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)

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/m(2)/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/m(2) (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.