Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial
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Updated: Apr 19, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Giovanni Grignani1, Emanuela Palmerini2, Virginia Ferraresi3
1Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.
Background:
Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment.
Methods:
We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374.
Findings:
We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths.
Interpretation:
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 PFS of 50% or greater.
Funding:
Italian Sarcoma Group.
Insights
Sorafenib combined with everolimus showed activity in advanced osteosarcoma, but did not meet the target 6-month progression-free survival. Further research is needed for this difficult-to-treat cancer.
Area of Science:
- Oncology
- Medical Research
Background:
- Sorafenib demonstrated limited efficacy in unresectable advanced and metastatic osteosarcoma.
- The mTOR pathway is implicated in treatment resistance to sorafenib.
- mTOR inhibitors may overcome resistance, suggesting combination therapy potential.
Purpose of the Study:
- To investigate the efficacy of sorafenib plus everolimus in patients with advanced, inoperable, high-grade osteosarcoma.
- To evaluate the 6-month progression-free survival (PFS) as the primary endpoint.
Main Methods:
- A non-randomized phase 2 trial conducted across three Italian Sarcoma Group centers.
- 38 adult patients with relapsed or unresectable osteosarcoma received daily sorafenib (800 mg) and everolimus (5 mg).
- Treatment continued until disease progression or unacceptable toxicity; intention-to-treat analysis was performed.
Main Results:
- 17 out of 38 patients (45%) achieved 6-month progression-free survival.
- Dose reductions or interruptions occurred in 66% of patients due to toxic effects.
- Common grade 3-4 adverse events included lymphopenia, hypophosphatemia, hand and foot syndrome, and thrombocytopenia.
Conclusions:
- The combination of sorafenib and everolimus demonstrated activity in advanced osteosarcoma patients.
- The study did not meet the predefined target of 50% or greater 6-month PFS.
- This combination may be considered a further-line treatment option, despite not reaching the primary endpoint.
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