Is There a Role for Mifamurtide in Nonmetastatic High-Grade Osteosarcoma? Results From the Italian Sarcoma Group (ISG/OS-2) and Spanish Sarcoma Group (GEIS-33) Trials

Abstract

Purpose: Outcome of patients with localized osteosarcoma is challenging. The role of mifamurtide is still a matter of debate. Two prospective trials were carried out in Italy (ISG/OS-2) and Spain (GEIS-33) with mifamurtide in ABCB1/P-glycoprotein (Pgp)-positive patients.

Patients and methods: Patients age ≤40 years with localized extremity high-grade osteosarcoma were eligible. Analysis of Pgp expression from diagnostic biopsy was centralized. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatinum (MAP) before surgery. Postoperatively, in case of Pgp overexpression (Pgp-positive), mifamurtide was added, combined with doxorubicin (one cycle) and four consecutive cycles of high-dose ifosfamide (HDIFO) for patients with poor histologic response, or with MAP in case of good response. Patients who were Pgp-negative received MAP postoperatively. We present the merged analysis of ISG/OS-2 and GEIS-33 trial, an observational study with same inclusion criteria and treatment of ISG/OS-2. The primary endpoint was 5-year event-free survival (EFS) according to the use of mifamurtide. Secondary endpoint was overall survival (OS).

Results: From March 2013 to April 2018, 398 patients were analyzed. The median age was 14 years (range, 4-40), male/female: 238/160 (1.48/1.0); 211 of 398 (53%) tumors were Pgp-positive, and 204 of 398 (51.3%) patients received mifamurtide. With a median follow-up of 70 months (IQR, 49-90 months), the 5-year EFS and OS were 65.2% (95% CI, 60.1 to 69.8) and 74.8% (95% CI, 69.8 to 79.0), respectively, with superior EFS for patients undergoing mifamurtide and chemotherapy as compared with EFS of patients undergoing chemotherapy alone (5-year EFS 71.4% v 58.3%; P = .0139) not confirmed at multivariable analysis (P = .0593).

Conclusion: In this merged analysis with a risk-adapted strategy for nonmetastatic osteosarcoma, the group with unfavorable prognoses, identified by Pgp expression, performed well when mifamurtide, combined with HDIFO in case of poor response, was administered after surgery.

Trial registration: ClinicalTrials.gov NCT04383288 NCT01459484.

FIG 1.

Treatment scheme of the ISG/OS-2 study by Pgp expression. HDIFO, high-dose ifosfamide; Pgp, P-glycoprotein.

FIG 2.

Probability of EFS for (A) the entire cohort and (B) by mifamurtide administration. Probability of OS for (C) the entire cohort and (D) by mifamurtide administration. EFS, event-free survival; OS, overall survival.

FIG A1.

A chronological roadmap for original manuscripts on P-glycoprotein role in osteosarcoma.

FIG A2.

Study flow diagram of the combined analysis of the Italian ISG/OS-2 and Spanish GEIS-33 studies.

FIG A3.

EFS according to induction chemotherapy and mifamurtide in (A) GRs and (B) PRs. EFS, event-free survival; GRs, good responses; HDIFO, high-dose ifosfamide; MAP, methotrexate, doxorubicin, and cisplatinum; PRs, poor responses.

FIG A4.

(A) EFS curves of Pgp-positive patients stratified according to tumor necrosis, (B) EFS curves of Pgp-negative patients stratified according to tumor necrosis. EFS, event-free survival; GR, good response; Pgp, P-glycoprotein; PR, poor response.