A case of organizing pneumonia in rearranged during transfection fusion‐positive lung adenocarcinoma treated with selpercatinib

Abstract

Selpercatinib is the first targeted therapy for rearranged during transfection (RET) fusion‐positive unresectable non‐small‐cell lung cancer (NSCLC). The main adverse effects of selpercatinib include hypertension, liver dysfunction, diarrhea, and QT prolongation on electrocardiograms. However, instances of drug‐induced interstitial lung disease (DI‐ILD) are infrequently reported. We describe the first case of a patient with RET fusion‐positive NSCLC treated with selpercatinib who developed DI‐ILD, confirmed pathologically. The patient, a 72‐year‐old woman, initiated selpercatinib treatment following the postoperative recurrence of lung adenocarcinoma. After 15 months of treatment, computed tomography scans revealed multiple infiltrates and ground‐glass opacities in both lungs. A thoracoscopic lung biopsy identified organizing pneumonia, attributed to DI‐ILD caused by selpercatinib. Although she was asymptomatic, the patient's selpercatinib treatment was discontinued, leading to a gradual improvement in the lung infiltrates. Despite the lack of detailed reports, DI‐ILD with selpercatinib represents a potentially serious adverse event and should be approached with caution.

Cases of drug‐induced interstitial lung disease (DI‐ILD) caused by selpercatinib are rarely reported. We present the first case of DI‐ILD in a patient with rearranged during transfection fusion‐positive lung adenocarcinoma treated with selpercatinib, diagnosed as organizing pneumonia based on pathologic findings.

INTRODUCTION

Rearranged during transfection (RET) fusions are oncogenic drivers found in 1%–2% of non‐small‐cell lung cancer (NSCLC). ¹ Patients with RET fusion‐positive NSCLC are characterized by younger age and non‐smoking status, and often have adenocarcinoma histology. ¹ RET fusions promote carcinogenesis by activating several downstream signaling pathways including RAS/MAPK/ERK, PI3K/AKT, and JAK/STAT. ²

Drilon et al. reported the efficacy of selpercatinib for RET fusion‐positive NSCLC, consequently being recommended as the first‐line of treatment. ³

Various adverse events have been reported with selpercatinib, but drug‐induced interstitial lung disease (DI‐ILD) is extremely rare, and thus accurate incidence rates, clinical findings, as well as imaging pattern and pathological features are largely unknown.

We report the first case of a patient with RET fusion‐positive NSCLC treated with selpercatinib who developed DI‐ILD, confirmed by pathological evidence.

Ethical approval for this case report was granted by the Research Ethics Committee of the Faculty of Medicine, University of Yamanashi (approval no. 2024‐2).

CASE REPORT

A 75‐year‐old female, a never‐smoker with a history of radiotherapy (60 Gy/30 Fr) and mastectomy for left breast cancer at the age of 72, diabetes mellitus, hypertension, and cerebral infarction, was referred to our hospital due to an enlarging pulmonary nodule in the right lower lobe. No evidence of radiation pneumonitis or other interstitial shadows was observed. Her medications included sitagliptin, amlodipine, cilostazol, and folic acid. In December 2016, she underwent a thoracoscopic lower lobectomy of the right lung and was diagnosed with adenocarcinoma (pT1bN0M0‐StageIA2). However, a recurrence involving the mediastinal lymph nodes was detected in December 2017. She received four cycles of carboplatin plus pemetrexed for the recurrence. Maintenance therapy with pemetrexed was initiated but discontinued in April 2019 due to side effects, including dizziness and hypertension.

After an untreated follow‐up period, in November 2021 an increase in carcinoembryonic antigen levels was noted and a computed tomography (CT) scan revealed enlarged mediastinal and supraclavicular lymph nodes, raising suspicions of recurrence. Subsequently, an endobronchial ultrasound‐guided transbronchial needle aspiration of the right lower paratracheal lymph node was performed, confirming the recurrence. Molecular analysis using Oncomine Dx Target Multi CDx revealed that the tumor was positive for the RET fusion gene (KIF5B‐RET).

She was initially treated with selpercatinib at a dosage of 160 mg twice a day. Two months later, selpercatinib was discontinued due to grade 3 liver dysfunction. After recovering to grade 1, it was resumed at half the dosage. The overall therapeutic response was classified as a partial response.

Fifteen months after selpercatinib resumption, a CT scan revealed multiple infiltrates and ground‐glass opacities in both lungs (Figure 1). Despite these findings, she remained asymptomatic with no signs of respiratory dysfunction. Blood tests showed a mild elevation in lactate dehydrogenase and diallylated carbohydrate antigen KL‐6 levels, measuring 253 U/L and 520 U/mL, respectively, but no increase in C‐reactive protein levels was observed. Differential diagnoses considered included recurrence of lung or breast cancer or a DI‐ILD. A thoracoscopic lung biopsy was performed to confirm the diagnosis. Histological findings were indicative of organizing pneumonia (OP), characterized by focal lymphocytic infiltration, alveolar wall thickening, and Masson's bodies (Figure 2). She was diagnosed with grade 1 DI‐ILD attributed to selpercatinib, leading to its discontinuation. Following the discontinuation of selpercatinib, there was a gradual improvement in the lung shadows. She has since remained untreated and relapse‐free.

FIGURE 1.

Chest computed tomography images. Enlarged mediastinal lymph nodes were observed before selpercatinib administration (a, b). The mediastinal lymph nodes shrunk 2 months after treatment with selpercatinib (c, d). Multiple infiltrates and ground‐glass opacities in both lungs appeared, while the mediastinal lymph nodes remained stable at 15 months after initiating selpercatinib treatment (e, f). Gradual improvement of the lung shadows was observed 2 months after discontinuation of selpercatinib (g, h).

FIGURE 2.

Histological findings from lung biopsy samples. Lymphocytic infiltration, alveolar wall thickening, and Masson's bodies (indicated by arrow) are visible in the hematoxylin and eosin (HE) staining (a) and Alcian blue staining (b).

DISCUSSION

We described the first case of DI‐ILD caused by selpercatinib, definitively diagnosed as OP based on CT and pathological findings. Possible causes of OP include post‐infectious factors, medications other than selpercatinib, radiation therapy, and collagen diseases, but all were ruled out. Notably, there are reports of OP occurring in areas not corresponding to the radiation field following radiotherapy for breast cancer, although these cases typically develop within 12 months. ⁴ In this case, 3 years have passed since the radiotherapy, making this cause unlikely. In general, DI‐ILD is a serious adverse event frequently associated with molecularly targeted drugs. However, incidents of DI‐ILD with selpercatinib are extremely rare, with no reported cases published thus far, and the details remain unclear. According to the Japanese Pharmaceuticals and Medical Devices Agency review report (https://www.pmda.go.jp/drugs/2022/P20220309002/530471000_30300AMX00448_A100_1.pdf), the incidence of ILD was five cases of 322 (1.6%), with no cases of grade 3 severity or higher based on the results of the phase I/II trial LOXO‐RET‐17001 (LIBRETTO‐001). The same report also mentions other clinical trials (J2G‐GH‐JZJK, J2G‐OX‐Y001) and post‐marketing surveillance, documenting five cases of severe ILD of grade 3 or higher. One case involved grade 5 ILD on day 463. The remaining four cases recovered either by pausing or discontinuing the medication. The onset occurred at 176, 89, 16, and 10 days, respectively, but no further details are provided. Furthermore, according to updated reports from LIBRETTO‐001, the incidence of pneumonia was 4%, and one case resulted in death due to acute respiratory failure. ⁵ However, it remains unclear whether these cases include ILD caused by selpercatinib without further details.

Meanwhile, for pralsetinib, which is approved by the US Food and Drug Administration for NSCLC, thyroid cancer, and medullary thyroid carcinoma with RET fusion genes, similar to selpercatinib, the frequency of ILD was 34 of 281 patients (12%). Although most cases were grade 1 and 2, six cases (2%) were observed to be grade 3 or higher. Of these 34 patients, 22 received treatment with corticosteroids, as reported. ⁶ The clear difference in the incidence of ILD between these two drugs, both targeting the same RET fusion gene, suggests that neither RET nor its downstream signaling pathways are directly involved in the development of ILD. Whether the difference in the occurrence of ILD is due to structural differences between the drugs or differences in off‐target effects remains unknown. However, understanding these factors could lead to the development of drugs that avoid ILD in the future.

While selpercatinib is considered one of the few molecularly targeted drugs that infrequently cause ILD, ⁷ rare fatal cases exist, necessitating caution. The case we experienced was mild, but given the lack of previous reports with clinical, radiographic, and pathological evaluations, it is considered a valuable case. The accumulation of further cases is important moving forward.

AUTHOR CONTRIBUTIONS

Hiroki Ohkoshi and Masafumi Saiki drafted the manuscript. Masafumi Saiki were in charge of this patient. Shinnosuke Ikemura and Kenzo Soejima helped to draft the manuscript. All authors read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

Dr. Soejima has potential financial conflicts as honoraria from AstraZeneca, Chugai‐Pharmaceutical, Ono Pharmaceutical, Bristol‐Myers Squibb Japan, MSD Oncology, Eli Lilly Japan, Taiho Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Pfizer, Asahi Kasei Pharma, Kyowa Kirin, Sanofi K.K., Nippon Boehringer Ingelheim, and Novartis Pharma and research funding from AstraZeneca. The remaining authors declare no conflict of interest.

Ohkoshi H, Saiki M, Takahashi N, Homma K, Furuya S, Shimamura S, et al. A case of organizing pneumonia in rearranged during transfection fusion‐positive lung adenocarcinoma treated with selpercatinib. Thorac Cancer. 2024;15(25):1863–1866. 10.1111/1759-7714.15412

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.