In the phase I/II ITCC-050 trial reported in The Lancet Oncology, Gaspar et al found that the combination of lenvatinib with etoposide/ifosfamide showed antitumor activity, including good progression-free survival outcomes, in patients with relapsed or refractory osteosarcoma.

Study Details

Patients aged 2 to 25 years from sites in six countries were enrolled between May 2016 and July 2019 into a dose-finding phase I cohort and a phase II expansion cohort. Patients could have received one previous VEGF or VEGFR inhibitor and had to have a life expectancy ≥ 3 months.

Patients received lenvatinib at a starting dose of 11 mg/m² daily, capped at 24 mg per day, and etoposide at 100 mg/m² per day plus ifosfamide at 3,000 mg/m² per day on days 1 to 3 in 21-day cycles for a maximum of five cycles. Lenvatinib monotherapy was continued after five cycles until disease progression or unacceptable toxicity.

The phase II primary endpoint was progression-free survival at 4 months calculated using a binomial estimate based on adequate tumor assessments up to week 18; patients without these data were included in the denominator but not the numerator of the binomial estimate.

Key Findings

The recommended phase II dose was 14 mg/m² per day of lenvatinib (daily dose cap of 24 mg) plus etoposide and ifosfamide dosed as above.

Among 35 patients from the phase I and II cohorts who received the recommended phase II dose, progression-free survival at 4 months was 51% (95% confidence interval [CI] = 34%–69%) in 18 patients using the binomial estimate analysis. Kaplan-Meier estimated 4-month progression-free survival was 80% (95% CI = 60%–90%) among all 35 patients. Median progression-free survival was 8.7 months (95% CI = 4.5–12.0 months).

An objective response was observed in 3 (9%) of 32 evaluable patients, with the median response duration not being estimable. The disease control rate was 71% among all 35 patients.

Among those 35 patients receiving the phase II dose, the most common grade 3 and 4 adverse events were neutropenia (77%; febrile neutropenia in 20%), thrombocytopenia (71%), anemia (54%), and decreased white blood cell count (54%). The most common nonlaboratory grade 3 and 4 adverse events were diarrhea (11%) and epistaxis (11%). Serious adverse events occurred in 74% of patients; serious adverse events were considered related to treatment in 57%, with the most common being febrile neutropenia (17%) and decreased white blood cell count (14%). No treatment-related deaths were observed.

The investigators concluded, “Lenvatinib with etoposide plus ifosfamide shows promising antitumor activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomized phase II study.”

Nathalie Gaspar, MD, of the Department of Childhood and Adolescent Cancer, Gustave Roussy Cancer Centre, Villejuif, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Eisai and Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.