Progression of infantile fibrosarcoma on first-line larotrectinib / entrectinib (acquired...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-IFS-TRANSFORMATION-PROGRESSION`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-IFS`
Sources	`SRC-NCCN-PEDIATRIC-SARCOMA` `SRC-ONCOKB`

Red Flag Origin

Definition	Progression of infantile fibrosarcoma on first-line larotrectinib / entrectinib (acquired NTRK kinase-domain solvent-front G595R / G667S mutation), new metastatic disease (lung most common), or rapid local progression — triggers second-generation TRK inhibitor (selitrectinib, repotrectinib) or salvage VAC / Ewing-like cytotoxic protocol.
Clinical direction	hold
Category	transformation-progression

Trigger Logic

{
  "any_of": [
    {
      "finding": "BIO-NTRK-FUSION",
      "value": "resistance_mutation"
    },
    {
      "finding": "ntrk_solvent_front_mutation",
      "value": true
    },
    {
      "finding": "new_metastatic_disease",
      "value": true
    },
    {
      "finding": "rapid_progression_on_trk_inhibitor",
      "value": true
    }
  ],
  "type": "composite_clinical"
}

Notes

Acquired resistance to 1st-gen TRK inhibitors typically emerges via on-target kinase-domain mutations (G595R for NTRK1, G623R for NTRK3, solvent-front and gatekeeper variants) within 12-24 months; off-target bypass via MAPK signaling described. Selitrectinib (LOXO-195) and repotrectinib (TPX-0005) are 2nd-gen designed to overcome these mutations — TRIDENT-1 enrolled pediatric with promising responses in TRK-resistant. Salvage cytotoxic (VAC, Ewing-like VDC/IE) reasonable if 2nd-gen unavailable. Re-biopsy at progression strongly recommended.

Used By

No reverse references found in the YAML corpus.