In a pooled analysis of the Italian Sarcoma Group (ISG/OS-2) and Spanish Sarcoma Group (GEIS-33) trials reported in the Journal of Clinical Oncology, Palmerini et al found evidence of activity with the addition of mifamurtide to chemotherapy in patients with nonmetastatic high-grade osteosarcoma with unfavorable prognoses based on P-glycoprotein (Pgp) expression.
Study Details
In the pooled studies, 398 ABCB1/Pgp-positive patients (aged ≤ 40) with localized extremity disease were enrolled between March 2013 and April 2018. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatin (MAP). After surgery, mifamurtide was added in patients with Pgp overexpression (Pgp-positive disease), in combination with one cycle of doxorubicin and four consecutive cycles of high-dose ifosfamide (HDIFO) for those with poor histologic response or in combination with MAP for those with good response. Patients who were Pgp-negative received postoperative MAP. The primary outcome measure was 5-year event-free survival.
Key Findings
The median patient age was 14 years (range = 4–40 years), 211 (53%) had Pgp-positive tumors, and 204 (51.3%) received mifamurtide. At a median follow-up of 70 months (interquartile range = 49–90 months), among all patients, the 5-year event-free survival rate was 65.2% (95% confidence interval [CI] = 60.1%–69.8%), and the 5-year overall survival rate was 74.8% (95% CI = 69.8%–79.0%).
The event-free survival rate at 5 years was 71.4% (95% CI = 64.5%–77.1%) in those given mifamurtide plus chemotherapy vs 58.3% (95% CI = 50.6%–65.3%) in those given chemotherapy (P =.01). On multivariate analysis, use of mifamurtide was associated with a borderline significant advantage (hazard ratio for no use vs use = 1.4, 95% CI = 1.0–2.0, P = .0593).
The overall survival rate at 5 years was 75.4% (95% CI = 68.4%–81.1%) with mifamurtide plus chemotherapy vs 65.8% (95% CI = 57.8%–72.6%) with chemotherapy (P = .01). On multivariate analysis, the hazard ratio for no use vs use of mifamurtide was 1.4 (P = .1480).
The investigators concluded: “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.”
Emanuela Palmerini, MD, PhD, of the Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Associazione Onlus Il Pensatore: Matteo Amitrano, Associazione Mario Campanacci, and others. For full disclosures of all study authors, visit ascopubs.org.
