Variant cheat sheet · NSCLC and medullary thyroid carcinoma
RET fusions in NSCLC and medullary thyroid carcinoma
Free clinical reference. Educational use only. Not a substitute for professional medical advice.
TL;DR
RET fusion-positive NSCLC and RET-altered MTC are AMP/ASCO/CAP Tier I-A. Selpercatinib (LIBRETTO-001) and pralsetinib (ARROW) are FDA-approved selective RET inhibitors with strong CNS activity and tolerable AE profiles. Tumor-agnostic RET indication for selpercatinib (FDA 2022 update) covers any solid tumor with RET fusion.
Biology
RET is a receptor tyrosine kinase critical for development and homeostasis. Fusions (KIF5B-RET is most common in NSCLC) and activating mutations (M918T in MTC) drive ligand-independent kinase activity and MAPK/PI3K signaling. Selective RET inhibitors spare off-target effects of multikinase inhibitors used historically (vandetanib, cabozantinib).
Epidemiology
RET fusions occur in ~1-2% of NSCLC, ~10-20% of papillary thyroid carcinoma, ~50% of sporadic medullary thyroid carcinoma (RET mutations, not fusions), and essentially all hereditary MTC in MEN2 syndromes.
Detection
- RNA NGS is optimal for fusion detection with partner identification.
- DNA NGS with fusion-calling pipelines.
- FISH for RET rearrangement screening.
- For MTC: germline RET mutation testing required at diagnosis (MEN2 evaluation).
FDA-approved targeted therapies
| Drug | Indication | Line | Tier |
|---|---|---|---|
| Selpercatinib | RET fusion-positive NSCLC, RET-altered MTC, tumor-agnostic RET fusion-positive solid tumor | 1L+ | I-A |
| Pralsetinib | RET fusion-positive NSCLC and RET fusion-positive thyroid cancer (RET-mutant MTC indication voluntarily withdrawn in the US, 2023) | 1L+ | I-A |
| Cabozantinib / vandetanib (historical multikinase) | MTC; less preferred than selective RET inhibitors due to off-target AEs | Historical / alternative | I-A |
Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to the human-readable FDA label on DailyMed where available. Synthetic data; consult primary sources before treatment.
Resistance pathways
- RET solvent-front mutations (G810R/S/C): most common acquired resistance to selpercatinib/pralsetinib.
- Bypass-track activation (MET amplification, KRAS mutations).
- Next-generation pan-RET inhibitors covering solvent-front mutations are in development.
Frequently asked questions
- Selpercatinib or pralsetinib?
- Both are FDA-approved selective RET inhibitors with similar efficacy in RET fusion-positive NSCLC. Selpercatinib has the broader tumor-agnostic label (added 2022) and the longer follow-up. Pralsetinib had US distribution and supply considerations historically that affected access, and its RET-mutant MTC indication was voluntarily withdrawn in 2023, so for RET-mutant MTC only selpercatinib carries a current FDA indication. Institutional preference and AE profile drive the call.
- Are RET-altered MTCs the same as RET fusion NSCLC?
- Similar druggability but different biology. MTC has activating point mutations (most commonly M918T) and germline mutations (MEN2 syndromes). NSCLC has fusions (KIF5B-RET, CCDC6-RET). In RET-mutant MTC, selpercatinib is the FDA-approved selective RET inhibitor; pralsetinib's RET-mutant MTC indication was voluntarily withdrawn in 2023 after the confirmatory trial became infeasible, though it remains approved for RET fusion-positive NSCLC and thyroid cancer. The testing modality differs (mutation panel for MTC, fusion-aware NGS for NSCLC).
- What about checkpoint inhibitor therapy in RET fusion NSCLC?
- RET fusion-positive NSCLC, like other driver-mutation subsets, responds poorly to single-agent PD-1/PD-L1 inhibitors. Selective RET TKIs are the standard.