larotrectinib

Overview

Larotrectinib (Vitrakvi) is an FDA-approved pan-TRK (NTRK1/2/3) tyrosine kinase inhibitor indicated for solid tumors harboring NTRK gene fusions, regardless of histology. It is the prototypic tumor-agnostic TRK inhibitor. It relies on the presence of an activating NTRK fusion (most notably ETV6-NTRK3 in infantile fibrosarcoma and secretory breast/salivary carcinoma) for efficacy.

Evidence in the corpus

  • In a PDTO functional screen of 92 sarcoma specimens, SARC0127 (suspected infantile fibrosarcoma) PDTOs were resistant to larotrectinib. Because infantile fibrosarcoma (IFS) carries an ETV6–NTRK3 fusion in approximately 90% of cases, the negative PDTO response correctly predicted eventual reclassification of the tumor as high-grade spindle cell/sclerosing rhabdomyosarcoma (SCSRMS). PDTO prediction was delivered within one week versus 18 days for formal pathology PMID:39305899.
  • ETV6 FISH was negative in SARC0127, corroborating the PDTO larotrectinib resistance signal and supporting the reclassification; this exemplifies functional precision medicine complementing molecular diagnostics when histology is ambiguous PMID:39305899.
  • FDA-recognized level 1 biomarker: NTRK1 fusions (e.g., LMNA::NTRK1) predict response to larotrectinib across solid tumor types including gallbladder carcinoma; 1 patient in the MSK GBC cohort (n=233) harbored an actionable NTRK1 fusion PMID:36228155
  • NTRK fusion-positive CCA: 75% ORR in 55 NTRK-fusion patients including 2 CCA; treatment-naïve TRK-fusion update ORR 77%, mPFS 59 mo across tumor types PMID:25526346

Resistance mechanisms

  • Absence of NTRK fusion (FISH-negative ETV6) predicts larotrectinib non-response in sarcomas initially suspected to be IFS; PDTO assay can reveal this resistance within days of tumor collection PMID:39305899.

Cancer types (linked)

  • IFS — infantile fibrosarcoma (expected responder via ETV6-NTRK3 fusion; PDTO resistance prompted diagnostic reclassification)
  • SCSRMS — sclerosing/spindle cell rhabdomyosarcoma (reclassified from suspected IFS after larotrectinib PDTO resistance)

Sources

  • PMID:39305899 — Al Shihabi et al. 2024, Cell Stem Cell. Sarcoma PDTO functional precision-medicine screen; larotrectinib resistance enabled diagnostic reclassification from IFS to SCSRMS.

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14.