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

Background: RET gene fusions define a distinct molecular subset of non-small cell lung cancer (NSCLC) that commonly affects younger and non-smoking individuals. Selective RET inhibitors such as pralsetinib have shown favorable outcomes in advanced or metastatic settings; however, their role in perioperative or locally advanced disease remains poorly defined. Integrating targeted therapy into a multidisciplinary "sandwich" strategy, which includes neoadjuvant, surgical, and adjuvant components, may offer improved outcomes and requires further exploration. Case Description: We report the case of a 34-year-old male patient with a 15-year smoking history, who presented with persistent right-sided chest pain. Imaging revealed a 3.4 cm × 2.4 cm × 4.4 cm mass in the right middle lobe with mediastinal and left supraclavicular lymphadenopathy. Supraclavicular node biopsy confirmed metastatic poorly differentiated adenocarcinoma. Immunohistochemistry supported a pulmonary origin, and molecular testing via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) detected a RET exon 12 fusion. The clinical stage was cT2N3M0 (stage IIIB). The patient declined chemotherapy and underwent neoadjuvant pralsetinib therapy. After 3 months, a partial response (PR) was observed. On April 13, 2023, the patient underwent video-assisted thoracoscopic surgery (VATS) with right middle lobectomy. Postoperative pathology revealed a pathological complete response (pCR) with 0% viable tumor cells. Pralsetinib was resumed as adjuvant therapy post-surgery. The patient also began elective regional radiotherapy targeting bilateral supraclavicular drainage areas, but the treatment was terminated early due to grade 3 acute esophagitis. At the 24-month follow-up, the patient remained disease-free on pralsetinib maintenance with preserved performance status. Conclusions: This case highlights the potential benefit of pralsetinib-based "sandwich" therapy in the treatment of RET fusion-positive NSCLC. Incorporating targeted therapy with surgery and tailored adjuvant treatment may lead to durable remission in selected patients with locally advanced disease. Prospective studies need to be conducted to further define the treatment sequencing and validate this multi-modal approach.