Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas

Bone sarcomas are rare primary bone cancers, although, their frequency has been increasing by 0.3% per year over the last decade. They include a very large number of tumour types belonging to the family of primary malignant bone tumours and originate from bone as Osteosarcomas (OS), Chondrosarcomas (CS), Fibrosarcomas, Chordomas, …

Current conventional treatments for OS combine chemotherapy and surgery. Chemotherapy treatment is commonly given for OS over a period of 6-10 months, with a period of preoperative chemotherapy, to facilitate local surgical treatment. The conventional cocktail used in OS is composed by a minimum of three drugs (reference combination: methotrexate, doxorubicin and cisplatin (MAP)).

The currently recommended treatments for Ewing sarcomas (for both localized and metastatic diseases) consist of multimodal approaches including surgery and/or radiotherapy associated to neoadjuvant and adjuvant chemotherapy, comprising respectively from 3 to 6, and then from 6 to 10 cycles. Doxorubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin and etoposide are considered as the most active substances. Current trials require combination chemotherapies, and most of them are based on the combination of 5-6 of these substances.

Concerning chondrosarcomas, the treatment is adapted according to the subtype. Thus, the treatment regimen for mesenchymal chondrosarcomas and dedifferentiated chondrosarcomas differs. Indeed, an Ewing-type chemotherapy regimen is usually suggested to treat mesenchymal chondrosarcomas while dedifferentiated chondrosarcomas are often treated as high-grade bone sarcoma, with systemic and local therapies.

Compared with surgery alone, multimodal treatment of high-grade sarcomas increases disease-free survival probabilities from only 10%-20% to 50-65% depending on the bone sarcoma type. In general, despite second-line treatment, the prognosis of recurrent disease has remained poor, with long-term post-relapse survival of <20%.

The outcome of bone sarcoma has been dramatically improved by the addition of chemotherapy in the 70' and 80' but has remained remarkably stable in the last 3 decades, with a survival rate largely plateaued, despite introduction of novel regimens, both in localized and metastatic disease, in children and in adults. Primary bone cancer presented challenges in new drug development partly because of their rarity and heterogeneity. Thus, improving treatments for these diseases is a high priority, but advances have been few in recent years. In this context, maintenance therapy may be an interesting option as a way to prolong the benefit of first-line chemotherapy.

Regorafenib may play a role in the maintenance setting for bone sarcomas (as improved Progression-Free Survival and sustained responses were observed in the REGOBONE study) in maintaining the initial response to standard treatments and delaying the need for further treatment at relapse, while exerting a manageable associated toxicity and minimal negative impact on health-related quality of life.

Currently there is no available agent used as maintenance therapy after first-line treatments. In the context of a clinical trial with close monitoring, it is, thus, acceptable to consider a placebo-control group.

On this basis, this study propose to conduct a double-blinded randomized controlled trial to evaluate the efficacy of regorafenib versus placebo in the treatment of patients with bone sarcomas, who have no evidence of disease after standard multimodal treatments based on the histological subtype.

The main goal of the present study is then to explore whether sequential addition of regorafenib after completion of a standard treatment in patients with bone sarcomas would improve outcomes in term of event-free-survival (EFS) defined by local or distant recurrence of the disease.

Results will be stratified on the "high-risk" versus "low-risk" of relapse. As response to neoadjuvant chemotherapy and metastatic status at time of diagnosis are known to be important on patient's outcome, stratification will rely on a combined criteria taking into account these two factors. Thus, "high-risk" of relapse will be defined by the group of patients who are poor responders to neoadjuvant chemotherapy and/or in metastatic setting at diagnosis, whereas "low-risk" of relapse will be defined by the group of patients who have no metastatic disease at time of diagnosis and are good responders to neoadjuvant chemotherapy.