How rare is NTRK fusion-positive cancer?

Less than 1% pan-tumor in adult cancer, but extremely enriched in some rare tumors (infantile fibrosarcoma, MASC of salivary gland, secretory breast carcinoma). The tumor-agnostic indication means it's worth testing across virtually all solid tumors when broad NGS is being run.

Larotrectinib or entrectinib?

Both are FDA-approved tumor-agnostic. Larotrectinib is TRK-specific; entrectinib also has activity against ROS1 and ALK. Larotrectinib has a slightly broader pediatric label and longer cumulative experience. Entrectinib has stronger CNS data. Repotrectinib is the newer option with activity against resistance mutations.

Is RNA NGS required or is DNA NGS enough?

DNA NGS with adequate intronic coverage and fusion-calling pipelines can detect NTRK fusions, but RNA NGS has higher sensitivity and resolves partner identity more reliably. Pan-TRK IHC can serve as a screen. For rare tumors with high NTRK fusion prior probability, RNA NGS is strongly preferred.

Variant cheat sheet · any solid tumor (tumor-agnostic)

NTRK fusions in solid tumors (tumor-agnostic)

Free clinical reference. Educational use only — not a substitute for professional medical advice.

TL;DR

NTRK1/2/3 fusion-positive solid tumors are AMP/ASCO/CAP Tier I-A for larotrectinib and entrectinib tumor-agnostic FDA approvals. Repotrectinib (TRIDENT-1) covers ROS1 and now NTRK fusions including treatment-resistant cases. Overall rare (~1% pan-tumor) but extremely actionable when present, especially in rare tumors with poor standard-of-care options.

Biology

NTRK1, NTRK2, NTRK3 encode TRKA, TRKB, TRKC receptor tyrosine kinases. Fusions retain the kinase domain and acquire a 5' partner driving ligand-independent dimerization and constitutive activation. Fusions are exquisitely sensitive to selective TRK inhibitors. They are enriched in rare tumors (infantile fibrosarcoma, secretory breast carcinoma, mammary analog secretory carcinoma of salivary gland) but occur at low frequency across almost all solid tumor types.

Epidemiology

NTRK fusions occur in ~0.3% of adult solid tumors overall but are enriched in rare tumors (90%+ in infantile fibrosarcoma, MASC of salivary gland). Less than 1% in common adult cancers (NSCLC, colorectal, etc.). Across all comers, the tumor-agnostic indication makes them worth testing for universally.

Detection

RNA NGS: highest sensitivity for fusions with partner identification.
DNA NGS with fusion calling: detects but partner resolution is lower-fidelity.
Pan-TRK IHC: useful screen, especially when NGS is unavailable.
FISH break-apart panels exist but are gene-by-gene rather than fusion-resolving.

FDA-approved targeted therapies

Drug	Indication	Line	Tier
Larotrectinib	Tumor-agnostic NTRK fusion-positive solid tumor	1L+	I-A
Entrectinib	Tumor-agnostic NTRK fusion-positive solid tumor; also ROS1 NSCLC	1L+	I-A
Repotrectinib	ROS1+ NSCLC and NTRK fusion+ solid tumor including post-TKI (TRIDENT-1)	1L / post-TKI	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

TRK kinase-domain solvent-front mutations (G595R, G623R, G667).
Bypass-track activation (KRAS, BRAF, MEK).
Repotrectinib retains activity against many first-generation TKI-resistant mutations.

Frequently asked questions

How rare is NTRK fusion-positive cancer?: Less than 1% pan-tumor in adult cancer, but extremely enriched in some rare tumors (infantile fibrosarcoma, MASC of salivary gland, secretory breast carcinoma). The tumor-agnostic indication means it's worth testing across virtually all solid tumors when broad NGS is being run.
Larotrectinib or entrectinib?: Both are FDA-approved tumor-agnostic. Larotrectinib is TRK-specific; entrectinib also has activity against ROS1 and ALK. Larotrectinib has a slightly broader pediatric label and longer cumulative experience. Entrectinib has stronger CNS data. Repotrectinib is the newer option with activity against resistance mutations.
Is RNA NGS required or is DNA NGS enough?: DNA NGS with adequate intronic coverage and fusion-calling pipelines can detect NTRK fusions, but RNA NGS has higher sensitivity and resolves partner identity more reliably. Pan-TRK IHC can serve as a screen. For rare tumors with high NTRK fusion prior probability, RNA NGS is strongly preferred.