MTC progression on first-line RET-selective inhibitor (acquired RET solvent-front mutatio...

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

ID	`RF-MTC-TRANSFORMATION-PROGRESSION`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-MTC`
Sources	`SRC-ATA-THYROID-2015` `SRC-NCCN-THYROID-2025`

Red Flag Origin

Definition	MTC progression on first-line RET-selective inhibitor (acquired RET solvent-front mutation G810R / G810S / G810C), rapid calcitonin doubling time (<6 months — adverse prognostic marker), new bone / liver / brain metastases, or symptomatic carcinoid-like diarrhea (calcitonin-driven, debilitating) — triggers switch to next-gen RET inhibitor (TPX-0046, vepafestinib in trials), cabozantinib re-challenge, or peptide receptor radionuclide therapy.
Clinical direction	hold
Category	transformation-progression

Trigger Logic

{
  "any_of": [
    {
      "finding": "ret_solvent_front_mutation",
      "value": true
    },
    {
      "comparator": "<",
      "finding": "calcitonin_doubling_time_months",
      "threshold": 6
    },
    {
      "finding": "new_bone_liver_brain_mets",
      "value": true
    },
    {
      "finding": "carcinoid_diarrhea_symptomatic",
      "value": true
    }
  ],
  "type": "composite_clinical"
}

Notes

Calcitonin doubling time <6 months is a validated adverse prognostic marker (Barbet et al, JCEM 2005) — predicts rapid clinical progression and shorter OS; serves as biomarker-based progression signal even before RECIST. Acquired RET solvent-front mutations (G810R/S/C) are the dominant on-target resistance to selpercatinib / pralsetinib (~30% of progressors). Next-gen RET inhibitors (vepafestinib / TPX-0046; LOX-260) in trials. Cabozantinib re-challenge has limited but documented activity post-RET-selective failure. Carcinoid-like diarrhea (calcitonin-driven) is debilitating — somatostatin analogs (octreotide / lanreotide) for symptom control. PRRT (¹⁷⁷Lu- DOTATATE) for somatostatin-receptor-positive metastatic MTC.

Used By

No reverse references found in the YAML corpus.