1625MO - ABCB1/P-glycoprotein (Pgp) expression as stratification factor for treatment of patients with non metastatic extremity high grade osteosarcoma: An Italian Sarcoma Group (ISG) multicentric prospective trial (ISG/OS-2)

Background

Overexpression of ABCB1/P-glycoprotein (Pgp) predicts poor outcome in retrospective osteosarcoma series. Two prospective trials with Pgp expression as stratification factor were activated in Italy and Spain.

Methods

Patients ≤ 40 years with extremity high-grade osteosarcoma were eligible. Pgp expression was centralized. Preoperatively, all patients received MAP (methotrexate, adriamycin, platinum). In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months than weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor response (PR) to MAP. Patients without overexpression of Pgp (Pgp-) received MAP postoperatively, regardless the pathological response. From March 2013, an amendment increased high dose methotrexate (HDMTX) cumulative dose from 60 g/m2 (5 cycles) to 120 mg/m2 (10 cycles). In the same period, this regimen was adopted in an observational prospective study performed by the Spanish Sarcoma Group (GEIS) (NCT04383288).

Results

From June 2011 to March 2018, 291 ISG patients were screened and 279 were included: 110 were Pgp-, 154 were Pgp+, while in 15 patients Pgp expression was not evaluable. With a median follow-up of 58 months (range 1.2 – 102.2), the 3-year EFS and OS were 65.5% (95% CI 59.4-70.9) and 85.8% (95% CI 81-89.6), respectively, with improved survival after 10 HDMTX cycles (table). Table: 1625MO

°not evaluable in 15 patients

Conclusions

In this prospective uncontrolled study, EFS compared favorably with all our previous series. With a limited number of HDMTX cycles, EFS was suboptimal, and significantly improved after an amendment increasing HDMTX cycles to 10. Pgp+ patients performed well in this study, in which they were added mifamurtide and HDIFO after a PR to MAP: a pre-planned merged analysis of this study with a twin GEIS observational series is ongoing.

Clinical trial identification

NCT01459484; Eudract: 2011-001659-36.

Editorial acknowledgement

Legal entity responsible for the study

Italian Sarcoma Group (ISG).

Funding

The Onlus Association “Il Pensatore - Matteo Amitrano”; Fondazione Carisbo Clinical and Translational Research Grant 2019.

Disclosure

E. Palmerini: Honoraria (institution), Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Eusa Pharma ; Advisory/Consultancy: Deciphera; Honoraria (self), Travel/Accommodation/Expenses: Eli Lilly; Travel/Accommodation/Expenses: Takeda; Travel/Accommodation/Expenses, Non-remunerated activity/ies: PharmaMar; Honoraria (self), Honoraria (institution): Amgen; Non-remunerated activity/ies: Bristol Mayer Squibb; Non-remunerated activity/ies: Pfizer. M. Gambarotti: Honoraria (self), Honoraria (institution): Amgen. P.G. Casali: Honoraria (self): Bayer; Honoraria (self): Deciphera; Honoraria (self): Eisai; Honoraria (self): Eli Lilly; Honoraria (self): Nektar Therapeutics ; Honoraria (self): Pfizer; Honoraria (institution): Advencen Laboratories; Honoraria (institution): Amgen Dompé; Honoraria (institution): AROG Phaermaceuticals; Honoraria (institution): Bayer; Honoraria (institution): Blueprint medicines; Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Deciphera; Honoraria (institution): Eisai; Honoraria (institution): Eli Lilly; Honoraria (institution): Epizyme Inc; Honoraria (institution): Glaxo; Honoraria (institution): Karyopharm Pharmaceuticals; Honoraria (institution): Novartis; Honoraria (institution): Pfizer; Honoraria (institution): PharmaMar. P. Picci: Honoraria (self), Travel/Accommodation/Expenses: Takeda; Honoraria (self), Honoraria (institution): Amgen. S. Ferrari: Honoraria (self): Takeda. All other authors have declared no conflicts of interest.