Pathological complete response in RET-positive non-small cell lung cancer: a case report of pralsetinib-based “sandwich” therapy

Introduction

Lung cancer is one of the most prevalent and deadly malignancies worldwide (1). Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases (2). The treatment of locally advanced NSCLC is complex and controversial. Historically, concurrent chemoradiotherapy was the recommended approach for NSCLC patients (3). However, the identification of molecular driver alterations has revolutionized the management of NSCLC, enabling the development of targeted therapies that significantly improve clinical outcomes. Among these oncogenic driver mutations, RET gene fusions have emerged as a key driver in a subset of NSCLC patients, particularly in younger, non-smoking individuals (4). RET gene fusions [RET-positive (RET⁺)] are recognized as oncogenic drivers in 1–2% of NSCLC cases, and are commonly associated with poorly differentiated histology (5-9). RET fusions, most commonly involving KIF5B (70%) and CCDC6 (20%), lead to the constitutive activation of the RET tyrosine kinase receptor, driving tumorigenesis via aberrant MAPK/ERK and PI3K/AKT signaling (7,10,11).

The advent of selective RET inhibitors, such as pralsetinib, has transformed the treatment landscape for RET⁺ NSCLC. Historically, RET⁺ tumors exhibited a response rate of 30–45% to chemotherapy (12). However, in the phase I/II ARROW trial, pralsetinib had an objective response rate (ORR) of 72% (95% confidence interval: 60–82%) in treatment-naïve patients, who had a median progression-free survival (PFS) of 16.5 months (13). Despite these promising outcomes, current National Comprehensive Cancer Network guidelines primarily endorse RET inhibitors for metastatic disease, but have not defined their perioperative applications (10,11). Pralsetinib has been shown to be effective in many cases; however, optimal treatment regimens, especially those that combine targeted therapy with other modalities such as surgery and radiotherapy, need to be further explored. “Sandwich” therapy, which integrates systemic therapy followed by surgical intervention and subsequent adjuvant therapy, offers a novel approach that may enhance therapeutic outcomes and provide long-term disease control in RET⁺ NSCLC patients.

This report discusses the case of a 34-year-old male patient with RET⁺ NSCLC who underwent pralsetinib-based “sandwich” therapy. The patient achieved a remarkable pathological complete response (pCR) after receiving targeted therapy, followed by surgery and adjuvant treatment. This case is noteworthy because it shows the potential benefits of combining targeted therapy with surgical resection and radiotherapy to achieve an exceptional clinical outcome in RET⁺ NSCLC. It provides valuable insights into the efficacy of personalized treatment strategies and supports further investigation into multi-modality treatment approaches in this patient population. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-969/rc).

Case presentation

Patient characteristics

A 34-year-old male with a 15-year history of smoking (of approximately 10 cigarettes per day) underwent a chest computed tomography (CT) scan on December 5, 2022, at Haizhu District Hospital of Integrated Traditional Chinese and Western Medicine due to persistent right-sided chest pain lasting for over 1 month. The scan revealed a space-occupying lesion in the medial segment of the right middle lobe, measuring approximately 2.3 cm × 3.2 cm × 4.2 cm. Following this finding, the patient presented to The First Affiliated Hospital of Guangzhou Medical University on December 7, 2022 for further evaluation and management.

The patient had no significant past medical history and denied any known allergies, previous surgeries, or blood transfusions. His Eastern Cooperative Oncology Group performance status score at presentation was 1.

A contrast-enhanced chest CT performed at The First Affiliated Hospital of Guangzhou Medical University revealed a lobulated soft-tissue mass in the right middle lobe (measuring 34 mm × 24 mm × 44 mm) with relatively well-defined borders and mild-to-moderate enhancement, partially extending toward the right cardiophrenic angle. Enlarged mediastinal and left supraclavicular lymph nodes were also observed, of which the largest measured approximately 11 mm and showed peripheral ring enhancement anterior to the superior vena cava (Figure 1A,1B).

Figure 1 Baseline imaging and pathological assessment at diagnosis. (A) Axial lung window image from contrast-enhanced chest CT showing a lobulated soft-tissue mass in the medial segment of the right middle lobe (solid red circle), with relatively well-defined margins and partial extension toward the right cardiophrenic angle. (B) Corresponding mediastinal window image showing mild-to-moderate contrast enhancement of the lesion (solid red circle). (C) Ultrasound image of the left supraclavicular region prior to core needle biopsy, showing an enlarged lymph node under real-time guidance. (D,E) Histopathological examination of the biopsied lymph node revealed poorly differentiated carcinoma. Hematoxylin-eosin staining; (D) magnification ×20; (E) magnification ×40. CT, computed tomography.

Staging investigations, including contrast-enhanced magnetic resonance imaging (MRI) of the brain and color Doppler ultrasonography of the abdomen, adrenal glands, and urinary system, showed no evidence of distant metastasis.

An ultrasound-guided core needle biopsy of the left supraclavicular lymph node revealed poorly differentiated carcinoma (Figure 1C). Immunohistochemical analysis demonstrated diffuse positivity for cytokeratin (CK)7, thyroid transcription factor-1, and Napsin A, and negativity for CK20 and caudal-type homeobox 2, consistent with metastatic pulmonary adenocarcinoma (Figure 1D,1E).

On December 12, 2022, a multi-gene panel for lung cancer using ARMS-PCR identified a RET exon 12 fusion. According to the 8^th edition of the tumor-node-metastasis classification published by the International Association for the Study of Lung Cancer (IASLC), the clinical stage was T2N3M0 (stage IIIB).

Treatment plan

After surgical consultation, the patient was deemed inoperable and refused chemotherapy. With informed consent and based on genetic testing results, oral RET inhibitor pralsetinib [400 mg once daily (QD)] was initiated on December 16, 2022. One month into treatment, the patient contracted coronavirus disease 2019. Although he continued taking pralsetinib for the first 2 days post-diagnosis, he discontinued it due to discomfort as recommended by his physician. The medication was paused for 5 days and then resumed at 200 mg QD, and the dosage was later increased to 400 mg QD; however, the patient reported headaches and lower abdominal pain. Consequently, the dosage was adjusted to 300 mg QD based on adverse reactions and tolerability.

Follow-up and response to treatment

A chest CT scan 3 months after initiating treatment indicated significant shrinkage of the lesion in the middle segment of the right lung to approximately 8 mm × 5 mm. The enlarged lymph nodes in the mediastinum and left supraclavicular fossa were also reduced, with the largest measuring less than 10 mm in short diameter. The therapeutic effect was assessed as a partial response (PR). Adverse reactions during treatment included dizziness, occasional muscle soreness in the back, weakness in both lower limbs, tongue numbness, dry skin and mouth, and constipation, which were alleviated through traditional Chinese medicine treatment.

Surgical intervention

Given the next steps in treatment, a surgical consultation was conducted. Positron emission tomography/CT results on March 20, 2025 indicated significant reduction in lesion volume compared to previous scans, and mildly increased metabolism. Most tumor activity appeared to be inhibited, although some residual activity was noted in multiple lymph node metastases in the original mediastinum and bilateral supraclavicular regions, with no abnormal lymph nodes or increased metabolism detected.

After the surgical evaluation confirmed indications for surgery, the patient underwent chest video-assisted thoracoscopic surgery (VATS) for right middle lung sub-lobectomy on April 13, 2023. Intraoperatively, a hard gray-black nodule approximately 1 cm in size was identified in the medial segment of the right middle lung lobe, with a concave surface pleura. No significantly enlarged lymph nodes were observed in the hilum or mediastinum, but membranous adhesions were noted on the pleura, particularly on the posterior chest wall, without pleural effusion. Extensive sampling of the lung tissue showed local fibrous tissue proliferation in the tumor bed, scattered lymphocytic infiltration, and numerous foam cells with multi-nucleated giant cell reaction and cholesterol crystal deposition. Pathological assessment according to the 2020 IASLC criteria indicated 0% viable cancer cells, 100% stroma, and no metastatic cancer in the lymph nodes (Figure 2A,2B).

Figure 2 Postoperative histopathology revealed fibrotic tissue, chronic inflammation, foamy macrophages, giant cell reaction, and cholesterol clefts, with no residual tumor. Hematoxylin-eosin staining; (A) magnification ×20; (B) magnification ×40.

Postoperative management

Two weeks post-surgery, minimal residual disease detection of plasma circulating tumor DNA was negative. The patient continued treatment with pralsetinib (200 mg QD) as targeted adjuvant therapy; the dosage was later adjusted to 300 mg QD.

Radiotherapy and current status

Three months post-surgery, based on patient preference, a radiologist was consulted to evaluate whether the patient should undergo consolidative therapy. Bilateral supraclavicular lymph node drainage area radiotherapy commenced on August 15, 2023. However, by the ninth session at the end of August, the patient experienced a severe sore throat, with pain exacerbated by swallowing, leading to a diagnosis of severe acute esophagitis and the subsequent discontinuation of radiotherapy. After 1 week of corticosteroid therapy, the patient recovered.

As of April 16, 2025, the patient was receiving pralsetinib (300 mg QD) and had maintained a favorable functional status. Surveillance imaging, including chest CT, abdominal and brain MRI, and neck ultrasonography, showed no evidence of disease recurrence. The complete treatment timeline is illustrated in Figure 3. The study was approved by the Institutional Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (approval No. ES-2025-K222-01). Written informed consent was obtained from the patient for 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 3 Treatment timeline. +, positive. COVID-19, coronavirus disease 2019; CT, computed tomography; LN, lymph node; pCR, pathological complete response; PET, positron emission tomography; PR, partial response; QD, once daily; VATS, video-assisted thoracoscopic surgery.

Discussion

This case report shows the effectiveness of a pralsetinib-based “sandwich” therapy, which combined targeted therapy, surgery, and radiotherapy, in a RET⁺ NSCLC patient. The patient achieved a remarkable pCR as defined by the IASLC criteria (14), underscoring the potential of multi-modality treatment in this setting. While RET inhibitors like pralsetinib have revolutionized the treatment of RET⁺ NSCLC, evidence on how best to integrate these agents with surgical and radiotherapeutic interventions, particularly in younger patients with more aggressive disease, is limited. This case addresses this gap by providing evidence that combining pralsetinib with surgical resection and adjuvant therapy can lead to exceptional clinical outcomes, particularly in terms of tumor reduction and long-term disease control. Additionally, the “sandwich” therapy approach offers a promising strategy for optimizing treatment sequencing in RET⁺ patients, contributing to the growing body of literature on personalized therapy for NSCLC. Although a pCR was achieved, adjuvant pralsetinib and elective radiotherapy were administered to consolidate systemic and locoregional control, given the patient’s baseline N3 supraclavicular lymph node involvement and the limited evidence regarding the long-term durability of remission with RET inhibitors alone. The decision was guided by the high initial disease burden and the theoretical risk of micrometastatic persistence. Adjuvant radiotherapy was delivered to the supraclavicular drainage area in accordance with the principle of involved-field radiotherapy (IFRT) for stage III NSCLC, aiming to enhance regional control since the affected nodes were not surgically dissected. However, radiotherapy was discontinued early due to grade 3 acute esophagitis. Although the patient has remained disease-free during follow-up, the incomplete course limits the ability to determine the true contribution of radiotherapy to long-term remission. This experience underscores the need to carefully balance therapeutic benefit and toxicity when considering adjuvant interventions after pCR, and further investigation is warranted to define the optimal role and timing of radiotherapy within multimodal “sandwich” regimens.

In this case, the major tumor and nodal regression occurred following neoadjuvant pralsetinib, suggesting that targeted therapy was the primary driver of disease response. Surgery subsequently provided pathological confirmation of complete remission and ensured removal of any potential residual lesions, while adjuvant therapy served to consolidate systemic and locoregional control. Although the relative contribution of each component cannot be precisely determined, their sequential integration likely contributed synergistically to the durable remission observed. A similar finding was reported in a 2022 case of stage IIIA KIF5B-RET fusion-positive lung adenocarcinoma, in which neoadjuvant pralsetinib led to radiologic downstaging, a 74% pathological response in the primary tumor, and no residual viable tumor cells in lymph nodes (15). This further supports the critical role of targeted therapy in achieving disease control prior to surgery and reinforces the rationale for integrating RET inhibitors within multimodal treatment strategies.

Pralsetinib is a highly selective RET kinase inhibitor that has demonstrated substantial antitumor activity in RET fusion-positive NSCLC (16,17). In the phase I dose-escalation stage of the ARROW trial, pralsetinib was evaluated across doses ranging from 30 to 600 mg QD, and 400 mg QD was subsequently selected as the recommended phase II dose based on efficacy and tolerability (18). In this case, the patient experienced temporary treatment interruptions and dose reductions due to infection and adverse effects, yet still achieved a pCR. This observation suggests that effective RET inhibition may be maintained even with short-term dose modification. It also raises the question of whether interindividual differences in pharmacokinetics or drug sensitivity may warrant tailored dosing strategies. Further clinical studies are needed to clarify optimal dosing approaches across diverse patient populations and treatment contexts.

The patient declined standard concurrent chemoradiotherapy, which remains the recommended treatment for stage IIIB NSCLC. Therefore, pralsetinib-based targeted therapy was initiated as an alternative approach based on molecular findings and clinical judgment. Currently, pralsetinib and selpercatinib are both recommended as first-line treatments for patients with stage IV RET fusion-positive NSCLC. The favorable outcome in this case suggests that earlier use of such targeted therapies in locally advanced disease may have the potential to improve survival and surgical conversion rates, a hypothesis that warrants further validation in prospective studies.

RET⁺ NSCLC has gained significant attention due to its aggressive nature, particularly in younger patients. Although RET inhibitors such as pralsetinib and selpercatinib have shown promising efficacy in clinical trials (19,20), challenges remain in optimizing their use in clinical practice. Existing studies have shown that RET inhibitors can significantly improve PFS and the ORR of RET⁺ NSCLC patients when used as monotherapy (4,13,21). However, the combination of these targeted agents with surgery and radiotherapy has not been extensively studied. RET inhibitors have been shown to effectively control both local and distant disease in many cases; however, the integration of systemic therapy with surgical resection and radiotherapy remains underexplored in clinical settings. The concept of “sandwich” therapy, which combines systemic therapy with surgery and adjuvant therapy, has the potential to enhance treatment efficacy and reduce relapse risk, but its long-term benefits remain uncertain. More extensive clinical trials and extended follow-up data are needed to validate the use of this approach in RET⁺ NSCLC. This case report highlights the potential of combining targeted therapy with surgery and radiotherapy, while also pointing out the research gaps that need to be addressed.

This case provides valuable insights into the potential benefits of combining pralsetinib with surgery and radiotherapy in the treatment of RET⁺ NSCLC. It aligns with recent findings that underscore the promising efficacy of RET inhibitors, particularly pralsetinib, in the management of RET⁺ tumors. While previous studies have primarily focused on the role of targeted therapy alone, this case showed that combining pralsetinib with surgical resection and adjuvant radiotherapy led to a significant pCR, suggesting that multi-modality approaches may offer enhanced outcomes. This finding supports the concept of “sandwich” therapy, which has shown success in other cancers (22,23) but remains underexplored in the context of RET⁺ NSCLC. Further, this case challenges the current treatment paradigm by emphasizing the need for personalized therapy that integrates various modalities, especially for younger patients with more aggressive disease. By showing that this multi-modal strategy can result in substantial tumor shrinkage and long-term disease control, this case provides a valuable addition to the growing body of literature and may lead to further research into optimizing treatment sequencing for RET⁺ NSCLC. Another unresolved issue concerns the optimal duration of adjuvant targeted therapy after achieving a pCR, which remains undefined in RET⁺ NSCLC. Determining appropriate treatment duration is essential to balance durable remission, long-term safety, and financial considerations. A limitation of this case is that ARMS-PCR identified a RET exon 12 fusion but did not determine the specific fusion partner or co-occurring mutations, which could have provided additional biological and therapeutic insights. In addition, future studies should explore the potential interplay between RET inhibition and host immune responses, which may provide new insights into combination strategies and mechanisms of durable remission. In summary, this case illustrates the potential role of pralsetinib-based sandwich therapy in RET fusion-positive NSCLC, but further studies are required to validate its generalizability and clinical applicability.

Conclusions

This case report underscores the potential of using a multi-modality treatment approach that combines pralsetinib with surgery and radiotherapy for RET⁺ NSCLC. The patient’s remarkable achievement of a pCR highlights the effectiveness of integrating targeted therapy with surgical resection and adjuvant treatment. This case adds to the growing body of evidence supporting the notion that personalized, combination therapies may offer improved outcomes in RET⁺ NSCLC patients, particularly in younger individuals with more aggressive disease. While the success of the “sandwich” treatment approach in RET⁺ NSCLC requires further validation through larger studies, this case provides a compelling rationale for exploring tailored treatment regimens that combine targeted therapy with other modalities. The findings suggest that optimizing treatment sequencing may enhance both local and systemic disease control, providing a promising avenue for improving the long-term survival of this patient population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-969/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-969/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-2025-969/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. The study was approved by the Institutional Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (approval No. ES-2025-K222-01). Written informed consent was obtained from the patient for 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

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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(English Language Editor: L. Huleatt)