Phase II study of concomitant radiotherapy with atezolizumab in oligometastatic soft tissue sarcomas: STEREOSARC trial protocol

Abstract

IntroductionUp to 50% of soft tissue sarcoma (STS) patients develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumour response rates of 25% at first line and ≤10% at later lines. In oligometastatic stage, stereotactic body radiation therapy (SBRT) allows reaching high control rates at treated sites (≥80%) and is potentially equally effective to surgery in term of overall survival. In order to shift the balance towards antitumour immunity by multisite irradiation, radiation could be combined with inhibitors of the immunosuppressive pathways.Methods and analysisSTEREOSARC is a prospective, multicentric, randomised phase II, designed to evaluate the efficacy of SBRT associated with immunotherapy versus SBRT only. Randomisation is performed with a 2:1 ratio within two arms. The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic multisite irradiation in oligometastatic sarcoma patients. The secondary objectives include PFS by immune response criteria, overall survival, quality-of-life evaluation and developing mathematical models of tumour growth and dissemination predictive of oligometastatic versus polymetastatic evolution. Patients will be randomised in two groups: SBRT with atezolizumab and SBRT alone. The total number of included patients should be 103.Trial registrationThe trial is registered on ClinicalTrials.gov (ID: NCT03548428).Ethics and disseminationThis study has been approved by Comité de Protection des Personnes du sud-ouest et outre-mer 4 on 18 October 2019 (Reference CPP2019-09-076-PP) and from National Agency for Medical and Health products Safety (Reference: MEDAECNAT-2019-08-00004_2017-004239-35) on 18 September 2019.The results will be disseminated to patients upon individual request or through media release from scientific meetings. The results will be communicated through scientific meetings and publications.

Current Landscape of Immunotherapy for Advanced Sarcoma

“…Following the results of SARC028, a phase II randomized trial is currently studying neoadjuvant pembrolizumab combined with RT in high-risk UPS or DDLPS of the extremities (SUC2C-SARC032) [ 127 ]. Another phase II trial (STEREOSARC) is evaluating concomitant RT with atezolizumab in oligometastatic STS [ 128 ]. There is a rationale for combining ICIs and RT since RT induces the release of TAA following immunogenic cell death, which activates TILs and leads to the recruitment of more effector cells to the TME [ 129 ].…”

Effect of Favorable Pathologic Response After Neoadjuvant Radiation Therapy Alone in Soft-tissue Sarcoma

“… 34 , 35 To this end, there has been growing interest in integrating immunomodulatory agents with RT, with the hope of a synergistic immunogenic effect. 36 , 37 Further understanding of the drivers behind the immunomodulatory effects of RT in sarcoma are required, appropriately selecting patients based on gene profiling 38 and improved understanding of the influence of tumor-infiltrating lymphocytes. 39 …”

Radiation Therapy in Metastatic Soft Tissue Sarcoma: From Palliation to Ablation

“…The study randomizes patients to SBRT and atezolizumab versus SBRT alone. The primary objective of the study is progression free survival at 6 months [ 61 ]. Results from this trial, as well as other similar trials in other malignancies, will help elucidate the potential clinical benefit of combining radiation with immunomodulatory agents.…”