(P 043) A MULTICENTER, OPEN-LABEL, RANDOMIZED, PHASE 2 STUDY OF LENVATINIB IN COMBINATION WITH IFOSFAMIDE AND ETOPOSIDE VERSUS IFOSFAMIDE AND ETOPOSIDE IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH RELAPSED OR REFRACTORY OSTEOSARCOMA

Objective: We report the primary analysis of progression-free survival (PFS) from a global, open-label, randomized, phase 2 study (OLIE) that explored the efficacy and safety of lenvatinib + ifosfamide + etoposide (Len + Ifo + Eto) versus Ifo + Eto in children, adolescents, and young adults with relapsed/refractory (r/r) osteosarcoma, in collaboration with the Innovative Therapies for Children with Cancer (ITCC) consortium (NCT04154189; ITCC-082).

Methods: Patients (pts) aged 2–25 years with r/r osteosarcoma (after 1–2 prior lines of systemic therapy) that was measurable or evaluable per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), were randomly assigned 1:1 to receive either Len 14 mg/m2 daily + Ifo 3000 mg/m2/d + Eto 100 mg/m2/d or Ifo 3000 mg/m2/d + Eto 100 mg/m2/d. Treatment was received in 21-day cycles, Ifo and Eto were both given intravenously on days 1–3 of each cycle for up to 5 cycles; pts in the Len + Ifo + Eto arm could continue Len after 5 cycles until discontinuation criteria were met. Randomization was stratified by the time from diagnosis to first r/r disease ( < 18 or ≥ 18 months) and by age ( < 18 or ≥ 18 years). The primary endpoint was PFS per RECIST v1.1 by independent imaging review (IIR), with an assumed hazard ratio of 0.4, a 1-sided type 1 error rate of 0.025, and a power of 80%. Secondary endpoints included PFS at 4 months (PFS4), overall survival (OS), and safety/tolerability. Pts could have surgery to remove baseline lesions after the week 18 tumor assessment, and pts in the Ifo + Eto arm could cross over to receive Len following disease progression assessed by IIR.

Results: 81 Pts were randomly assigned: 40 to Len + Ifo + Eto and 41 to Ifo + Eto. 39 Pts in each arm received treatment. 20 Pts in the Len + Ifo + Eto arm and 18 in the Ifo + Eto arm had received Ifo as prior therapy. As few pts ( < 15% per arm) enrolled had r/r disease occurring ≥ 18 months from diagnosis, the time to first r/r disease stratum was not applied to the efficacy analysis. By the data cutoff date (June 22, 2022), 14 pts had crossed over from the Ifo + Eto arm to receive Len ± (Ifo + Eto). The median duration of follow-up was 11.6 months (95% CI 9.1–12.7) in the Len + Ifo + Eto arm and 13.8 months (95% CI 9.3–15.3) in the Ifo + Eto arm.

Median PFS was 6.5 months (95% CI 5.7–8.2) in the Len + Ifo + Eto arm and 5.5 months (95% CI 2.9–6.5) in the Ifo + Eto arm (HR 0.54 [95% CI 0.27–1.08]; P = 0.0396); PFS4 was 76.3% (95% CI 59.3–86.9) in the Len + Ifo + Eto arm and 66.0% (95% CI 47.7–79.2) in the Ifo + Eto arm. These findings were also consistent for pts who received prior Ifo (median PFS: 6.3 vs 4.1 months for Len + Ifo + Eto vs Ifo + Eto; PFS4: 69.3% vs 63.3% for Len + Ifo + Eto vs Ifo + Eto). Median OS was 11.9 months (95% CI 10.1–not estimable [NE]) in the Len + Ifo + Eto arm and 17.4 months (95% CI 14.2–NE) in the Ifo + Eto arm (HR 1.28 [95% CI 0.60–2.70]; P = 0.7451). Notably, a smaller proportion of pts in the Len + Ifo + Eto arm versus the Ifo + Eto arm had received subsequent anticancer medication (37.5% vs 51.2%) or surgical lesion removal (22.5% vs 43.9%).

38 (97.4%) Pts in both treatment arms had a treatment-related treatment-emergent adverse event, most commonly hypothyroidism (82.1%) in the Len + Ifo + Eto arm and platelet count decreased (41.0%) in the Ifo + Eto arm. 23 Pts (59.0%) in the Len + Ifo + Eto arm and 12 (30.8%) in the Ifo + Eto arm had a treatment-related serious adverse event; most commonly febrile neutropenia in either arm (Len + Ifo + Eto: 35.9%; Ifo + Eto: 17.9%).

Conclusion: Although PFS was numerically improved with Len + Ifo + Eto (6.5 months) vs Ifo + Eto (5.5 months), the primary endpoint (PFS) was not met as the P-value was not below the boundary for significance (0.025). Greater proportions of pts in the Ifo + Eto arm underwent surgery or had subsequent anticancer therapy than in the Len + Ifo + Eto arm; this situation, along with pt crossover, may have impacted OS outcomes. Overall, the safety profile of Len + Ifo + Eto was consistent with the known safety profiles of the individual agents, and no new safety signals were detected. This study demonstrates the importance of intercontinental collaboration and randomized controlled trials in the treatment of pts with r/r osteosarcoma.

Clinicaltrials.gov identifier: NCT04154189

Funding source: Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC, a subsidiary of
Merck & Co., Inc., Rahway, NJ, USA. Medical writing support was provided by Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Nutley, NJ, USA, and Merck Sharp & Dohme LLC,
a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.