Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) by osimertinib and continued treatment with dose reduction for postoperative recurrence of lung adenocarcinoma: a case report
Machiko Nishii, Masanori Shimomura
, Satoru Okada, Tatsuo Furuya, Taiyo Kawamura, Takumi Nakagawa, Rintaro Kawanishi, Masayoshi Inoue
Contributions: (I) Conception and design: M Nishii; (II) Administrative support: M Shimomura, S Okada, M Inoue; (III) Provision of study materials or patients: M Shimomura; (IV) Collection and assembly of data: M Nishii; (V) Data analysis and interpretation: M Nishii; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Background: Osimertinib is the standard third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) of choice for EGFR mutation-positive non-small cell lung cancer. Its major adverse effects include diarrhea and skin symptoms, although syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported as a rare event. In previous reports, patients were switched to another drug after the onset of SIADH. We report the first case of osimertinib-induced SIADH in a patient with lung adenocarcinoma with an EGFR T790M mutation, with, therefore, no effective therapeutic alternative, where the patient was able to resume treatment at a reduced dose without recurrence of SIADH.
Case Description: An 80-year-old man with a history of hypertension, diabetes mellitus, and partial right nephrectomy for right renal cell carcinoma, but with preserved renal function, underwent thoracoscopic left upper lobectomy in 2013 for lung adenocarcinoma with the EGFR mutation of exon 19 deletion. He was administered gefitinib for multiple postoperative recurrent lung metastases in 2017. However, since a right lower lobe nodule continued to grow and a biopsy confirmed the presence of the resistant mutation of Exon 20 T790M, we administered 80 mg/day osimertinib in 2022, with subsequent shrinkage of the metastases. Seven months later, the patient developed hyponatremia. Evaluation confirmed SIADH diagnosis, and without lung cancer progression, osimertinib-induced SIADH was suspected. Hence, we discontinued osimertinib and initiated saline infusion, oral sodium chloride, and water restriction, which led to normalization of serum sodium levels by day 14. One month later, osimertinib 80 mg/day was resumed; however, two months later, hyponatremia recurred, necessitating discontinuation of osimertinib and initiation of water restriction and oral sodium chloride therapy. Five days later, serum sodium normalized. Based on his clinical course, the cause of SIADH was attributed to osimertinib. Osimertinib was then restarted at 40 mg/day, without recurrence of SIADH. At 18 months after dose reduction, there has been no growth of the pulmonary metastases.
Conclusions: This case suggests that osimertinib treatment can be continued with dose reduction in lung adenocarcinoma patients who develop SIADH, especially when alternative treatment options are limited.
Keywords: Osimertinib; syndrome of inappropriate secretion of antidiuretic hormone (SIADH); adverse effect; lung cancer; case report
Submitted Mar 10, 2025. Accepted for publication Jul 03, 2025. Published online Sep 19, 2025.
doi: 10.21037/tlcr-2025-278
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Key findings
• This is the first report of a patient with EGFR T790M mutation-positive lung cancer who developed osimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and was able to continue osimertinib treatment with dose reduction.
What is known and what is new?
• SIADH has been reported in two previous cases as a rare adverse effect of osimertinib. In both cases, osimertinib was switched to other anti-lung cancer drugs after the onset of SIADH.
• Dose reduction of osimertinib allowed our patient’s cancer treatment to continue without recurrence of SIADH.
What is the implication, and what should change now?
• Osimertinib can be continued after the onset of SIADH with dose reduction and careful monitoring for good lung cancer control, especially when the availability of alternative treatments is limited.
Introduction
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is currently the first-line treatment for EGFR mutation-positive non-small cell lung cancer (NSCLC), including with the T790M mutation. Postoperative adjuvant osimertinib for completely resected EGFR-mutated NSCLC has been reported to improve the prognosis (1,2). Hence, it is likely that osimertinib will become even more important for the treatment of lung cancer in the future. The major adverse effects of osimertinib include diarrhea (58%) and skin symptoms (dry skin in 32% and acne-like rash in 25%) (3), although two rare cases of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have also been reported (4,5). Both those patients were treated with osimertinib as the first-line therapy for EGFR exon 19 deletion-positive NSCLC, with the drug being stopped after the onset of SIADH, followed by subsequent treatment with alternative drugs for lung cancer. This is the first reported case in which a patient who developed SIADH after receiving osimertinib continued osimertinib treatment with dose reduction, since no alternative agent with comparable efficacy was available due to the presence of the EGFR T790M mutation, and there was no recurrence of SIADH. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-278/rc).
Case presentation
An 80-year-old man with a history of hypertension, diabetes mellitus, and partial right nephrectomy for right renal cell carcinoma, but with preserved renal function, underwent thoracoscopic left upper lobectomy for left upper lobe lung adenocarcinoma (pT1bN1M0, stage IIA) in 2013, in which an EGFR exon 19 deletion was identified. In 2017, he developed multiple pulmonary metastatic nodules, and a biopsy at that time again revealed the same EGFR exon 19 deletion. Based on this finding, he was started on gefitinib (Figure 1A-1C). Although the nodules shrank in size with this treatment, one right lower lobe nodule gradually grew (Figure 1D-1F), although its fluorodeoxyglucose accumulation was low in positron emission tomography/computed tomography (PET/CT) (Figure 1G). Evaluation of a CT-guided lung biopsy specimen from the nodule identified EGFR T790M mutation, and osimertinib treatment (80 mg/day) was started in 2022.
After starting osimertinib, the right lower lobe nodule decreased in size (Figure 2), although he developed anorexia and fatigue seven months after the start of osimertinib. Examination revealed hyponatremia with a serum sodium concentration of 117 mEq/L. Additional laboratory evaluation indicated a urine osmolality of 253 mOsm/kg, plasma osmolality of 241 mOsm/kg, and urine sodium concentration of 61 mEq/L. Thyroid and corticosteroid hormone levels were normal and arginine vasopressin (AVP) secretion was not suppressed despite hyponatremia. Since the patient met all the diagnostic criteria for SIADH, the cause of the hyponatremia was diagnosed as SIADH (Table 1) (6). At the same time, CT showed that the metastatic lesion in the lower right lung lobe remained in remission, with no evidence of worsening of the lung cancer. CT also showed no abnormalities of note in the abdomen, and cranial magnetic resonance imaging (MRI) showed no brain metastases, hemorrhage or infarction. Hence, we ruled out the possibility of SIADH due to worsening lung cancer and intra-abdominal or intracranial lesions, and made a diagnosis of drug-induced SIADH. We discontinued osimertinib due to the possibility that it was the cause of the hyponatremia. Further, since the patient was also taking indapamide, a thiazide-like diuretic drug for hypertension, which might have contributed to hyponatremia, it was also discontinued and not resumed. Treatment for hyponatremia was initiated with saline infusion, oral sodium chloride administration, and water restriction. On the 14th day of this treatment, his serum sodium concentration improved to the normal range.
Table 1
| Category | Criteria |
|---|---|
| I. Main symptom | Lack of physical findings of dehydration |
| II. Laboratory findings | 1. Serum sodium concentration lower than 135 mEq/L |
| 2. Plasma osmolality lower than 280 mOsm/kg | |
| 3. Plasma arginine vasopressin concentration is not suppressed despite hyponatremia and hypo-osmolar state | |
| 4. Urinary osmolality higher than 100 mOsm/kg | |
| 5. Urinary sodium concentration higher than or equal to 20 mEq/L | |
| 6. Normal renal function | |
| 7. Normal adrenal function | |
| 8. Normal thyroid function |
Definitive diagnosis of SIADH is established when I and all items in II are fulfilled. Adapted from: The Japan Endocrine Society. Guideline 2023 for hypothalamic pituitary dysfunction, congenital renal enuresis and related diseases. Folia Endocrinologica Japonica 2023;99:21-3 (6). SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
One month later, because the patient’s serum sodium concentration remained stable, we resumed osimertinib at the dose of 80 mg/day. Two months later, however, we discontinued it because hyponatremia with a serum sodium concentration of 131 mEq/L was observed. Once again, with water restriction and oral sodium chloride administration, the serum sodium concentration improved to the normal range after five days. Based on the patient’s clinical course, osimertinib was considered the cause of SIADH.
Subsequently, we resumed osimertinib at a reduced dose of 40 mg/day, without recurrence of hyponatremia or growth of lung cancer metastases (Figure 3). Currently, 18 months after the dose reduction, the patient’s serum sodium level is well controlled without oral sodium chloride administration or fluid restriction, and the patient has remained stable without any exacerbation of lung cancer (Figure 4).
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 Declaration of Helsinki and its subsequent amendments. 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
In this case, the patient developed SIADH due to osimertinib, and after restarting the drug at a reduced dose, he was able to continue effective treatment for lung cancer without recurrence of SIADH.
Tumor-associated SIADH is mainly seen in small cell lung cancer, although it has also rarely been reported in NSCLC (7). However, in the present case, since there was no worsening of lung cancer on examination, we ruled out tumor-associated SIADH. While indapamide was also suspected as a cause of hyponatremia, we determined that osimertinib was the cause of SIADH because the hyponatremia recurred when osimertinib was restarted, despite discontinuing indapamide following the initial onset of hyponatremia. Although the residual effects of indapamide and its potential interaction with osimertinib as a cause of hyponatremia in this case cannot be completely ruled out, this was unlikely for two reasons: (I) The elimination half-life of indapamide is 13.2 to 19.8 hours, and the patient had no renal dysfunction that could have delayed excretion of either of the drugs. (II) Recurrence of hyponatremia occurred one month after the discontinuation of indapamide, ruling out a possible role of this drug.
Previously, two cases of SIADH with osimertinib have been reported (4,5). In both cases, osimertinib was used as first-line therapy for NSCLC with EGFR exon 19 deletion, and was changed to a different drug after the occurrence of SIADH. In the present case, the patient had EGFR T790M-mutated lung adenocarcinoma that responded to osimertinib. We considered it desirable to continue treatment with osimertinib as long as possible, because we thought that SIADH, a drug-related adverse event of osimertinib, was controllable by water restriction and oral sodium chloride. On the other hand, considering the possibility that long-term oral sodium chloride and water restriction might be burdensome for the patient and would affect his adherence to medication, we decided to try to reduce the dose of osimertinib. The long-term impact of reducing the dose of osimertinib on lung cancer disease is controversial. Although it has been reported that early dose reduction after the introduction of osimertinib is associated with an increased incidence of brain metastases (8), we judged osimertinib dose reduction as being possible in this case because seven months had elapsed since the introduction of osimertinib. Regarding the efficacy of low dose osimertinib, Poh et al. reported good efficacy and tolerability of low dose osimertinib as second-line treatment in patients with EGFR-mutated advanced NSCLC (9). Meanwhile, a retrospective study on osimertinib as first-line treatment suggested that early dose reduction of osimertinib in response to adverse events might prolong progression-free survival (PFS), in addition to reducing the severity of adverse events (10). In cases such as this one, in which there are no effective alternative therapies due to the presence of the EGFR T790M mutation, it might be especially important to reduce the dose of osimertinib and continue therapy at a reduced dose for as long as possible, before adverse events reach a severity that would require their discontinuation.
The mechanism by which osimertinib causes SIADH is not clear. Additionally, the clinical data obtained from this case are insufficient to reasonably speculate on the exact pathophysiological process involved. There have been several reports of SIADH caused by TKIs, and Liapis et al. reported a case of SIADH in a patient with acute lymphocytic leukemia treated with a high dose of imatinib, which improved with dose reduction (11). Since there has been no recurrence of SIADH in our patient after osimertinib dose reduction, it is possible that the onset of SIADH with osimertinib is also dose-dependent, although further case studies are warranted to confirm our results. This would enable even patients who develop SIADH to continue osimertinib at a reduced dose and under careful monitoring.
This report has several limitations. First, it describes a single case involving an elderly patient with comorbidities, and thus, the findings might not be generalizable to a broader population. Second, the follow-up period after dose reduction of osimertinib was limited, and therefore, its long-term impact on disease progression could not be evaluated.
Conclusions
We experienced a case of osimertinib-induced SIADH. This case suggests that osimertinib treatment can be continued at a reduced dose in patients who develop SIADH, especially when the availability of alternative treatments is limited. Careful monitoring might help maintain treatment efficacy while reducing side effects.
Acknowledgments
The abstract of this report was presented at the 65th Annual Meeting of the Japan Lung Cancer Society.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-278/rc
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-278/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-278/coif). The 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 Declaration of Helsinki and its subsequent amendments. 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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