What are the recommended first-line and second-line targeted therapies for soft tissue sarcoma, including GIST (Gastrointestinal Stromal Tumor), leiomyosarcoma, and liposarcoma?

Targeted Therapy for Soft Tissue Sarcoma

For soft tissue sarcomas, targeted therapy selection should be based on specific histologic subtype, with imatinib as first-line therapy for GIST, pazopanib for non-adipogenic STS, and eribulin for liposarcomas. 1

Gastrointestinal Stromal Tumors (GIST)

First-line therapy:

• Imatinib 400 mg daily 1
  • For patients with KIT exon 9 mutations: Consider dose escalation to 800 mg daily (400 mg twice daily) 1, 2
  • Continue until disease progression or intolerance

Second-line therapy:

• Sunitinib after imatinib failure 1, 3
  • Dosing options:
    • 37.5 mg orally once daily continuously, or
    • 50 mg orally once daily on a schedule of 4 weeks on/2 weeks off

Disease progression management:

• If progression on standard-dose imatinib: Consider dose escalation to 800 mg daily (400 mg twice daily) before switching to sunitinib 1
• For limited disease progression: Consider surgical resection with continuation of imatinib post-surgery 1

Non-GIST Soft Tissue Sarcomas

Leiomyosarcoma:

• First-line: Anthracycline-based chemotherapy (standard treatment) 1
• Second-line options:
  1. Trabectedin - particularly effective for leiomyosarcoma 1
  2. Gemcitabine combinations (with dacarbazine or docetaxel) 1
  3. Pazopanib 1

Liposarcoma:

• First-line: Anthracycline-based chemotherapy (standard treatment) 1
• Second-line options:
  1. Eribulin - specifically approved for liposarcoma after doxorubicin failure 1
  2. Trabectedin - particularly effective for myxoid liposarcoma 1
  3. High-dose ifosfamide (12-14 g/m²/cycle) for well-differentiated/dedifferentiated liposarcoma 1

Histology-Specific Targeted Therapies

Sarcoma Subtype	Recommended Targeted Therapy
Dermatofibrosarcoma protuberans	Imatinib [1]
Inflammatory myofibroblastic tumor	Crizotinib (if ALK translocation present) [1]
PEComas	mTOR inhibitors (sirolimus) [1]
Alveolar soft part sarcoma	Anti-angiogenic TKIs (pazopanib) [1]
Solitary fibrous tumor	Pazopanib or sunitinib [1]
Extraskeletal myxoid chondrosarcoma	Pazopanib [1]
Angiosarcoma	Paclitaxel, liposomal doxorubicin, or anti-angiogenics [1]
NTRK fusion-positive sarcomas	NTRK inhibitors (larotrectinib, entrectinib) [1]

Important Clinical Considerations

1. Molecular testing:

   • KIT and PDGFRA mutation testing is essential for GIST management 1
   • NTRK fusion testing for potential targeted therapy 1
   • ALK testing for inflammatory myofibroblastic tumors 1

2. Treatment sequencing:

   • For most non-GIST sarcomas, targeted therapy is typically used after failure of conventional chemotherapy 1
   • Exception: Specific molecular-driven subtypes may benefit from upfront targeted therapy 1

3. Monitoring:

   • Regular imaging (typically every 2-3 months initially) to assess response
   • Monitor for specific toxicities associated with each targeted agent

4. Common pitfalls to avoid:

   • Treating all soft tissue sarcomas as one entity - histologic subtyping and molecular testing are critical
   • Continuing ineffective therapy - consider switching therapy if progression occurs
   • Overlooking potential drug interactions, especially with CYP3A4 inhibitors/inducers for sunitinib 3
   • Failing to adjust imatinib dose based on KIT mutation status in GIST 1, 2

Remember that soft tissue sarcomas are a heterogeneous group of diseases requiring specialized multidisciplinary care. Treatment should be coordinated through centers with expertise in sarcoma management whenever possible 1.