Sorafenib Plus Everolimus Shows Some Activity in Progressive Unresectable High-Grade Osteosarcoma


Key Points

  • Six-month progression-free survival was 47%.
  • Median progression-free survival was 5 months.

In an Italian Sarcoma Group phase II study reported in The Lancet Oncology, Grignani et al found that the combination of sorafenib (Nexavar) and everolimus (Afinitor) was active in unresectable high-grade osteosarcoma progressing after standard treatment, but did not produce the study goal of ≥ 50% 6-month progression-free survival. Previous data suggested that mTOR inhibition (eg, with everolimus) might help prolong the short-term responses observed with sorafenib in this setting.

Study Details

In the study, 38 adult patients with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin with or without ifosfamide) from three Italian Sarcoma Group centers were enrolled between June 2011 and June 2013 and were treated with sorafenib at 800 mg plus everolimus at 5 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival, with a goal of ≥ 50%.


At 6 months, 17 (45%, 95% confidence interval [CI] = 28%–61%) of 38 patients were progression free. Median progression-free survival was 5 months (95% CI = 2–7 months), and eight patients (21%) received sorafenib and everolimus for ≥ 8 months. At 2 months, 63% of patients had no disease progression, with a median response duration of 5 months. There were two partial responses (10%) and two minor responses (10%), and 20 patients (53%) had stable disease.


Adverse events led to dose reductions or short interruptions in 66% of patients and discontinuation of treatment in 5%. The most common grade 3 or 4 adverse events were lymphopenia (16%), hypophosphatemia (16%), hand-foot syndrome (13%), thrombocytopenia (11%), and fatigue, oral mucositis, diarrhea, and anemia (5% each). One patient had grade 3 pneumothorax that required transthoracic drainage and that recurred at disease progression. No other serious adverse events were reported, and there were no treatment-related deaths.

The investigators concluded: “Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month [progression-free survival] of 50% or greater.”

Giovanni Grignani, MD, of Candiolo Cancer Institute-FPO, IRCCS, is the corresponding author for The Lancet Oncology article.

The study was funded by the Italian Sarcoma Group. For full disclosures of the study authors, visit

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