Lenvatinib With Etoposide Plus Ifosfamide Shows Antitumor Activity in Refractory and Relapsed Osteosarcoma


The recommended phase 2 dose for lenvatinib was 14 mg/m2 in relapsed/refractory osteosarcoma.

Antitumor activity was found in treatment of lenvatinib (Lenvima) with etoposide plus ifosfamide and no new additional safety signals were found in patients with refractory or relapsed osteosarcoma, according to the results of a phase 1 multicenter trial (NCT02432274) published in The Lancet Oncology.

The 4-month progression-free survival (PFS) rate was 51% (95% CI, 34%-69%). The median overall survival (OS) was 16.3 months (95% CI, 12.6–not estimable) and the median follow-up time to OS was 9.6 months (IQR 7.5-18.6).

Among those who enrolled on the study, 30 patients were screened for enrollment to cohort 3A and 22 patients were screened for cohort 3B. Between the 2 groups, there were 10 patients who were ineligible for the study. In cohort 3A, 7 patients received lenvatinib at a starting dose of 11 mg/m2 per day up to 24 mg/m2 with etoposide (100 mg/m² per day) plus ifosfamide (3000 mg/m² per day). Additionally, 15 patients in cohort 3A received lenvatinib at a dose of 14 mg/m2 per day with the same chemotherapy backbone. A total of 15 patients from cohort 3A and 20 patients from 3B were included in the pooled analysis.

All patients had previously received anticancer treatment and most patients had lung metastases. During follow-up, several patients received anticancer therapy or had an anticancer procedure.

In the study’s second phase, the recommended dose for lenvatinib was determined to be 14 mg/m2 per day orally coupled with 100mg/m2 of etoposide per day plus ifosfamide at a dose of 3000 mg/m2 administered intravenously on days 1 through 3 of each 21-day cycle for a maximum of 5 cycles.

The median duration of treatment among those who received 11 mg/m2 of lenvatinib was 7.1 months compared with 5.0 months (95% CI, 2.7-9.5) in the 14 mg/m2 lenvatinib dose group. However, there were 4 patients in the 14 mg/m2 lenvatinib group who received treatment for more than a year. For patients taking etoposide (IQR 4.0-5.0) plus ifosfamide (IQR 4.0-5.0) the median number of chemotherapy cycles was 5.0 for patients in the lenvtinib 14 mg/m2 group.

The 4-month PFS was 50% (95% CI, 27%-73%) among those who received the recommended phase 2 dose. The median PFS was 8.7 months (95% CI, 4.5-12.0) and the median follow-up time for PFS was 5.8 months (IQR, 4.1-9.7).

In total, 9% (n =3) of the 32 evaluable patients (95% CI, 2-25) achieved an objective response. The duration of response was not estimable. In 71% (n = 25) of 35 evaluable patients (95% CI, 54%-85%) disease control was achieved, with a clinical benefit achieved in 37% (n =13) of evaluable patients (95% CI, 21%-55%). For patients in the Lenvatinib 14 mg/m2 group, the best overall response was pooled.

Treatment-emergent adverse effects (TEAE) led to withdrawal from all 3 agents in 14% of patients who received 11 mg/m2 of lenvatinib. The most common grade 3/4 TEAEs were neutropenia (77%), thrombocytopenia (71%), anemia (54%), and decreased white blood cell count (54%). 

Serious TEAEs occurred 71% (n = 5) of patients in the 11 mg/m2 lenvatinib group and 74% (n = 26) of patients in the 14 mg/m2lenvatinib group. Four patients experienced TEAE were related to the study drug in the 11 mg/m2 group, as well as 20 patients in the 14 mg/m2 group.

Within this study or during follow-up, 15 deaths occurred during the study and 11 deaths occurred more than 30 days after the last treatment, 4 of which considered to be treatment emergent. Grade 5 TEAE occurred in 2 patients in each group, which was determined to be from progressive disease and not treatment related. This included dyspnea, hypoxic brain injury, and malignant neoplasm progression.


Gaspar N, Venkatramani R, Hecker-Nolting S, et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. Published Online August 17, 2021. doi:10.1016/S1470-2045(21)00387-9

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