Adjuvant sirolimus does not improve outcome in pet dogs receiving standard of care therapy for appendicular osteosarcoma: A prospective, randomized trial of 324 dogs

Purpose: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically-achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression. Experimental design: 324 pet dogs diagnosed with treatment-naive appendicular osteosarcoma were randomized into a 2-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb followed by adjuvant carboplatin chemotherapy {plus minus} oral sirolimus therapy. The primary outcome measure was DFI, as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2- year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes. Results: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days (95% CI: 144-237), and 282 days (95% CI: 224-383); for SOC + sirolimus dogs, it was 204 days (95% CI: 157-217) and 280 days (95% CI: 252-332), respectively. Conclusions: In a population of pet dogs non-genomically segmented for predicted mTOR inhibition response, sequentially-administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend disease-free interval or survival in dogs with appendicular osteosarcoma.