Senthil Kumar: Management of Advanced/Metastatic Gastrointestinal Stromal Tumor

Senthil Kumar, Medical Oncologist at Red Hills Chennai, shared a post on X:

“Management of Advanced/Metastatic Gastrointestinal Stromal Tumor (GIST)

Molecular Testing

KIT Mutations:

Found in ~80% of GISTs (exons 11, 9, 13, 17).

PDGFRA Mutations:

Occur in exons 1, 14, 18.

D842V Mutation:

Resistant to imatinib, sensitive to avapritinib. Dasatinib may be considered as a second-line option after avapritinib failure.

SDH-Deficient GIST:

Insensitive to imatinib; may respond to sunitinib, regorafenib, and pazopanib.

NTRK Fusion

Larotrectinib and entrectinib.

BRAF Mutations:

BRAF inhibitors.

NF-1 mutations

Germline Testing

For family history of GIST or specific genetic syndromes like Carney-Stratakis syndrome.

Prognostic Factors

Molecular Prognostic Factors:

KIT Exon 11 Mutation:
Better response to imatinib (B2222, BFR14 trials).

KIT Exon 9 Mutation:
Imatinib dose escalation to 800 mg/day.

PDGFRA D842V Mutation:
Poor response to standard TKIs, sensitive to avapritinib. Dasatinib in subsequent line

PDGFRA Mutations (Non-D842V):
Imatinib 400 mg/day

SDH-Deficient GIST
Indolent disease.

Clinical Prognostic Factors:

Age

Tumor burden

Performance status (PS)

Feasibility of surgery, ablation, embolization.

First-Line and Sequential Tyrosine Kinase Inhibitor (TKI) Therapy

Imatinib

Indication:
Effective for all KIT mutations and PDGFRA mutations except D842V.

Dose:
400 mg/day; 800 mg/day for KIT exon 9 mutations.

Median PFS: ~30 months.

Median OS: ~57 months.

ORR: 40–70%.

Chief Adverse Effects:
Edema, fatigue, muscle cramps, nausea, diarrhea.

Avapritinib

Indication:
First-line for PDGFRA exon 18 D842V mutations.

Dose: 300 mg/day.

NAVIGATOR Trial:

ORR: 90%.

Median Duration of Response: 27 months.

Chief Adverse Effects: Cognitive impairment, edema, fatigue, CNS bleeding, seizures.

Sunitinib

Indication: Second-line after imatinib failure or intolerance; effective in SDH-deficient GIST.

Dose: 50 mg/day (4-weeks-on, 2-weeks-off) or continuous 37.5 mg/day.

Time to Progression (TTP): ~6 months.

Chief Adverse Effects: Hypertension, fatigue, diarrhea, hand-foot syndrome.

Regorafenib

Indication: Third-line after imatinib and sunitinib failure. May also be used as second-line therapy in patients intolerant to sunitinib.

Dose: 160 mg/day (3-weeks-on, 1-week-off).

Chief Adverse Effects: Hypertension, hand-foot skin reaction, diarrhea, fatigue.

Ripretinib

Indication: Fourth-line after failure of ≥3 TKIs.

Dose: 150 mg/day continuously.

Dose Escalation: May increase to 150 mg BID upon progression.

Chief Adverse Effects: Alopecia, fatigue, nausea, hand-foot syndrome.

Surgical and Local Therapies

Resection: For previously unresectable disease that becomes resectable post-TKI.

Limited Progression: Surgery for isolated lesions progressing while others are controlled.

Emergency Surgery: In cases of bleeding, obstruction, or perforation.

Metastasectomy: For isolated or oligometastatic disease.

Ablation/Embolization: For liver metastases or unresectable disease.

Palliative Radiotherapy: For symptomatic progression or pain control.

Alternative Therapies

• Dasatinib
• Cabozantinib
• Everolimus + TKI
• Nilotinib
• Pazopanib
• Ponatinib
• Sorafenib

Any previously used effective regimen may be rechallenged

Treatment Algorithm

1. KIT Exon 11 Mutation:

First-line: Imatinib 400 mg/day.

Progression: Escalate to 800 mg/day or Sunitinib → Regorafenib → Ripretinib.

2. KIT Exon 9 Mutation:

First-line: Imatinib 800 mg/day.

Progression: Sunitinib → Regorafenib → Ripretinib.

3. PDGFRA D842V Mutation:

Preferred : Avapritinib 300 mg/day for symptomatic or progressive disease

Progression: Dasatinib / Clinical trial

For Indolent Disease: Observation is advised to avoid avapritinib toxicity, particularly cognitive side effects.

4. Wild-Type GIST (SDH-deficient, NF1):

First-line: Sunitinib / regorafenib / clinical trial.”