What are the experimental treatment options for chordoma?

Experimental Treatment Options for Chordoma

For patients with advanced or recurrent chordoma, targeted therapies such as imatinib and sorafenib represent the most evidence-supported experimental treatment options, with molecular profiling recommended to guide therapy selection. 1

Targeted Therapy Options

First-Line Targeted Therapies

• Imatinib: Shows the strongest evidence among targeted therapies

  • Clinical benefit rate of 64% in a phase II trial with 70% of patients achieving stable disease 1
  • Median progression-free survival of 9 months 1
  • Recommended for PDGFR-positive tumors 2

• Sorafenib: Also has significant evidence supporting its use in advanced chordoma 1

  • Both imatinib and sorafenib can slow disease progression and provide palliative symptom relief

Second-Line Targeted Therapies

• EGFR inhibitors: Case reports support activity in imatinib-resistant disease 1

  • Cetuximab
  • Erlotinib
  • Gefitinib

• Combination approaches for imatinib-resistant disease:

  • Imatinib + cisplatin 1
  • Imatinib + sirolimus (mTOR inhibitor) 1
  • Erlotinib + cetuximab 1

Molecular Profiling to Guide Treatment

• Tumor molecular profiling is strongly recommended to guide therapy selection 1, 2
  • Test for PDGFR expression (for imatinib sensitivity)
  • Test for EGFR expression (for EGFR inhibitor sensitivity)
  • INI1 loss in dedifferentiated chordomas may predict sensitivity to EZH2 inhibitors 1

Emerging Experimental Approaches

• Immunotherapy: Promising early results in case reports 3

  • Anti-PD1 antibodies have shown impressive clinical responses in some patients with metastatic/advanced disease
  • Tumor-based vaccines have demonstrated clinical responses in select cases

• Differentiation therapy: Laboratory evidence suggests potential benefit 4

  • Combination of chemotherapeutic agents with all-trans retinoic acid (ATRA) showed enhanced effect against chordoma cells in vitro
  • Particularly effective with etoposide and cisplatin

• Clinical trials: The Chordoma Foundation maintains an up-to-date list of trials

  • Available at www.chordomafoundation.org/clinical-trials/ 1
  • Target dashboard summarizing therapeutically-relevant targets: www.chordomafoundation.org/targets/ 1

Important Considerations and Limitations

• Conventional cytotoxic chemotherapy is generally ineffective for conventional chordoma 1

  • Exception: May have activity in high-grade/dedifferentiated chordoma and some pediatric cases

• Clinical trial design challenges:

  • Rarity of disease makes randomized trials difficult 1
  • Slow growth rate makes overall survival endpoints impractical 1
  • Surrogate endpoints beyond dimensional response may be needed to capture quality of life improvements 1

• Patients should be encouraged to enroll in registries or observational studies to improve understanding of disease and optimize future treatments 1

Treatment Algorithm

1. Confirm recurrence/advanced disease with appropriate imaging
2. Perform molecular profiling of tumor tissue
3. First-line therapy:
   • If PDGFR-positive: Imatinib
   • If EGFR-positive: Consider EGFR inhibitor
4. Upon progression:
   • Consider combination therapy (imatinib + cisplatin/sirolimus or erlotinib + cetuximab)
   • Consider clinical trial enrollment
   • Consider immunotherapy in appropriate candidates

Regular monitoring with MRI every 3-6 months for at least the first 3 years is recommended to assess treatment response 1.