November 2021.\u003c/p\u003e \u003cp\u003eCompared with the CT in July of 2021(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), a PR was achieved after osimertinib administration for one month (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Unfortunately, three months after osimertinib initiation, the patient developed chest tightness after exercise, which did not, however, seriously affect their daily life. The patient did not have a cough, sputum, fever, or chills. A chest CT on 28 February 2022 revealed no significant changes in the tumor lesions; however, new diffuse ground-glass opacities developed in both lungs (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). To further clarify the diagnosis, electronic bronchoscopy was performed, which revealed no obvious abnormalities. Bronchoalveolar lavage fluid was sent for pathogenic microorganism culture, and no pathogens were detected by routine laboratory tests. The levels of inflammatory markers such as CRP, leukocytes, neutrophils, and calcitonin were within the normal ranges.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on the patient\u0026rsquo;s symptoms, imaging, and laboratory tests, osimertinib was identified as the cause of grade 3 ILD. Osimertinib was immediately discontinued, and oxygen and methylprednisolone (40 mg/day) were administered. The patient\u0026rsquo;s chest tightness improved significantly, and chest CT revealed diffuse ground-glass shadows in both lungs, which were reduced after 3 days (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). The methylprednisolone tablets were reduced to 32 mg orally daily after one week and then further reduced to 4\u0026ndash;8 mg weekly until discontinuation. CT on 20 April 2022 revealed that these diffuse ground glass shadows in both lungs were significantly reduced (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). The MRI suggested that the liver metastases were smaller than in the MRI findings of 4 January 2022. Combined with adverse reaction regression and drug efficacy, low-dose aumolertinib (55 mg/day) was administered to control tumor progression, with the patient\u0026rsquo;s consent, on 21 April 2022, and oral methylprednisolone (4 mg/day) was administered to prevent the occurrence of ILD. The scattered ground-glass shadows in both lungs continued to decrease after treatment with aumolertinib for one month. The aumolertinib dose was increased to 110 mg/day under steroid protection (4 mg methylprednisolone daily) on 19 May 2022. Chest CT indicated that the scattered ground-glass shadows were largely absorbed, and the patient continued to receive aumolertinib without steroid protection as of 2 June 2022. The patient did not exhibit signs of worsening of the respiratory symptoms. Chest CT performed in August and December 2022 showed that the lung lesions were stable and there were no interstitial pneumonia changes (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). The liver metastases continued to shrink. The patient achieved a partial response (PR). To date, the patient has experienced no obvious adverse drug reactions to aumolertinib, and ILD has not recurred.\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eLung cancer is the second most commonly diagnosed cancer worldwide, and it remains the leading cause of cancer death (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The five-year overall survival rate remains below 5% for patients with metastatic NSCLC treated with chemotherapy. IPASS research has established the potential of targeted therapy in the field of advanced NSCLC treatment; The PFS has been reported to be significantly longer for gefitinib than for carboplatin/paclitaxel (median PFS 9.6 months vs. 6.3 months, respectively) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). New TKIs are constantly being developed to further improve PFS and OS. The FLAURA trial showed that osimertinib significantly prolonged the median OS compared with the control group (38.6 months vs. 31.8 months, respectively; HR\u0026thinsp;=\u0026thinsp;0.80, P\u0026thinsp;=\u0026thinsp;0.046) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, this therapy presents new challenges to clinicians because of its inherently different spectrum of toxicity, which is unique to the pharmacodynamic profile of each drug.\u003c/p\u003e \u003cp\u003eRashes, paronychia, diarrhea, stomatitis, liver dysfunction, and pulmonary toxicity are frequently observed in patients treated with EGFR-TKIs. The treatment-related AEs are usually tolerable. However, among the adverse effects of TKIs, interstitial lung disease is a rare but serious off-target adverse reaction that has been reported to be fatal even after intensive supportive therapy (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe patient was a 67-year-old woman who developed recurrent stomatitis after first-line use of gefitinib, which not only affected their quality of life but also prevented them from undergoing normal treatment owing to repeated discontinuation. Given the differences in the incidence and severity of adverse events associated with EGFR-TKIs, substitution between different TKIs has become a direction to be explored. The incidence of all-grade stomatitis caused by gefitinib is approximately 17%, and that of grade 3 or higher stomatitis is \u0026lt;\u0026thinsp;1% (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In the CONVINCE study, stomatitis was not reported following icotinib (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Icotinib is associated with fewer treatment-related adverse events than gefitinib, suggesting that icotinib may have a better safety profile (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In this patient, their stomatitis resolved after treatment replacement with icotinib, which was well tolerated.\u003c/p\u003e \u003cp\u003eThird-generation EGFR TKIs are used to treat patients with EGFR T790M-positive NSCLC who experience secondary drug resistance following first- or second-generation EGFR-TKI therapy (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Additionally, since third-generation EGFR-TKIs significantly prolong the median PFS (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and improve overall survival (OS) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) compared to first-generation EGFR-TKIs, they are also the first-line standard treatment for patients with advanced NSCLC.\u003c/p\u003e \u003cp\u003eHowever, the patient developed drug resistance (EGFR T790M mutation) after 17 months of treatment. Unfortunately, although the tumor achieved PR, this was associated with grade 3 ILD after receiving osimertinib for three months. Although the clinical recognition of ILD is increasing, the molecular mechanisms mediating the association between EGFR-TKIs and lung injury remain unknown. This may be due to the following reasons. Alveolar type II epithelial cells express EGFR, which plays an essential role in maintaining epithelial cells. EGFR-TKIs inhibit tumor growth but may also impair epithelial cell growth and repair of damage, thereby leading to tissue injury (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Interleukin 6 (IL-6) is also known to induce interstitial pneumonia. EGFR-TKIs activate activating protein-1 (AP-1) in cancer cells and induce the production of large amounts of IL-6, which increases the risk of chemoresistance and acute interstitial pneumonia (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). However, ILD may also be the result of immune-mediated allergic reactions to EGFR-TKIs (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). According to previous studies, the risk of ILD needs to be assessed in patients receiving EGFR-TKIs. To date, the listed risk factors of ILD include being male, a history of smoking, age\u0026thinsp;\u0026ge;\u0026thinsp;55 years, Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS)\u0026thinsp;\u0026ge;\u0026thinsp;2, presence of contralateral lung metastases, a history of radiation therapy within one year, early treatment initiation after diagnosis, pre-existing interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), lung infectious disease, previous treatment with anti-programmed cell death protein-1 monoclonal antibodies (PD-1), coexisting heart disease, and normal lung area\u0026thinsp;\u0026lt;\u0026thinsp;50% (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Combined with the medical history, the patient had no other high-risk factors for ILD except for advanced age. Additionally, previous TKIs such as gefitinib and icotinib had been used without the adverse events of ILD.\u003c/p\u003e \u003cp\u003eAfter remission of osi-ILD, it is necessary to choose appropriate drugs to control tumor progression and prolong patient survival. In principle, patients who develop grade 3 or greater ILD usually discontinue their treatment permanently. Since the patients discontinue the effective drug because of ILD, the subsequent antitumor treatment options are limited. Kosuke et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) reported a total of 11 cases of successful EGFR-TKI rechallenge after recovery from gefitinib- or erlotinib-induced ILD, and the OS of patients with EGFR-TKI rechallenge was longer than that in patients without EGFR-TKI rechallenge (15.5 vs. 3.5 months, respectively; p\u0026thinsp;=\u0026thinsp;0.029). Combined with imaging changes and routine laboratory tests, the patient exhibited grade 3 ILD, albeit without severe symptoms. The patient had only slight chest tightness after activity, without hypoxemia. After administering methylprednisolone (40 mg/day) for 3 days, the patient\u0026rsquo;s symptoms improved significantly, and chest CT revealed that the ground-glass opacity was significantly reduced. These findings indicate that the patient was sensitive to steroid therapy. For this patient, based on successful treatment with icotinib after gefitinib-induced stomatitis, we believe that other third-generation EGFR-TKIs can also be considered after rapid control of ILD.\u003c/p\u003e \u003cp\u003eILD adverse reactions occur in 2\u0026ndash;3% of osimertinib treatments (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). There is a high prevalence of ILD in Japanese patients, and pneumonitis occurred in 12.3% of patients treated with osimertinib (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAumolertinib is a novel, irreversible, small-molecule, third-generation EGFR TKI with high selectivity for EGFR-sensitizing and T790M resistance mutations. The structure of aumolertinib was innovatively optimized based on osimertinib, but with the replacement of a cyclopropyl group on the indole nitrogen. As a result, some non-selective metabolites that inhibit the WT EGFR may not be generated during drug metabolism in order to reduce wild-type EGFR-related adverse reactions caused by non-selective metabolites while still ensuring antitumor activity. The most common adverse reactions of aumolertinib are CPK elevation, mild skin rash, and diarrhea, while associated ILD was extremely rare (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlmost two months after the discontinuation of Osimertinib, imaging showed that the tumor continued to shrink. The patient was evaluated as having a PR, indicating that she was sensitive to third-generation TKIs. According to some reported cases, continued use of osimertinib to control tumor progression may be an option after ILD has been controlled (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). However, the same-drug rechallenge is not recommended when other drugs are available. Owing to the low incidence of aumolertinib-associated ILD, the patient received an EGFR-TKI rechallenge. Under close monitoring, low-dose aumolertinib (55 mg/day) was administered along with corticosteroids. After one month, CTs showed no ILD aggravation; therefore, aumolertinib was added at the normal dose (110 mg per day). The CT was repeated after 15 days, and no ILD occurred. The patient consequently discontinued the corticosteroid therapy. To date, the tumor has been successfully controlled for more than 17 months, with no adverse drug reactions such as ILD.\u003c/p\u003e \u003cp\u003eThird-generation EGFR-TKIs differ in the incidence or severity of adverse events, and replacement with different third-generation EGFR-TKIs has become a direction of exploration. Careful use of EGFR-TKIs should be considered after a thorough assessment of their clinical benefits and potential risks. First, patients with advanced NSCLC can achieve partial or complete responses to previous EGFR-TKI treatments. Second, ILD subsides or heals in grade 1\u0026ndash;2 patients. In principle, patients who develop grade 3 ILD usually stop treatment permanently; however, if the patient has no serious symptoms and is sensitive to corticosteroid therapy, the inflammation can subside within a short period, and TKI can be considered for reactivation. Most importantly, the patients have no other treatment options. The condition needs to be closely monitored during rechallenge, and TKI should be permanently discontinued if ILD recurs.\u003c/p\u003e \u003cp\u003eIn conclusion, we report on a case of successful aumolertinib rechallenge with corticosteroids after osimertinib-induced ILD. In the case of a high fatal risk of ILD or a rechallenge strategy after ILD, aumolertinib can be considered to control tumor progression by balancing the risks and benefits.\u003c/p\u003e"},{"header":"4. Conclusions","content":"\u003cp\u003eWe report a case of successful rechallenge with two different EGFR-TKIs. Faced with serious adverse effects such as ILD, the rechallenge can be attempted after a thorough assessment of clinical benefits and potential risks. Aumolertinib is an effective and well-tolerated third-generation EGFR-TKI that can be used to control tumor progression after ILD remission.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThe authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003eInformed consent was obtained from all patients for publication of the information/images prior to the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003eThere are no conflicts of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was not been supported by fundings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions: \u003c/strong\u003e(I) Conception and design: XN Liu,YR Xie; (II) Administrative support: YR Xie,KJ Zhu; (III) Provision of study materials or patients: XN Liu, JH Huang; (IV) Collection and assembly of data: XN Liu; (V) Data analysis and interpretation: XN Liu,YR Xie; (VI)\u003c/p\u003e\n\u003cp\u003eManuscript writing: All authors; (VII) Final approval of manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003eThe authors thank the patient who participated in this study.This study was supported by the Lishui Municipal Central Hospital.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eQiu H, Cao S, Xu R. Cancer incidence, mortality, and burden in China: a time-trend analysis and comparison with the United States and United Kingdom based on the global epidemiological data released in 2020. Cancer Commun (Lond). 2021;41(10):1037\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). 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Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(2):113\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Y, He Y, Li W, et al. Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Target Oncol. 2021;16(2):165\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki H, Aoshiba K, Yokohori N, et al. Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res. 2003;63(16):5054\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndo M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2006;24(16):2549\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshiguro Y, Ishiguro H, Miyamoto H. Epidermal growth factor receptor tyrosine kinase inhibition up-regulates interleukin-6 in cancer cells and induces subsequent development of interstitial pneumonia. Oncotarget. 2013;4(4):550\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKataoka K, Taniguchi H, Hasegawa Y, et al. Interstitial lung disease associated with gefitinib. Respir Med. 2006;100(4):698\u0026ndash;704.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi L, Tang J, Tong L, et al. Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: a systematic review and meta-analysis of clinical trials. Lung Cancer. 2014;83(2):231\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchoenfeld AJ, Arbour KC, Rizvi H, et al. 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Ther Adv Med Oncol. 2021;13:17588359211018028.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhe Y, Imamura F, Nogami N, et al. Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset. Jpn J Clin Oncol. 2019;49(1):29\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang JC, Camidge DR, Yang CT, et al. Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial. J Thorac Oncol. 2020;15(12):1907\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyauchi E, Ichinose M, Inoue A. Successful Osimertinib Rechallenge in a Patient with T790M-Mutant Non-Small Cell Lung Cancer after Osimertinib-Induced Interstitial Lung Disease. J Thorac Oncol. 2017;12(5):e59\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammed T, Mangeshkar S, Rathmann J. Successful Rechallenge with Osimertinib after Very Acute Onset of Drug-Induced Pneumonitis.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Zhang L, Shi X, et al. Successful treatment with osimertinib and its subsequent resistance mechanism in a patient with non-small-cell lung cancer harboring acquired EGFR T790M mutation after recovery from AC0010-induced interstitial lung disease. Onco Targets Ther. 2019;12:5545\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"EGFR-TKI rechallenge, aumolertinib, stomatitis, grade 3 interstitial lung disease","lastPublishedDoi":"10.21203/rs.3.rs-3812219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3812219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRechallenge with EGFR tyrosine kinase inhibitors (TKIs) can be successful as a result of different TKI adverse event profiles. Grade 3 stomatitis seriously affects a patient’s life and leads to drug discontinuation, which can affect survival. Serious adverse effects caused by EGFR-TKIs, such as interstitial lung disease (ILD), can be fatal. This study provides new treatment options for patients who develop grade 3 stomatitis or ILD following EGFR-TKI therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Description:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe present the case of a 67-year-old female patient with stage IV adenocarcinoma involving an EGFR exon 19 deletion mutation who received gefitinib for three months and then discontinued treatment due to grade 3 stomatitis. Icotinib was readministered without any adverse events (AEs). After stable control for 14 months, new liver metastases appeared, and three cycles of pemetrexed and carboplatin plus bevacizumab were administered. Subsequent next-generation sequencing of plasma indicated an EGFR T790M mutation, and the patient subsequently received osimertinib for three months. However, as the patient developed osimertinib-induced grade 3 ILD, the TKIs were discontinued, and high-dose methylprednisolone was administered. After symptomatic remission, half-dose aumolertinib and steroid protection were administered. As there was no ILD recurrence, aumolertinib was increased to the standard dose in 1 month, and the tumor achieved a partial response (PR) .The progression-free survival (PFS) with aumolertinib was more than 17 months without obvious AEs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report a case of successful rechallenge with two different EGFR-TKIs. Faced with serious adverse effects such as ILD, the rechallenge can be attempted after a thorough assessment of clinical benefits and potential risks.\u003c/p\u003e","manuscriptTitle":"Successful rechallenge twice with different EGFR-TKIs in a patient with lung adenocarcinoma after EGFR- TKI-induced grade 3 stomatitis and interstitial lung disease: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-03 17:03:25","doi":"10.21203/rs.3.rs-3812219/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ca4a14e-1473-4dd5-b042-25579971b8a3","owner":[],"postedDate":"April 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-20T11:21:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-03 17:03:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3812219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3812219","identity":"rs-3812219","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}