Furmonertinib re-challenge for epidermal growth factor receptor-mutant lung adenocarcinoma after osimertinib-induced interstitial lung disease: A case report

Abstract

BACKGROUND

Most non-small cell lung cancer patients have epidermal growth factor receptor (EGFR) activating mutations, such as exon 19 deletion and exon 21 replacement mutations. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitors approved for the treatment of lung cancer patients carrying EGFR activating mutations. Osimertinib-induced interstitial lung disease (ILD) is a rare and potentially fatal pulmonary toxic manifestation of drug therapy. At present, there is no international consensus on the risks and treatment of the osimertinib-induced ILD.

CASE SUMMARY

We report a case of a 56-year-old woman who was diagnosed with lung adenocarcinoma with lung hilum, mediastinal lymph nodes and brain metastases (T4N3M1c stage IVB). The patient received targeted treatment with osimertinib after radiotherapy and chemotherapy. But she developed ILD after osimertinib treatment. Following active symptomatic treatment and hormone treatment, the lung injury alleviated. The patient was retreated with furmonertinib combined with prednisone and did not experience ILD again. So far, she has survived for 14 months without disease progression.

CONCLUSION

Retreatment with furmonertinib under prednisone could be considered as an effective therapeutic option after risk-benefit assessment for EGFR-mutant lung adenocarcinoma patients.

Key Words: Furmonertinib; Osimertinib; Lung adenocarcinoma; Interstitial lung disease; Case report

Core Tip: We report a case of a 56-year-old woman who was diagnosed with lung adenocarcinoma with lung hilum, mediastinal lymph nodes and brain metastases (T4N3M1c stage IVB). The patient received targeted treatment with osimertinib after radiotherapy and chemotherapy, but she developed interstitial lung disease following osimertinib treatment. After active treatment, her lung injury improved. The patient was retreated with furmonertinib combined with prednisone and did not experience interstitial lung disease again. So far, she has survived for 14 months without disease progression. This study suggests that retreatment with furmonertinib under steroid coverage could be considered as an effective therapeutic option after careful risk-benefit assessment for patients with epidermal growth factor receptor-mutant lung adenocarcinoma.

INTRODUCTION

Lung cancer is the most common cause of cancer-related deaths worldwide, and 85% are non-small cell lung cancer (NSCLC). Most NSCLC patients have epidermal growth factor receptor (EGFR) activation mutations, such as exon 19 deletion and exon 21 replacement mutations. The development of tyrosine kinase inhibitors (TKIs) targeting EGFR activating mutations has improved the prognosis of many lung cancer patients[1]. Osimertinib is a third-generation EGFR-TKI approved for the treatment of lung cancer patients carrying EGFR activating mutations. The common adverse reactions include diarrhea, rash, paronychia, oral mucositis, etc. Osimertinib-induced interstitial lung disease (ILD) is a rare and potentially fatal pulmonary toxicity of drugs disease[2]. Herein we report a lung adenocarcinoma patient who developed ILD following treatment with osimertinib. After active symptomatic and hormone treatment, her lung injury alleviated. Then the patient was retreated with furmonertinib combined with prednisone and did not experience ILD again. It is suggested that retreatment with furmonertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant lung adenocarcinoma. It is also necessary to closely monitor adverse reactions and efficacy in order to adjust the treatment plan in a timely manner.

CASE PRESENTATION

Chief complaints

A 56-years-old woman complained of dizziness and discomfort without obvious inducement in December 2022, accompanied by a feeling of soreness and swelling in her neck and back. The patient had no headache, nausea, vomiting, double vision, tinnitus, limb twitching, or sensory disorders. After self-massage at a clinic, her symptoms were relieved. Two days later, the patient experienced dizziness and obvious headache, accompanied by general fatigue and slow walking. After another massage at the clinic, however, her symptoms did not improve. Later, intravenous therapy was administered, but the symptoms still did not improve significantly. In the following days, the patient developed more symptoms such as coughing, sore throat, and difficulty in coughing up. A head computed tomography (CT) scan at a local hospital showed a left cerebellar and parietal lobe mass, suggesting a metastatic tumor. The patient then visited our outpatient department and was diagnosed with “intracranial mass lesions” and admitted to our hospital.

History of present illness

The patient suffered from repeated dizziness and headache for over a month without obvious cause.

History of past illness

The patient had had grade II hypertension before admission to our hospital. She denied a history of diabetes, coronary heart disease, hepatitis, tuberculosis or other infectious diseases. She had no history of major surgery, trauma, or blood transfusion. She also denied any history of medication, or food allergies.

Personal and family history

The patient had no history of exposure to toxic substances or radioactive substances. She had no smoking or alcohol addiction either. She denied any family history of lung cancer or malignant tumors.

Physical examination

Her physical examination revealed clear consciousness, normal calculation, memory, orientation, judgment, and logical thinking abilities. Her performance status score was 1, Glasgow Coma Scale score was 15 (E4V5M6). The head size is normal without any deformities. There is no enlargement of the thyroid gland. Bilateral percussion shows clear sounds, with coarse breathing sounds in both lungs and slight moist rales in both lower lungs. The heart rate is 88 beats per minute and the rhythm is consistent. There is no tenderness or rebound pain in the entire abdomen, no percussion pain in the liver and kidney areas, and no edema in both lower limbs.

Laboratory examinations

Tumor markers were as follows: (1) Alpha fetoprotein: 2.34 ng/mL (reference value: ≤ 7.0 ng/mL); (2) Carcinoembryonic antigen: 5.10 ng/mL (reference value: 0-5 ng/mL); (3) Carbohydrate antigen 125: 10.40 U/mL (reference value: 0-25 U/mL); (4) Carbohydrate antigen 19-9: 6.31 U/mL (reference value: ≤ 30 U/mL); (5) Carbohydrate antigen 15-3: 77.70 U/mL (reference value: ≤ 24 U/mL); (6) Carbohydrate antigen 72-4: 7.08 U/mL (reference value: ≤ 6.9 U/mL); (7) Squamous cell carcinoma antigen: 1.02 ng/mL (reference value: 0.5-3 ng/mL); (8) Ferritin: 251.00 ng/mL (reference value: 25-325 ng/mL); (8) Neuron-specific enolase: 18.40 ng/mL (reference value: 0-16.3 ng/mL); (9) Cytokeratin 19 fragment: 4.30 ng/mL (reference value: 0-3.3 ng/mL); and (10) B subunit of human chorionic gonadotropin: 1.0 IU/L (reference value: ≤ 2.0 IU/L).

Imaging examinations

Chest CT indicated that: (1) A space occupying lesion in the anterior segment of the left upper lobe, suggesting central type lung cancer; (2) Diffuse miliary nodules in both lungs; (3) Enlarged lymph nodes in both pulmonary hilum and mediastinum, considering metastases; and (4) Magnetic resonance imaging of the brain revealed multiple abnormal signals in the left occipital lobe, bilateral parietal lobes, bilateral cerebellum, and cerebellar vermis, suggesting the possibility of metastatic tumors (Figure 1). Ultrasound examinations found no significant abnormalities in the urinary system, abdomen, cervical vascular system, or gynecological system.

Figure 1 Lung adenocarcinoma with lung hilum, lymph nodes in mediastinum and brain metastases. A: A mass in the left upper lobe (arrow) with blurred boundaries; B: Enlarged lymph nodes (arrow) in both pulmonary hilum and mediastinum; C: Magnetic resonance imaging of the brain suggested multiple abnormal signals (arrows) in the left occipital lobe, bilateral parietal lobes, bilateral cerebellum, and cerebellar vermis.

Immunological examination

Puncture biopsy was performed on the mass in the anterior segment of the left upper lobe of the lung, and immunohistochemical examinations showed the following results: Pan-cytokeratin (+), cytokeratin 7 (+), NapsinA (+), thyroid transcription factor 1 (+), cytokeratin 5/6 (-), P40 (-), CD56 (-), Ki-67 (+, 5%). The results suggested invasive adenocarcinoma of the lung.

FINAL DIAGNOSIS

The patient was diagnosed with lung adenocarcinoma with lung hilum, mediastinal lymph nodes and brain metastases (T4N3M1c stage IVB).

TREATMENT

The patient underwent intensity-modulated radiation therapy for brain metastases from January 18 to February 15, 2023, with 95% gross tumor volume 5600 cGy/20 fractions/28 days and 95% planning target volume dose of 4000 cGy/20 fractions/28 days, respectively. On January 30, during the same period, nedaplatin 100 mg chemotherapy was administered. Genetic testing results indicated EGFR19 mutation, with an abundance of 62%. Starting from February 16, regular targeted therapy with 80 mg of osimertinib was administered once a day.

On February 21, 2023, the patient complained of difficulty breathing. Her lung CT showed that the mass in the upper lobe of the left lung was reduced compared to before, and there were pleural effusions on the right side. There were also arterial embolisms in the lateral segment of the lower lobe of the right lung. Blood tests including white blood cells, C-reactive protein, procalcitonin, aspergillus, and tests for detection of galactomannan (GM) showed no abnormalities. Anticoagulation and hormone symptomatic treatment were given. On March 8, the chest CT showed a decrease in bilateral lung patchy shadows compared to before, and the lesion in the lower lobe of the right lung was slightly reduced compared to before. The patient continued taking targeted treatment with osimertinib afterwards. On May 28, her chest CT showed multiple consolidations, nodules, and new patchy high-density shadows in the upper lobe of the left lung. Broncho-alveolar lavage fluid showed no gram-positive bacteria, gram negative bacteria, fungi, or acid-fast bacilli. Blood routine, C-reactive protein, and procalcitonin were normal. Respiratory syncytial virus, mycoplasma pneumoniae, cytomegalovirus, adenovirus infections, influenza A and B virus, parainfluenza virus, and aspergillus were all negative, as well as tests for detection of GM. The patient discontinued treatment with osimertinib and received symptomatic treatment with steroids and anticoagulants. On July 27, 2023, her chest CT showed a reduced range of patchy shadows in the upper lobe of the left lung near the hilum, and absorption and disappearance of patchy shadows in both lungs compared to before. The inflammation was significantly improved, but the tumor progressed. On July 27, the patient started taking 80 mg per day of furmonertinib combined with prednisone (20 mg/day, reducing by 5 mg per week after discharge until discontinuation) for retreatment. On September 9, her lung CT showed no inflammatory change in the lungs, and the tumor significantly shrank. Regular follow-up examinations were conducted to ensure stable conditions of lung tumors and brain metastases. The last follow-up was on July 14, 2024 (Figure 2). The treatment regimen is shown in Figure 3.

Figure 2 Changes in lung lesions before and after medication. A: Changes during the treatment of lung adenocarcinoma (arrow indicates the mass in the left upper lobe); B: Changes during the treatment of lung adenocarcinoma and mediastinal lymph node metastasis (arrow indicates enlarged lymph nodes); C: Inflammation in lung tissues (arrows). D: Pulmonary vasculature changes before and after medication, regular use of anticoagulant drugs and thrombosis disappearance (arrow indicates pulmonary vasculature).

Figure 3 Treatment regimen. qd: Per day.

OUTCOME AND FOLLOW-UP

The patient received targeted treatment with 80 mg osimertinib per day after radiotherapy and chemotherapy. Due to intolerable side effects of osimertinib, the treatment was discontinued and the patient was retreated with 80 mg per day of furmonertinib combined with prednisone (20 mg/day, reducing by 5 mg per week after discharge for one week until discontinuation). After furmonertinib administration, no ILD occurred and the tumor significantly shrank. The patient’s condition has been stable currently and has had no disease progression for 14 months since.

DISCUSSION

ILD is a group of diffuse lung diseases that involve extensive changes in the lung interstitium, alveolar cavity, or bronchioles, resulting in the loss of lung functional units. Its clinical manifestations mainly include active dyspnea, restrictive ventilation dysfunction, decreased diffusion function, and hypoxemia[3]. Although ILD caused by osimertinib is rare, it is often fatal. The mechanism of osimertinib-induced ILD is not yet clear. EGFR is widely distributed in various tissues and plays an important physiological role in maintaining airway epithelium and its renewal. Meanwhile, it is also expressed in type II lung epithelial cells and participates in the reconstruction and repair of alveolar walls[2]. Osimertinib is a third-generation EGFR-TKI that can inhibit EGFR expression in tumor tissues, interfere with epithelial cell growth and migration, and alter cytokine expression, leading to recruitment of inflammatory cells and tissue damage. It can also block EGFR phosphorylation, thereby preventing the regeneration and proliferation of damaged epithelial cells, exacerbating immune inflammatory reactions, which may be one of the main reasons for osimertinib-induced ILD[4].

The clinical manifestations of ILD include cough, acute/subacute dyspnea, fever, chest pain, fatigue, etc[3]. The risk factors for ILD after using EGFR-TKIs mainly include: (1) Basic characteristics: Male, age ≥ 55 years, smoking, performance status score ≥ 2; (2) Cardiovascular and pulmonary function: Previous pulmonary fibrosis or chronic obstructive pulmonary disease, concomitant heart disease, normal lung area ≤ 50%, previous ILD; (3) Previous chemotherapy regimen: Having a history of radiotherapy and chemotherapy within one year, receiving EGFR-TKIs treatment in combination with immune checkpoint inhibitors; and (4) Race: The incidence rate of ILD in Japanese patients after using EGFR-TKIs is higher[4-6]. At present, there is no international consensus on the risks and therapy of osimertinib-induced ILD. The ILD related to EGFR-TKIs can be divided into 4 levels. The consensus of Chinese EGFR-TKIs adverse reaction management experts suggests that for pulmonary toxicity levels 2-4, EGFR-TKIs should be discontinued and oxygen therapy and hormone therapy should be started[7]. However, there is no consensus on whether EGFR-TKIs can be challenged again and the timing. The American Society of Clinical Oncology guidelines for managing adverse reactions related to immunotherapy state that lifelong discontinuation of immune checkpoint inhibitors is recommended for grade 3-4 immune related pulmonary toxicity, while grade 2 immune related pulmonary toxicity can be treated with immune checkpoint inhibitors again after being downgraded to grade 1 immune related pulmonary toxicity by hormone therapy in 2021. According to the United States Food and Drug Administration regulations, once ILD is confirmed to be caused by EGFR-TKIs such as osimertinib or afatinib, the EGFR-TKIs must be permanently discontinued.

In this report, the patient underwent radiotherapy and chemotherapy treatment from January to February 2023. After genetic testing for EGFR19 mutation, targeted treatment with osimertinib was started on February 16. After taking osimertinib for 6 days, the patient complained of respiratory distress. CT scan of the lung showed right-sided pleural effusion and right lung hypoplasia, as well as arterial embolisms in the lateral segment of the lower lobe of the right lung. After 16 days of hormone and anticoagulant therapy, the inflammation improved upon follow-up. There are reports[8,9] on the re-challenge of osimertinib. For grade 1-2 osimertinib related ILD, re-challenge of osimertinib is relatively safe after clinical symptoms improve. For grade 3-4 patients, the risk of re-challenge is higher. However, there are also successful cases of re-challenge. On March 8, our patient underwent a follow-up chest CT, which showed a reduction in both lung patchy shadows, and a slight reduction in the lesion in the lower lobe of the right lung compared to before. The patient continued to take targeted treatment with osimertinib. About 3 months later, the patient developed lung lesions again, with multiple consolidations, nodules, and newly observed patchy high-density shadows in the upper lobe of the left lung. Osimertinib was discontinued. The risk factors for EGFR-TKIs related ILD in this case include age ≥ 55 years and a recent history of radiotherapy and chemotherapy (6 months ago). In addition, the infection indicators of the patient did not increase, and the broncho-alveolar lavage fluid showed no gram-positive bacteria, gram-negative bacteria, fungi, or acid-fast bacilli. Blood routine, C-reactive protein, and procalcitonin were normal. Respiratory syncytial virus, mycoplasma pneumoniae, cytomegalovirus, adenovirus infections, influenza A and B virus, parainfluenza virus, aspergillus and tests for detection of GM were all negative, ruling out the possibility of lung bacterial, fungal, or viral infections, and immune related diseases. Based on expert evaluation criteria for adverse drug reactions, combined with the instructions for osimertinib and the clinical manifestations, imaging and laboratory test results of the patient before and after using osimertinib, it is suggested that there is a significant causality relationship between ILD and the use of osimertinib. The patient’s ILD-related symptoms improved significantly after glucocorticoid treatment, with clear absorption of ground glass opacities in both lungs. Consequently, the patient was considered to have ILD caused by osimertinib. The patient had diffuse changes in both lungs and presented with symptoms of pneumonia, but it had not affected the daily activities of self-care. According to Common Terminology Criteria for Adverse Events version 5.0, the patient was classified as grade 2 ILD[10].

The incidence of ILD caused by osimertinib is higher than that by the first-generation EGFR-TKIs, and there is a greater risk of ILD after reusing EGFR-TKIs. To reduce the incidence of ILD after reusing EGFR-TKIs, measures can be taken such as switching to other EGFR-TKIs, using EGFR-TKIs in combination with glucocorticoids, or adjusting the dosage of EGFR-TKIs[8,11]. Compared with the first/second-generation EGFR-TKIs, the use of third-generation EGFR-TKIs represented by osimertinib and furmonertinib has greater benefits in prolonging progression-free survival and overall survival of patients[12]. Furmonertinib, also known as a third-generation EGFR-TKI, has been approved for the treatment of adult patients with locally advanced or metastatic NSCLC who have previously received EGFR targeted drug therapy or experienced disease progression after treatment, and have been confirmed to have EGFR T790M mutation with gene testing, as well as for first-line treatment of adult patients with locally advanced or metastatic NSCLC who have EGFR exon 19 deletion or exon 21 substitution mutation[13]. At the same time, clinical practice has shown that adverse reactions of furmonertinib include digestive system reactions, anemia, fatigue, abdominal pain, and skin reactions, and there are no reports of ILD at a dose of 80 mg/day[14]. Therefore, compared to other EGFR-TKIs, furmonertinib, as a small molecule targeted drug for subsequent treatment, is more effective and safer. In the subsequent treatment, the present patient recovered rapidly with glucocorticoid therapy, but she experienced ILD again after reusing osimertinib. Osimertinib was discontinued, but the tumor progressed. Meanwhile, her symptoms were not completely improved. Therefore, in order to reduce the risk of ILD recurrence after repeated use of EGFR-TKIs, after weighing the risks and benefits of the patient in the absence of other effective treatment options, and obtaining informed consent from the patient and her family, we treated the patient with a combination of furmonertinib (80 mg per day) and oral prednisone. Due to the recurrent symptoms of ILD, the initial dose of prednisone was 20 mg/day, reduced by 5 mg per week after discharge for one week until discontinuation. The patient has been without disease progression for 14 months. In summary, our case suggests that in some cases, following the recovery of grade 1-2 ILD induced by osimertinib, it may be feasible and beneficial to rechallenge with furmonertinib (in combination with glucocorticoid). However, in the event of ILD, it is necessary to carefully weigh the risks and benefits of choosing the same or similar drugs to rechallenge. If necessary, multidisciplinary consultations can be sought to intervene. We hope this case can provide references for clinical decision-making for some lung cancer patients.

CONCLUSION

We report a lung adenocarcinoma patient who developed ILD after receiving treatment with osimertinib. After active symptomatic and hormone treatment, the lung injury was relieved. The patient was retreated with furmonertinib combined with prednisone and did not experience ILD again. Currently, there has been no disease progression for 14 months. It is suggested that retreatment with furmonertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant lung adenocarcinoma.