• Giovanni Grignani, Emanuela Palmerini, Virginia Ferraresi, Lorenzo D'Ambrosio, Rossella Bertulli, Sebastian Dorin Asaftei, Angela Tamburini, Ymera Pignochino, Dario Sangiolo, Emanuela Marchesi, Federica Capozzi, Roberto Biagini, Marco Gambarotti, Franca Fagioli, Paolo Giovanni Casali, Piero Picci, Stefano Ferrari, Massimo Aglietta, and Italian Sarcoma Group.
• Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. Electronic address: giovanni.grignani@ircc.it.
• Lancet Oncol. 2015 Jan 1; 16 (1): 98-107.

BackgroundResults 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.MethodsWe 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.FindingsWe 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.InterpretationAlthough 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.FundingItalian Sarcoma Group.Copyright © 2015 Elsevier Ltd. All rights reserved.

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