Off-label use of targeted therapies in osteosarcomas: data from the French registry OUTC’S (Observatoire de l’Utilisation des Thérapies Ciblées dans les Sarcomes)

Abstract

BackgroundThe objective of this study is to explore the off-label use of targeted therapies (TTs) for patients with osteosarcoma registered within the French Sarcoma Group – Bone Tumor Study Group (GSF-GETO) national registry.MethodsAll patients with an osteosarcoma, registered between January 1, 2009 and July 15, 2013 were analyzed.ResultsTwenty-nine patients with refractory relapsed osteosarcomas received 33 treatment lines of TTs. The median age at the beginning of treatment was 19 years (range 9–72). The median number of previous lines of chemotherapy was 3 (range 1–8). Before inclusion, 3 patients were in second complete remission, 26 were in progression for metastatic relapse. Twenty-three patients received sirolimus (in combination with cyclophosphamide for 18); 5, sunitinib; 4, sorafenib; and one, pazopanib. Stable disease was observed for 45.5 % of patients (95 % Confidence Interval (CI) [20–52.8]). The median Progression-Free Survival (PFS) was 3 months (95 % CI [2–5.4]) for patients treated by sirolimus and 1.8 months (95 % CI [1.3–2.8]) for patients receiving multi-targeted tyrosine kinase inhibitors; 6-month PFS 15 %. The median Overall Survival (OS) was 6.8 months (95 % CI [4.7–12.1]), and one-year OS was 24 %. In a multivariate analysis, PFS was superior for patients receiving sirolimus compared to other TTs (Hazard Ratio (HR) = 2.7, 95 % CI [1.05–7.1]). No toxic death was reported. Grade 3 and 4 toxicities were observed in 27 and 6 % of cases respectively.ConclusionOff-label TTs, especially sirolimus, reported benefit in the treatment of refractory osteosarcomas with an acceptable toxicity profile, including in pediatric population.

Prolonged response to sorafenib in a patient with refractory metastatic osteosarcoma and a somatic PDGFRA D846V mutation

“…In 35 patients with chemotherapy refractory osteosarcoma, sorafenib was found to yield progression‐free ratios at levels above those suggested in the literature for soft‐tissue sarcomas, with 14 months reported as the longest duration of use . Furthermore, in refractory relapsed osteosarcoma, off‐label use of sorafenib led to stabilization of disease in 3 of 4 patients, where the median duration of response was 3.1 months …”

Gene expression profiles and pathway enrichment analysis of human osteosarcoma cells exposed to sorafenib

“…Based on our study, we speculated that sorafenib may inhibit osteosarcoma by influencing the tumor immune microenvironment and angiogenesis process, and that the hub genes and seed gene play important roles. However, the benefit of sorafenib was small in clinical trials, and the progression of chemorefractory osteosarcoma was temporarily inhibited only [33,34]. The discrepancy between preclinical data and clinical data cannot be explained by our study and needs further research.…”

A review of the mechanism of action and clinical applications of sorafenib in advanced osteosarcoma

“…However, only 29% had stable disease at 6 months: the benefits were ultimately transient [39] . The other trial involved 4 patients with relapsed, chemorefractory osteosarcoma being treated with sorafenib [40] . Of these patients, three achieved disease stabilisations.…”

“…However, the median response duration was 3 months, after which the disease continued to progress. This study tested a number of other drugs such as sunitimab in identical circumstances, and each of these agents stabilised disease progression for a longer duration than sorafenib [40] . Thus, these trials established that chemorefractory osteosarcoma progression can be temporarily inhibited by sorafenib [39] , [40] .…”