Abstract
BACKGROUND: Immunotherapy has significantly improved survival in patients with metastatic melanoma, achieving objective response rates of 45-60% and long-term survival. However, there is scope and a need to further improve outcomes. Preclinical and early clinical data suggest synergistic effects between stereotactic body radiotherapy (SBRT) and checkpoint inhibitor immunotherapy with an acceptable safety profile. METHODS: AXIOM is a phase II, multicentre, randomised trial designed to evaluate the effectiveness and safety of upfront SBRT to all radiologically identified metastasis with immunotherapy over historical immunotherapy alone (standard of care) in patients with 1-5 extracranial melanoma oligometastases. The sample size calculation is based on a single-arm design along with a contemporary control arm to confirm historical data, without a formal comparison between the two arms. The study is 80% powered to detect a 15% absolute improvement in OS rate at the 3-year landmark in the interventional arm. A total of 129 patients will be randomised in a 2:1 ratio to receive either SBRT combined with immunotherapy (n = 86) or immunotherapy (n = 43). SBRT delivers minimum biologically effective dose of 48 Gy₁₀ to all lesions between cycles 1-3 of immunotherapy. Immunotherapy options include anti-PD-1 monotherapy or combination with anti-CTLA-4 or anti-LAG-3 agents. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, overall response rate, local control, safety, and quality of life assessment. Correlative translational studies will explore potential predictive and prognostic biomarkers related to response, resistance or toxicity to treatment. CONCLUSION: The results will inform the design of larger phase III trials and may identify patient subgroups most likely to benefit from combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06767306.