Response to imatinib plus sirolimus in advanced chordoma

Ann Oncol. 2009 Nov;20(11):1886-94. doi: 10.1093/annonc/mdp210. Epub 2009 Jul 1.

Abstract

Background: Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma.

Patients and methods: Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis.

Results: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (> or =10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD > or =6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off.

Conclusion: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides
  • Blotting, Western
  • Chordoma / drug therapy*
  • Chordoma / pathology
  • Female
  • Humans
  • Imatinib Mesylate
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Oncogene Protein v-akt / biosynthesis
  • Oncogene Protein v-akt / drug effects
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Sacrum / pathology
  • Sirolimus / administration & dosage*
  • Sirolimus / adverse effects
  • Skull Base Neoplasms / drug therapy*
  • Skull Base Neoplasms / pathology
  • Spinal Neoplasms / drug therapy*
  • Spinal Neoplasms / pathology
  • Treatment Outcome
  • Young Adult

Substances

  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Oncogene Protein v-akt
  • Sirolimus