Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study

Cancer. 2018 Oct 15;124(20):4056-4063. doi: 10.1002/cncr.31685. Epub 2018 Sep 14.

Abstract

Background: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma.

Methods: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response.

Results: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively.

Conclusions: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

Keywords: chemotherapy; chordoma; everolimus; imatinib; mTOR.; sarcoma.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / mortality
  • Bone Neoplasms / pathology
  • Chordoma / drug therapy*
  • Chordoma / mortality
  • Chordoma / pathology
  • Disease Progression
  • Everolimus / administration & dosage*
  • Everolimus / adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Imatinib Mesylate / administration & dosage*
  • Imatinib Mesylate / adverse effects
  • Male
  • Middle Aged
  • Sarcoma / drug therapy
  • Sarcoma / mortality
  • Sarcoma / pathology
  • Skull Base Neoplasms / drug therapy
  • Skull Base Neoplasms / mortality
  • Skull Base Neoplasms / pathology
  • Spinal Neoplasms / drug therapy
  • Spinal Neoplasms / mortality
  • Spinal Neoplasms / pathology
  • Survival Analysis

Substances

  • Imatinib Mesylate
  • Everolimus