Phase 2 study for nonmetastatic extremity high-grade osteosarcoma in pediatric and adolescent and young adult patients with a risk-adapted strategy based on ABCB1/P-glycoprotein expression: An Italian Sarcoma Group trial (ISG/OS-2)

Abstract

Background: According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed.

Methods: This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m2 /d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp- patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed.

Results: In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp-, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp- patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%).

Conclusions: This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Trial registration: ClinicalTrials.gov NCT01459484.

Keywords: ATP binding cassette subfamily B member 1 (ABCB1); P-glycoprotein; adolescents and young adults (AYAs); chemotherapy; high-grade bone sarcoma; mifamurtide; osteosarcoma; pediatric bone tumors.

Conflict of interest statement

Emanuela Palmerini has served on advisory boards for Amgen, Daiichi Sankyo, Lilly, Deciphera, Eusa Pharma, and SynOx Therapeutics; has received other research support from Bristol‐Myers Squibb, Pfizer, PharmaMar, Daiichi Sankyo, and Incyte; and has received travel support from Lilly, PharmaMar, and Takeda. Virginia Ferraresi has served on advisory boards for Bristol‐Myers Squibb, Novartis, MSD, Pierre‐Fabre, and PharmaMar. Giuseppe M. Milano has served on advisory boards for GSK and Pfizer. Marco Gambarotti has received institutional funding from Amgen outside the submitted work. Paolo D’Angelo reports being a member of the Associazione Italiana di Ematologia e Oncologia Pediatrica and the International Society of Paediatric Oncology. Eric L. Staals has served on advisory boards for Daiichi Sankyo. Toni Ibrahim reports participation on a board for Amgen‐PharmaMar. Piero Picci has received institutional funding from Amgen and PharmaMar outside the submitted work. Stefano Ferrari has received honoraria from Takeda and PharmaMar. The other authors made no disclosures.

© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

Figures

Figure 1

Chemotherapy and mifamurtide schedule and doses by Pgp expression. Pgp indicates P‐glycoprotein.

Figure 2

Study profile. GR indicates good responder; Pgp, P‐glycoprotein; PR, poor responder.

Figure 3

(A) EFS among Pgp+ patients. (B) OS among Pgp+ patients. (C) EFS among Pgp+ patients according to necrosis. (D) OS among Pgp+ patients according to necrosis. (E) EFS among Pgp– patients. (F) OS among Pgp– patients. EFS indicates event‐free survival; GR, good responder; OS, overall survival; Pgp, P‐glycoprotein; PR, poor responder.