Neoadjuvant Selpercatinib for Stage IIIA Primary Pulmonary Adenocarcinoma With RET Fusion: A Case Report

ABSTRACT

Selpercatinib represents the first targeted therapeutic agent approved for RET fusion‐positive unresectable non‐small cell lung cancers. This case report describes a patient with stage IIIA (cT2aN2M0) RET fusion‐mutated adenocarcinoma of the left upper lobe. Following 9 months of selpercatinib therapy, the patient achieved clinical downstaging and subsequently underwent curative resection. Postoperative pathologic staging was IIA (ypT1bN1M0). Adjuvant therapy with selpercatinib was continued postoperatively. The patient remained recurrence‐free on continued follow‐up with 17 months since diagnosis and 8 months since surgery.

This case describes a 55‐year‐old female with stage IIIA RET fusion‐positive lung adenocarcinoma and thromboembolic contraindications who achieved significant tumour downstaging after neoadjuvant selpercatinib therapy, enabling successful curative resection. The patient remained recurrence‐free on continued follow‐up with 17 months since diagnosis and 8 months since surgery, demonstrating selpercatinib's potential as neoadjuvant therapy for RET‐positive NSCLC.

1. Introduction

As a gene‐driven disease, lung cancer has three major driver genes, including EGFR, ALK and ROS1 that play a key role in cancer development and precision management [1]. Rearranged during transfection (RET) fusions are drivers in 1%–2% of NSCLC, particularly in young, non‐smoking adenocarcinoma patients. These fusions activate downstream pathways (PI3K/AKT, RAS/MAPK/ERK, JAK/STAT), promoting carcinogenesis [2, 3]. Selpercatinib is a tyrosine kinase inhibitor that could inhibit the abnormal activity of RET protein and block the growth signals of cancer cells, thereby delaying the progression of the tumour. Drilon et al. reported the efficacy of selpercatinib for RET fusion‐positive NSCLC, and in 2020, the FDA approved selpercatinib as a potent RET inhibitor [4]. This report presents a real‐world RET‐positive case benefiting from selpercatinib, achieving cancer downstaging and enabling radical surgery. The patient had given informed consent.

2. Case Report

A 55‐year‐old never‐smoker female with diabetes and hypertension presented with cough and chest pain sought medical attention at local hospital on 20 December 2023. An enhanced CT scan showed occupation of the left upper lung (37 mm × 22 mm) and enlarged mediastinal lymph nodes (Figure 1A). Then the patient was admitted to the Department of Respiratory Medicine at our hospital on 25 December 2023. Transbronchial lung biopsy (TBLB) of the tumour confirmed as lung adenocarcinoma and endobronchial ultrasound‐guided transbronchial needle aspiration of left paratracheal lymph node confirmed the metastases. No other signs of metastasis were detected. However, the laboratory results show that the level of D‐dimer increased significantly so a tomography pulmonary angiography (CTPA) was conducted and revealed multiple pulmonary embolisms in the branches of the right pulmonary artery (Figure 1A). The patient was diagnosed with lung adenocarcinoma (stage IIIA, cT2aN2M0) and pulmonary embolism (low‐risk group). Next‐generation sequencing (NGS) analysis (Geno‐Truth Dx) of patient's tumour tissue revealed RET fusion positivity (KIF5B‐RET) and other mutations were all negative. Following a discussion of multi‐disciplinary team (MDT, including respiratory physicians, oncologists, thoracic surgeons, pathologists, and radiologists), oral selpercatinib 160 mg twice daily (bid) and rivaroxaban 10 mg bid was recommended.

FIGURE 1.

Chest CT scans of the patient during neoadjuvant therapy. (A) Baseline imaging demonstrates a 37 mm × 22 mm abnormal lung mass in the upper lobe of the left lung and multiple pulmonary embolisms in the branches of the right pulmonary artery (red arrows). (B) After 2 months of selpercatinib therapy, the chest CT scan shows mass shrinkage to 15 × 12 mm, achieving a partial response (PR). Multiple pulmonary emboli in the right pulmonary artery have shown marked improvement. (C–E) Chest CT scans after 6 and 9 months of treatment with selpercatinib, the mass neither decreased nor increased, achieving stable disease (SD). PET/CT shows slight elevation of tumour (SUVmax: 1.97) and hilar lymph nodes (SUVmax: 2.95) glucose metabolism.

After 2 months of treatment with selpercatinib, patient's liver function tests showed a Grade 3 increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which was considered related to the drug. Therefore, the patient was admitted to hospital again to receive supporting treatment and radiologic assessments. CTPA (29 February 2024) shows the tumour has significantly shrunk (15 mm × 12 mm) and the multiple pulmonary embolisms improved (Figure 1B). Radiographic assessment was partial response (PR) based on the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). During hospitalisation, we discontinued the use of selpercatinib for 5 days and reduced the dosage to 80 mg bid after discharge. We also stopped rivaroxaban and advised the patient to receive radiologic assessments every 3–4 months. The transaminase elevations resolved to Grade 1 within 2 weeks.

On 21 June 2024, and 13 September 2024, the patient underwent twice chest CT scans, both of which the tumour did not increase or decrease further (Figure 1C,D). Radiographic assessment revealed stable disease (SD). Subsequent positron emission tomography (PET/CT) showed slight elevation of tumour (SUVmax: 1.97) and hilar lymph nodes (SUVmax: 2.95) glucose metabolism, no distant metastasis (Figure 1E). After rediscussing, MDT considered the tumour was down‐staging successfully and advised patient to receive surgery. On September 23, 2024, the patient underwent a thoracoscopic left upper lobectomy with lymph node dissection, without interruption of selpercatinib prior to the surgery. Postoperative pathology reported the left upper lobe adenocarcinoma (acinar + papillary + micropapillary subtypes (20%)), no pleural invasion in elastic fibre staining and negative margins, metastasis identified in the left tracheobronchial lymph nodes (No. 11L: 1/3) and no other lymph nodes metastasis (No. 5: 0/1, No. 7: 1/0, No. 9L: 0/2, No. 10L: 0/3) (Figure 2). Immunohistochemistry analyses of the tumour showed CK7 (+), TTF‐1 (+), CK5/6 (+), P40 (−), P63 (−), ALK (−), Ki‐67 (30%), C‐MET (2+) and Napsin A (+). The final postoperative pathological stage was ypT1bN1M0, stage IIA. MDT recommends continuing adjuvant therapy with selpercatinib. After surgery, four cycles consolidation chemotherapy (pemetrexed 0.8 g + carboplatin 0.4 g) were performed and patients received comprehensive tumour panel and radiologic assessments every 3 to 4 months. At the last follow‐up (13 May 2025), the patient received approximately 17 months of selpercatinib as adjuvant treatment. No evidence of tumour recurrence or metastasis was observed. According to Common Terminology Criteria for Adverse Events version 5.0, no severe AEs were observed in this process, except elevated liver function tests (Grade 3). The process of clinical diagnosis and treatment for this patient is shown in Figure 3.

FIGURE 2.

Histological (100 ×) or cytological pathological evaluation before and after neoadjuvant selpercatinib. LN, lymph node.

FIGURE 3.

A summary of the treatment strategy employed in this patient.

3. Discussion

This case demonstrates successful neoadjuvant selpercatinib therapy in a stage IIIA RET fusion‐positive lung adenocarcinoma patient with pulmonary embolism contraindications. The patient achieved partial response (2 months) and prolonged stable disease (7 months), enabling radical surgery. However, selpercatinib's currently approved indications do not include preoperative neoadjuvant settings. In existing prospective studies of selpercatinib, the phase I/II LIBRETTO‐001 (ORR: 85%, PFS: 22 months) not specifically focused on operable cases [5]. The phase III LIBRETTO‐431 trial limited to metastatic disease. Additionally, Masaya Aoki et al. reported in 2024 on 10 stage IIIA‐IIIB lung cancer patients who received neoadjuvant TKI therapy, with eight subsequently undergoing adjuvant cytotoxic chemotherapy and two experiencing early recurrence without it. This suggests that adjuvant cytotoxic chemotherapy remains necessary after TKI neoadjuvant treatment. In the ADAURA trial, postoperative osimertinib for 3 years significantly prolonged five‐year overall survival (OS) in stage II‐IIIA patients [6]. These findings give reference for application of selpercatinib in perioperative settings.

According to the Phase III, randomised, multicentre NeoADAURA study, whereas early surgery within approximately 3 weeks after neoadjuvant treatment is encouraged, investigators have determined that osimertinib can be administered for up to nine weeks. This is to avoid potential tumour flare resulting from treatment cessation, as previously documented in patients with EGFRm NSCLC who discontinued erlotinib/gefitinib. This timeframe can serve as a reference for selpercatinib neoadjuvant therapy [7]. Regarding preoperative discontinuation timelines, the 3–5 days targeted therapy discontinuation window may serve as a reference. In addition, surgical feasibility was confirmed, with no treatment‐related fibrosis or bleeding complications. Although no guidelines exist for combining non‐vitamin K oral anticoagulants with TKI‐based cancer therapies, a retrospective study found increased bleeding risk with standard‐dose co‐administration—though prognosis was unaffected. However, the authors emphasised that when clinical indications (such as our patient's multiple pulmonary emboli) necessitate anticoagulation, our combinational therapy remains clinically justified [8]. Although this case developed hepatotoxicity during treatment, it was managed successfully with hepatic protectants and dose reduction.

To our knowledge, reports on perioperative selpercatinib for locally advanced RET‐positive patients are rare. This case highlights selpercatinib's potential for downstaging RET‐positive NSCLC. Prospective studies are needed to establish neoadjuvant protocols, optimal timing, and long‐term outcomes.

Author Contributions

Zihan Cui: writing – review and editing, writing – original draft preparation. Yizhuo Hu: writing – review and editing. Jun Zhao: writing – review and editing, conceptualization. Chuanyong Mu: writing – review and editing. Chang Li: writing – review and editing, conceptualization.

Consent

The authors declare that written informed consent was obtained for the publication of this manuscript and accompanying images and attest that the form used to obtain consent from the patient complies with the Journal requirements as outlined in the author guidelines.

Conflicts of Interest

The authors declare no conflicts of interest.

Cui Z., Hu Y., Zhao J., Mu C., and Li C., “Neoadjuvant Selpercatinib for Stage IIIA Primary Pulmonary Adenocarcinoma With RET Fusion: A Case Report,” Respirology Case Reports 13, no. 10 (2025): e70390, 10.1002/rcr2.70390.

Data Availability Statement

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