Advanced or Metastatic Gastrointestinal Stromal Tumor (GIST)

Evidence-based treatment sequencing for advanced GIST, using mutational status (KIT exon 9 vs exon 11/wild-type vs PDGFRA D842V) to guide frontline imatinib dosing versus frontline avapritinib, then non-cross-resistant tyrosine kinase inhibitor sequencing through sunitinib, regorafenib and ripretinib.

KIT / PDGFRA mutational status (KIT exon 11 or wild-type, KIT exon 9, or PDGFRA D842V) — frontline therapy selection

• KIT exon 11 or wild-type → Imatinib 400 mg daily (KIT exon 11 or wild-type)
• KIT exon 9 mutation → High-dose imatinib 800 mg daily (KIT exon 9)
• PDGFRA exon 18 D842V mutation → Avapritinib (PDGFRA exon 18 D842V)

1L: Imatinib 400 mg daily (KIT exon 11 or wild-type)

Standard frontline dose for KIT exon 11-mutant (and KIT/PDGFRA wild-type) advanced GIST; disease control in ~85% with median PFS ~20-24 months. Continue indefinitely until progression or intolerance — stopping in responders causes rapid regrowth. Monitor for edema, cytopenias, and hepatotoxicity.

• Progression / intolerance → Sunitinib

1L: High-dose imatinib 800 mg daily (KIT exon 9)

KIT exon 9-mutant GIST derives improved progression-free survival from imatinib 800 mg/day (two divided doses) per the MetaGIST meta-analysis. If 800 mg/day is poorly tolerated, sunitinib may be considered earlier.

• Progression / intolerance → Sunitinib

1L: Avapritinib (PDGFRA exon 18 D842V)

Frontline for PDGFRA exon 18 D842V-mutant GIST, which is intrinsically imatinib-resistant; avapritinib achieved an objective response rate above 90% in NAVIGATOR. Monitor for cognitive effects and intracranial hemorrhage; hold for thrombocytopenia and evaluate any CNS symptom promptly.

• Progression on avapritinib → Clinical trial or salvage therapy

2L: Sunitinib

Standard second line after imatinib progression or intolerance. Schedule 50 mg/day 4 weeks on / 2 weeks off, or 37.5 mg continuous. Activity is greater in KIT exon 9 and wild-type disease. Monitor for hypertension, hand-foot skin reaction, hypothyroidism, and fatigue.

• Progression → Regorafenib (third line)

3L+: Regorafenib (third line)

Third line after imatinib and sunitinib (GRID trial: PFS 4.8 vs 0.9 months). Dose 160 mg/day for 21 of 28 days with a low-fat meal. Monitor for hand-foot skin reaction, hypertension, and hepatotoxicity; consider a dose-escalation start to improve tolerability.

• Progression → Ripretinib (fourth line and beyond)

3L+: Ripretinib (fourth line and beyond)

Switch-control TKI for GIST after >= 3 prior kinase inhibitors including imatinib (INVICTUS: PFS 6.3 vs 1.0 months). Its broad coverage of secondary KIT resistance mutations (exons 13, 14, 17, 18) distinguishes it from earlier-line agents. Counsel on dermatologic self-surveillance for new cutaneous malignancies; monitor blood pressure and cardiac function.

• Progression → Clinical trial or salvage therapy

3L+: Clinical trial or salvage therapy

After the approved TKI ladder is exhausted (KIT-driven disease) or after progression on frontline avapritinib (PDGFRA D842V-driven disease), prioritize a clinical trial. Rechallenge with a previously tolerated TKI or consideration of surgery for limited progression may be appropriate in selected patients.