Background
Phase 2 OLIE (ITCC-082), randomized open-label multicenter. N=81 children/adolescents/young adults (age 5–25 yr) with relapsed/refractory osteosarcoma after standard first-line (MAP or similar). 20 sites Europe/North America, 2019–2022. Lenvatinib: multi-targeted RTK inhibitor (VEGFR1–3, FGFR1–4, PDGFRα, KIT, RET). Tested adding lenvatinib to ifosfamide+etoposide (IE) salvage doublet. NCT04154189.
Interventions and follow up
Arm A: Lenvatinib 14 mg/m² (≤60 kg) or 24 mg/day (>60 kg) PO daily + ifosfamide 3 g/m² IV days 1–3 q21d, up to 5 cycles, then lenvatinib monotherapy
Arm B: Ifosfamide 3 g/m² IV days 1–3 q21d, up to 6 cycles (control)
Primary endpoint: PFS (prespecified 1-sided threshold P≤.10)
mFollow up: ~12 mo
Arm B: Ifosfamide 3 g/m² IV days 1–3 q21d, up to 6 cycles (control)
Primary endpoint: PFS (prespecified 1-sided threshold P≤.10)
mFollow up: ~12 mo
Results
mPFS: 6.5 mo (lenvatinib + IE) vs 5.5 mo (IE alone); HR 0.54 (1-sided P=.04)
mOS: Similar between arms — not significantly different
Trial conclusion: Did not meet prespecified 1-sided P≤.10 threshold by primary analysis criteria; OS not significantly improved
mOS: Similar between arms — not significantly different
Trial conclusion: Did not meet prespecified 1-sided P≤.10 threshold by primary analysis criteria; OS not significantly improved
Adverse events
Lenvatinib-related: hypertension, proteinuria, diarrhea, fatigue — consistent with known pediatric profile
Grade ≥3 AEs: numerically higher in combination arm
Myelosuppression (IE): similar both arms
Dose modifications: required in a significant proportion on lenvatinib
Grade ≥3 AEs: numerically higher in combination arm
Myelosuppression (IE): similar both arms
Dose modifications: required in a significant proportion on lenvatinib
Conclusions
Adding lenvatinib to IE reduced progression risk ~46% (HR 0.54, 1-sided P=.04) in relapsed/refractory osteosarcoma but did not meet the prespecified primary threshold and did not improve OS. A potential signal warranting further study, but lenvatinib+IE cannot be recommended as standard salvage based on OLIE alone.
Key Limitations
Small phase 2 (N=81); liberal 1-sided P≤.10 threshold not met; PFS surrogate without OS benefit; open-label; unequal cycle caps (5 vs 6) between arms.
Clinical Context
No regulatory approval for lenvatinib in osteosarcoma. Relapsed osteosarcoma lacks a standard salvage regimen; IE, regorafenib, cabozantinib used off ESMO guidance. OLIE supports antiangiogenic-TKI signal but does not establish a new standard.