A recent phase II study (OLIE) published in JAMA Oncology reveals that the addition of lenvatinib to ifosfamide and etoposide did not significantly improve progression-free survival (PFS) in children and young adults with relapsed or refractory osteosarcoma. The global, open-label trial, involving 81 patients aged 2-25 years, highlights the challenges in treating this aggressive bone cancer and underscores the need for continued research in this area.
The study, led by Nathalie Gaspar, MD, PhD, from Gustave Roussy Cancer Campus, randomly assigned patients to receive lenvatinib at 14 mg/m2 daily in combination with ifosfamide (3,000 mg/m2) and etoposide (100 mg/m2) for up to five 21-day cycles, or ifosfamide/etoposide alone. The primary endpoint was progression-free survival assessed by independent imaging review.
Key Findings on Efficacy
Median follow-up was 12.2 months (95% CI = 9.5-14.1 months). The median progression-free survival was 6.5 months (95% CI = 5.7-8.2 months) in the lenvatinib group compared to 5.5 months (95% CI = 2.9-6.5 months) in the control group, with a hazard ratio (HR) of 0.54 (95% CI = 0.27-1.08, one-sided P = .04). Although the hazard ratio favored the lenvatinib arm, the result did not reach the prespecified one-sided significance threshold of 0.025. The rate at 4 months was 76.3% vs 66.0%.
Interestingly, median overall survival (OS) was 11.9 months (95% CI = 10.1 months to not estimable) in the lenvatinib group versus 17.4 months (95% CI = 14.2 months to not estimable) in the control group (HR = 1.28, 95% CI = 0.60-2.70, one-sided nominal P = .75). A total of 14 patients in the control group (34.1%) crossed over to receive lenvatinib upon disease progression.
Safety Profile
The addition of lenvatinib to ifosfamide/etoposide was associated with increased toxicity. Grade ≥ 3 treatment-related adverse events occurred in 89.7% of patients in the lenvatinib group compared to 79.5% in the control group. Treatment-related serious adverse events were also more frequent in the lenvatinib arm (59.0%) versus the control arm (30.8%). Notably, treatment-related pneumothorax occurred in 17.9% of patients receiving lenvatinib, while no cases were reported in the control group.
Implications for Future Research
Despite not meeting the primary endpoint, the investigators emphasized the importance of international collaboration and randomized clinical trials in rare cancers like relapsed osteosarcoma. The study may inform future trial designs and highlights the need for novel therapeutic strategies in this challenging patient population. As Dr. Gaspar noted, the study underscores "the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design."
The study was supported by Eisai Inc and Merck Sharp & Dohme LLC.
