Failure of the tyrosine kinase inhibitors osimertinib and erlotinib to manage a patient with EGFR-mutant lung adenocarcinoma: a case report

Introduction

Classified vastly as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), lung cancer is the leading cause of cancer death worldwide. Epidermal growth factor receptor (EGFR) exon 19 deletion (E19del) is an activating mutation that accounts for well-known cases of NSCLC including adenocarcinoma of the lung. EGFR is a transmembrane tyrosine kinase receptor. Lung adenocarcinoma, a type of NSCLC, is the most common type of lung cancer among non-smokers unlike the other types of lung cancers which predominate in smokers. It is also more common in Asian ethnicity and female sex. Lung adenocarcinoma in E19del mutation-positive cases are sensitive to regimens of tyrosine kinase inhibitors (TKIs).

Erlotinib and osimertinib are two known EGFR TKIs used in cases of lung adenocarcinoma. Erlotinib is a first generation TKI that binds reversibly to the adenosine triphosphate (ATP) binding site of the EGFR and inhibits it (1). A prolonged dose of erlotinib can present with adverse effects such as skin rash, diarrhea, eye irritation, and insomnia. Resistance to erlotinib develops in a wide range of cases because of which the average progression-free survival (PFS) decreases to a range of 9 to 15 months (1). The major mechanism of resistance is the development of the gatekeeper T790M mutation in EGFR exon 20 which prevents the binding of erlotinib and other first generation TKIs to the ATP binding site (1). Osimertinib is a third generation TKI that overcomes the T790M mutation and irreversibly inhibits the receptor (1). Osimertinib is used in cases that develop resistance to first- (erlotinib) and second-generation TKIs. Owing to the excellent central nervous system penetration of osimertinib, it resists brain metastasis, which is a common finding in advanced cases of lung adenocarcinoma (1). Resistance to osimertinib can be of two types, namely EGFR-independent mechanisms of resistance and EGFR-dependent mechanisms of resistance. EGFR-dependent mechanism of resistance includes the loss of T790M mutation while EGFR-independent mechanism of resistance includes bypass pathways like mesenchymal epithelial transition (MET) gene amplification, human epidermal growth factor receptor 2 (HER2) amplification, and RAS/mitogen activated protein kinase (RAS/MAPK) pathway activation etc. (1).

Henceforth, we discuss the case of a patient who received TKIs as a regimen for lung adenocarcinoma, and failed to respond to osimertinib and was switched to erlotinib but subsequently developed resistance to erlotinib as well. We also explore literature regarding the possible resistance mechanisms to TKIs, and regarding the potential approaches to overcome treatment failure. The following case is presented in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-122/rc).

Case presentation

A 48-year-old woman of average build came to the clinic with several complaints. She had been experiencing shortness of breath, a dry cough, headaches, low back pain, and fever for the past 3 months. It was discovered that she had metastatic adenocarcinoma of the lung. She had never smoked and had no family history of cancer. She had not been exposed to any occupational carcinogens. Additionally, she mentioned having trouble sleeping, a decreased appetite, and a significant weight loss of 14 kilograms during this time. The patient had been diabetic for the past 2 years, but her condition was managed with oral antidiabetic medication. She had a previous back surgery over 15 years ago. According to the patient, 3 years ago she sought medical help for worsening shortness of breath, a dry cough, and chest pain that did not improve with over-the-counter medication. A chest X-ray revealed a 2.9 cm mass with irregular margins in the right middle lobe of the lung, along with pleural effusion. The effusion was drained, and further tests including imaging, histopathology, and immunohistochemistry confirmed that she had stage IV adenocarcinoma of the lung with metastasis to the mediastinal lymph nodes. The computed tomography (CT) scans (Figures 1,2) revealed an infiltrating mass in the right lung, as well as pulmonary metastatic nodules, lymphangitis carcinomatosis, pleural metastasis, and metastasis to the liver, right adrenal gland, skeletal system, bilateral axillary lymph nodes, and upper abdominal lymph nodes. A comparison with a previous CT report from 6 months ago showed that the disease had progressed.

Figure 1 Ill-defined heterogeneously enhancing infiltrative soft tissue mass involving the perihilar region of the right upper and middle lobe, encasing the associated bronchi (red arrow) as well as abutting the adjacent upper lobe bronchi (yellow arrow). Pleural and septal nodularity (green arrow) are compatible with lymphangitis carcinomatosis.

Figure 2 Infiltrative mass involving the right hilum (red arrow), pulmonary parenchyma (yellow arrow), and pleura (green arrow).

The patient underwent two cycles of chemotherapy with carboplatin and pemetrexed, which significantly improved her symptoms. She then started targeted chemotherapy with osimertinib, as per the evidence supporting the use of osimertinib in EGFR-mutant NSCLC. Prior to initiating the treatment with osimertinib, molecular analysis indicated a positive EGFR E19del mutation, a positive T790M mutation, and a negative TP53 mutation. In addition to undergoing cancer treatment, she had been prescribed tramadol, an opioid agonist, to manage breakthrough generalized body pain that she experienced while being treated for lung adenocarcinoma. Her symptoms were satisfactorily controlled with osimertinib for 2 years; however, she began experiencing recurring chest discomfort, dyspnea, insomnia, and bone pain. A whole-body CT scan revealed metastasis to the paraaortic lymph nodes and lumbar spine. After conducting resistance testing, it was found that the T790M mutation had disappeared while other mutations remained unchanged. Based on literature supporting the use of erlotinib in such cases, the decision was made to change her chemotherapy regimen from osimertinib to erlotinib, which she had been taking for 6 months and resulted in significant improvement in her respiratory symptoms. However, despite taking the medication regularly, the patient gradually developed morning headaches and her insomnia worsened. A repeat magnetic resonance imaging (MRI) revealed metastasis of the tumor to the frontal and occipital lobes of her brain, showing that erlotinib had lost its efficacy against the newly mutated cancer cells. Additionally, she developed red papules and pustules on her face, back, and abdomen, which are among the commonly experienced adverse events associated with erlotinib treatment. Consequently, the patient was admitted to the hospital for symptomatic care and to receive radiotherapy for brain metastasis.

Notably, all procedures performed in this study 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 for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Lung adenocarcinoma with EGFR E19del responds to treatment with TKIs and are the first-line treatment for EGFR mutation-positive, advanced NSCLC (2). Additionally, studies have indicated that E19 deletion in lung adenocarcinoma, with EGFR positivity, is associated with a good prognosis, and this finding was linked to the extensive use of TKIs (2,3). Yoon et al. (2) demonstrated a substantial difference in the prognosis of the four EGFR mutation sites. The significantly higher survival rate in patients responding to TKIs was associated with a higher proportion of E19 dels. Furthermore, Choi et al. (3) retrospectively analyzed 60 patients with EGFR-positive advanced NSCLC patients and who received gefitinib therapy (250 mg/day) as a first-line treatment, and concluded that in all patients with E19 dels, the overall survival (OS) and median PFS was favorable after receiving gefitinib therapy.

Erlotinib is a reversible first-generation EGFR-TKI that binds to the ATP binding site of the EGFR and prevents the phosphorylation of its substrate in the cell signaling pathway (1). Despite the evident superior efficacy of first-generation and second-generation (afatinib) TKIs compared to the standard platinum-based chemotherapy and despite the exceedingly high objective response rate (ORR) of 60–70% to treatment with first-generation and second-generation TKIs in patients with EGFR mutation-positive advanced NSCLC, the development of resistance to such treatments leads to a decrease in median PFS to a range of 9 to 15 months (1). Indeed, the major mechanism of resistance involved is the prevention of binding of erlotinib and other first-generation TKIs to the ATP binding site of EGFR due to the development of the gatekeeper T790M mutation in EGFR exon 20 (1). The eventual failure of response to erlotinib in our patient could be linked to the development of a similar resistance mechanism, given the higher rates of mutations occurring in neoplastic cells with each cell division and given the presence of several extensive studies, supporting the development of inevitable resistance to first-generation TKIs within the first few months of treatment initiation. Similar resistance to erlotinib was demonstrated by Qin et al. (4) in a patient with advanced lung adenocarcinoma with EGFR L858R/Y891 double mutation, whereby, treatment with 150 mg of erlotinib daily for 3 months after radiation did not stop further metastasis of tumor to the brain and right pleura. This is consistent with the findings in our patient, whereby the tumor metastasized to the brain during the treatment with erlotinib.

The limitation to the use of first- and second-generation TKIs due to the development of resistance has been counterbalanced by third-generation TKIs (1). A widely used and irreversible third-generation TKI is osimertinib, that forms a covalent bond to the C797 residue in the ATP-binding site of EGFR and, thus, is particularly designed to target the activating EGFR and T790M-resistance mutations (1). This indicates that the T790M-positive patients who fail to respond to first- or second-generation EGFR-TKIs and experience worsening tumor progression could theoretically benefit from osimertinib (1). However, the practice of trying first and second generation TKIs before osimertinib has long been abandoned, as these medications have been found less effective in controlling the disease in its initial stages. For the treatment of advanced EGFR-mutated NSCLC, in 2018, osimertinib received approval to be used as a first-line treatment, irrespective of the T790M mutation (1). A recent phase 3, international trial, with 557 enrolled patients, concluded that in patients with EGFR mutation-positive advanced NSCLC, combining osimertinib with chemotherapy (platinum-based agent and premetrexed) in the first-line treatment led to a marked improvement in PFS, compared to osimertinib monotherapy (5). Notably, Niwa et al. (6) reported positive response to osimertinib following resistance to erlotinib after 2 years of treatment in a patient with uncommon exon 20 T790M and an exon 21 L858R mutation, indicating efficacy of osimertinib in treating both common and uncommon EGFR mutations.

Prior to initiating treatment with osimertinib, molecular analysis indicated a positive EGFR E19del mutation, a positive T790M mutation, and a negative TP53 mutation. Due to resource limitations, we did not test for the EGFR C797S mutation. After the failure of osimertinib, we re-conducted the molecular analysis and found that the T790M mutation had disappeared, but the TP53 mutation remained negative. This justified our decision to use erlotinib, as supported by the literature for cases where the T790M mutation has disappeared. Despite this, erlotinib eventually failed, and the patient was subsequently treated with radiotherapy. Like first- and second-generation TKIs, acquired resistance to osimertinib can occur via multiple molecular mechanisms, and poses a significant threat to clinical betterment owing to the scarce availability of further pharmacological agents post-osimertinib thus far (1). Osimertinib targets the activating EGFR and T790M-resistance mutations, and thus is effective in overcoming the treatment failure to erlotinib, however, it has become known that the loss of T790M mutation during treatment is a major mechanism of osimertinib resistance (1). Since resistance to first-generation TKIs occurs due to the development of T790M mutation, it is plausible to consider treatment with first-generation TKIs after the disappearance of this resistance mutation (1). Notably, Gursoy et al. (7) reported that when osimertinib failed to respond in a patient with erlotinib failure, complete response to re-treatment with erlotinib was observed in that patient when re-biopsy confirmed the absence of T790M mutation. In addition, Oxnard et al. (8) illustrated that development of additional mutations, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, small cell transformation and MET amplification, might accompany the disappearance of T790M mutation and these circumstances pose a significant challenge for re-treatment using first-generation TKIs, as first-generation TKIs cannot overcome such additional mutations (1). This outlines the significance of further research in the field for developing strategies, such as combination targeted therapies, that would help mitigate the problem of resistance development in future. Additionally, Ohtaki et al. (9) emphasized that salvage surgery following TKI treatment could potentially help in prolonging OS time [3-year OS after surgery, 75.1%, and 3-year recurrence-free survival (RFS) after surgery, 22.2%] and is considered feasible and safe. This illustrates the potential use of salvage surgery to enhance positive outcome and, possibly, to prevent the development of resistance to TKIs, including osimertinib, in patients with advanced EGFR positive lung adenocarcinoma.

In our case, both erlotinib and osimertinib were ineffective in controlling the malignancy. This raises the critical question of what evidence-based strategies should be considered next. A recent trial investigated the efficacy of amivantamab combined with carboplatin-pemetrexed (chemotherapy), with or without lazertinib, in patients with refractory EGFR-mutated advanced NSCLC (10). The global phase III trial included 657 patients with locally advanced or metastatic NSCLC who had progressed on osimertinib (10). The results were promising, showing significantly longer PFS for those treated with amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy compared to chemotherapy alone. Specifically, median intracranial PFS was also notably longer in the combination therapy groups (6.3 and 8.3 vs. 4.2 months, respectively) (10). These findings suggest that amivantamab-based regimens could be a viable option for patients with advanced NSCLC after osimertinib failure, although further follow-up is needed to confirm the long-term benefits of these treatments (10). Clinical guidelines suggest platinum-based chemotherapy as the subsequent line of treatment, typically resulting in a median PFS of 4.4–5.5 months for patients whose disease has progressed following TKI therapy (11). Due to the higher costs, and conflicting clinical evidence, and patient’s preference, we were unable to implement this regimen for our patient. Nonetheless, this approach may be valuable for similar cases in the future. While the use of osimertinib shows promise in improving clinical outcomes in patients with EGFR-positive advanced NSCLC, the emergence of resistance necessitates further research to be carried out. Appropriate knowledge and understanding of mechanism of action and resistance of TKIs is crucial for guiding subsequent treatment in cases of treatment failure with one or more agents.

Conclusions

In conclusion, our case demonstrates the complexities encountered during the treatment of EGFR-mutant advanced NSCLC with TKIs and provides clinical evidence that while osimertinib is effective in treating advanced NSCLC, the inevitable emergence of resistance to the medication limits its efficacy eventually. Further extensive research is imperative to help develop strategies to prevent resistance to first-, second- and third-generation TKIs and, hence, to prevent metastatic progression in patients with EGFR mutation-positive advanced NSCLC.

Acknowledgments

The authors acknowledge the cooperation of the patient and her family.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-122/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-122/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-122/coif). L.T. reports receiving royalties from Amazon and Google for 3 textbooks, Search Pattern: A Systematic Approach to Diagnostic Imaging [2020], A Brief Guide to the Neuroradiology Fellowship [2021], and How to be a More Efficient Radiologist: A Guide to Practice, Reporting, and Workflow Optimization [2023]. The other authors have no conflicts of interest to declare.

Ethical Statement: 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 this study 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 for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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