Lenvatinib Plus Chemotherapy Promising For Relapsed, Refractory Osteosarcoma

Author: By Shreeya Nanda, Senior medwireNews Reporter 

medwireNews: The combination of lenvatinib and etoposide plus ifosfamide has antitumour activity and manageable tolerability in patients with relapsed or refractory osteosarcoma, report trial investigators in The Lancet Oncology. 

Writing in a related commentary, Piotr Rutkowski, from the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland, says that based on these phase I/II results, “[w]e cannot definitively state that combining systemic chemotherapy with lenvatinib is a better option than standard treatment with etoposide plus ifosfamide or monotherapy with tyrosine kinase inhibitors.” 

But he hopes that the ongoing randomised phase II trial of the combination will “shed light on the efficacy of antiangiogenic drugs as additives to systemic chemotherapy.” 

The current study comprises multiple cohorts, including a dose-finding phase I cohort with 22 osteosarcoma patients aged 2–25 years and a phase II expansion cohort with 20 patients, all of whom had relapsed or refractory disease and had received no more than one prior VEGF- or VEGF receptor-targeted therapy, although there was no other limit regarding previous therapies. 

In phase I, participants received the multikinase inhibitor lenvatinib at a starting daily dose of 11 mg/m2 (capped at 24 mg per day) alongside up to five 21-day cycles of etoposide 100 mg/m2 plus ifosfamide 3000 mg/m2 on days 1–3 of each cycle, with single-agent lenvatinib continued thereafter until disease progression or toxicity. 

Dose-limiting toxicities with the combination were observed in one patient receiving lenvatinib 11 mg/m2 per day and two patients receiving lenvatinib 14 mg/m2 per day, and the latter was determined as the recommended phase II dose, report Nathalie Gaspar, from Gustave Roussy Cancer Centre in Villejuif, France, and co-researchers. 

They then pooled the data for the 35 patients treated at the recommended phase II dose in either cohort, and found that the binomial estimate for progression-free survival (PFS) at 4 months was 51%, while the Kaplan–Meier estimate gave a rate of 80% at this timepoint. 

The median PFS and overall survival durations were 8.7 and 16.3 months, respectively. 

Reporting on the toxicity of the combination, the researchers say that “[o]verall, the safety profile aligned with safety profiles of each study drug, and no unexpected adverse events were observed.” 

In the pooled lenvatinib 14 mg/m2 per day group, the most common treatment-emergent adverse events of grade 3–4 were neutropenia and thrombocytopenia, occurring in 77% and 71% of participants, respectively, followed by anaemia and decreased white blood cell counts, each in 54%. 

There were two grade 5 events – one case each of dyspnoea and malignant neoplasm progression – but these were judged by the investigators to be unrelated to the study treatment. 

Discussing the findings, the study authors note that the PFS rate of 51% was higher “than that previously observed (32%) with lenvatinib 14 mg/m2 per day in the single-agent cohort of this study”, and is also “favourable compared with other studies in the same population” that show rates ranging from 42% with cyclophosphamide plus etoposide to 46% with sorafenib monotherapy, but they stress that cross-trial comparisons have limitations. 

Nevertheless, the team believes that the combination warrants further investigation in this patient population. 

References 

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; Advance online publication 17 August 2021. doi: 10.1016/S1470-2045(21)00387-9

Rutkowski P. Antiangiogenic agents combined with systemic chemotherapy in refractory osteosarcoma. Lancet Oncol; Advance online publication 17 August 2021. doi: 10.1016/S1470-2045(21)00422-8