RET positive

Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors...Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.

The new discoveries of RET fusion partners were founded in NSCLC. In addition, the broad-panel NGS is essential for NSCLC patients to catch these rare/novel fusions that PCR or small panels might miss.

The validation of the NMA results could be assessed for progression-free survival of selpercatinib versus pembrolizumab + pemetrexed + platinum-based chemotherapy. Enabling the earlier assessment of single-arm trials, via pseudo comparator arms, will provide payers with greater confidence in anticipated treatment effects. In light of the joint clinical assessment, incorporation of single-arm trials within NMA facilitates the reporting of predicted treatment effects relative to multiple relevant comparators, which is important when considering the use of interventions for the global market.

P4, N=25, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

Drug-induced IL occurs with selpercatinib or pralsetinib treatment. The frequency increases with longer drug exposure. Serial monitoring is essential and when necessary, dose modification. Most cases do not lead to treatment discontinuation.

Given the current pricing, neither selpercatinib as a first-line therapy nor as a second-line therapy was deemed to be cost-effective compared with chemotherapy for advanced NSCLC patients with RET fusions. Further real-world studies of selpercatinib and development of health outcome estimate scales are needed to provide additional evidence for clinicians and health policy decision-makers.

The therapeutic strategy involved an immediate switch from rivaroxaban to therapeutic low-molecular-weight heparin (LMWH) and the initiation of dual targeted therapy with selpercatinib and tepotinib. Upon diagnosis of NBTE, a rapid oncologic work-up is warranted, as ongoing tumor progression is highly likely. This case questions the appropriateness of direct oral anticoagulants in patients with NBTE and active, progressive malignancy.

Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

P2, N=124, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Mar 2026 --> Dec 2026 | Trial primary completion date: Mar 2026 --> Dec 2026

P3, N=291, Active, not recruiting, Loxo Oncology, Inc. | Trial completion date: Feb 2026 --> Nov 2027

Following the development of resistance, combination therapy with pralsetinib and anlotinib successfully achieved a partial response again. This case underscores the importance of comprehensive molecular testing across multiple lesions to guide precision therapy and provides clinical insights into RET fusion-positive lung cancer treatment and post-resistance combination strategies.

Furthermore, the review elaborates on the clinical efficacy of highly selective RET inhibitors (selpercatinib and pralsetinib), including their breakthroughs in pediatric patients and radioactive iodine-refractory cases. Primary and acquired resistance mechanisms (on-target mutations, bypass activation) and corresponding strategies (next-generation inhibitors, combination therapies) are also analyzed. By integrating recent advances in basic and clinical research, this review provides a comprehensive reference for the precision diagnosis and treatment, mechanistic investigation, and drug development for RET fusion-positive PTC.