Selpercatinib or pralsetinib?

Both are FDA-approved selective RET inhibitors with similar efficacy. 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. 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). Both respond to selpercatinib and pralsetinib; 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.

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-altered MTC	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 openFDA labels 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. 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. 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). Both respond to selpercatinib and pralsetinib; 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.