Abstract
BackgroundWhile the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors.Methods/designNinety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study’s primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. Discussion: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. Trial registrationClinicaltrials.gov identifier: NCT03511391. Registered 17 April 2018.
Highlights
While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond
Pre-clinical and clinical evidence indicate that radiotherapy can act as an in-situ cancer vaccine by inducing immunogenic cell death, triggering the release of tumor-derived antigens and attracting CD8+ T cells to the tumor and hereby leading to an increase in immunogenicity
Patients diagnosed with locally advanced or metastatic melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma or head- and neck squamous cell carcinoma will be entered in a randomized phase II trial
Summary
While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Pre-clinical and clinical evidence indicate that radiotherapy can act as an in-situ cancer vaccine by inducing immunogenic cell death, triggering the release of tumor-derived antigens and attracting CD8+ T cells to the tumor and hereby leading to an increase in immunogenicity. This can in turn elicit a – potentially systemic – anti-tumor immune response [7,8,9,10], which may lead to tumor responses outside the irradiated regions, a phenomenon called the “abscopal” effect, as previously reported in several kinds of malignancies [11,12,13,14,15]. Stereotactic body radiotherapy (SBRT) is an innovative technique which allows the safe administration of this hypofractionated radiotherapy with high precision and limited toxicity
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