A groundbreaking phase II clinical trial named AXIOM is set to explore an innovative combination of stereotactic body radiotherapy (SBRT) and immunotherapy in the battle against metastatic melanoma, a notoriously aggressive skin cancer. Despite recent advances, metastatic melanoma remains a daunting clinical challenge due to its capacity to evade immune detection and resistance to conventional treatments. Immunotherapy has revolutionized treatment paradigms over recent years, offering hope by achieving objective response rates of up to 60% and extending long-term survival for many patients. Yet, the quest to amplify these benefits and overcome treatment plateaus drives this pioneering research.
The AXIOM trial, meticulously designed as a multicenter, randomized phase II study, aims to evaluate whether combining SBRT with immunotherapy can surpass the benefits delivered by immunotherapy alone in patients harboring 1 to 5 extracranial melanoma oligometastases. Oligometastatic disease, representing a limited tumor burden with metastases confined outside the brain, presents a unique therapeutic opportunity. By targeting these limited metastases precisely with high-dose radiation, SBRT may not only ablate measurable tumors but also potentiate systemic immune responses. The intriguing synergy between SBRT and immune checkpoint inhibitors forms the scientific basis of this trial.
Preclinical studies and early clinical observations have hinted at the enhanced immunogenic effects induced by SBRT. This focused radiation modality can induce immunogenic cell death, releasing tumor-associated antigens that prime the immune system. When combined with checkpoint blockade therapies that release the brakes on T cells—such as anti-PD-1, anti-CTLA-4, and anti-LAG-3 antibodies—this effect may be magnified. The AXIOM protocol capitalizes on this synergy, delivering a biologically effective dose of at least 48 Gy₁₀ to all metastatic lesions during the first cycles of immunotherapy, with the anticipation of amplifying systemic anti-tumor immune responses.
Patient enrollment is structured around a 2:1 randomization, enrolling 129 patients overall. Eighty-six patients will receive the combined SBRT-immunotherapy regimen, while forty-three will receive immunotherapy alone as the control group, reflecting current standards of care. This design, while not powered for formal hypothesis testing between arms, is powered at 80% to detect a 15% absolute improvement in overall survival at three years in the experimental arm—a significant milestone in melanoma research.
The primary endpoint of the study is overall survival, a gold standard measure reflecting meaningful clinical benefit. Equally critical are the secondary endpoints, including progression-free survival, tumor response rates, local control of irradiated lesions, safety profiles, and quality-of-life assessments. These secondary measures will provide a comprehensive understanding of the therapeutic impact and tolerability of the combined modality approach.
Importantly, AXIOM incorporates robust correlative translational research designed to interrogate biomarkers that may predict therapeutic response, resistance mechanisms, or toxicity. These investigations could unravel the complex interplay between tumor biology, immune environment, and radiation-induced modulation, paving the way for personalized medicine in melanoma treatment.
The potential implications of this trial are profound. Should concurrent SBRT and immunotherapy demonstrate superior efficacy and maintain an acceptable safety profile, it would challenge the current treatment paradigm. It may shift the therapy landscape towards aggressive local control of oligometastatic lesions integrated with systemic immunomodulation, maximizing survival outcomes.
Melanoma’s notorious ability to escape immune surveillance underscores the importance of innovative approaches like AXIOM. By potentially enhancing the immunogenicity of tumors through precise radiation-induced antigen release, combined with checkpoint inhibition, this strategy aims to transform the tumor microenvironment from immunosuppressive to immunostimulatory.
Moreover, the careful timing of SBRT delivery during early immunotherapy cycles exemplifies strategic therapeutic sequencing intended to optimize immune activation while minimizing adverse effects. Managing potential overlapping toxicities between radiotherapy and immunotherapy remains a crucial aspect of the study’s safety evaluation.
The multicenter nature of AXIOM ensures diverse patient enrollment, enhancing the generalizability of findings across varied clinical settings. This collaborative effort exemplifies the cutting-edge integration of radiation oncology and immunotherapy disciplines toward a common goal.
By systematically addressing the efficacy and safety of combined modality therapy, AXIOM also serves as a foundational study informing the design of future, larger phase III trials. These larger studies will be critical to conclusively define the role of SBRT-immunotherapy combinations in routine clinical practice.
If successful, AXIOM’s findings may lead to refined patient selection criteria, identifying those most likely to benefit based on clinical, pathological, or biomarker profiles. Personalized approaches will increase therapeutic precision, improve outcomes, and reduce unnecessary toxicities.
In the broader context, AXIOM represents a vital step forward in the dynamic evolution of cancer treatment paradigms. It integrates multidisciplinary advances and addresses unmet needs in metastatic melanoma, a disease where innovative strategies are urgently required.
As clinical oncology continues to embrace combination therapies, the insights from AXIOM will illuminate pathways for integrating local and systemic treatments, potentially applicable beyond melanoma to other oligometastatic malignancies.
Overall, the AXIOM trial embodies cutting-edge translational research, marrying technical sophistication in radiotherapy with immunological innovation. Its outcomes could herald a new era of synergistic cancer therapy, amplifying hope for patients with limited metastatic melanoma.
Subject of Research: Evaluation of concurrent stereotactic body radiotherapy combined with immunotherapy versus immunotherapy alone in patients with 1–5 extracranial melanoma oligometastases.
Article Title: Study protocol of a randomised phase II trial of concurrent stereotactic body radiotherapy with immunotherapy versus immunotherapy alone in patients with 1–5 extracranial melanoma oligometastases (AXIOM).
Article References:
Hong, A.M., Wang, T., Carlino, M.S. et al. Study protocol of a randomised phase II trial of concurrent stereotactic body radiotherapy with immunotherapy versus immunotherapy alone in patients with 1–5 extracranial melanoma oligometastases (AXIOM). BMC Cancer 25, 1615 (2025). https://doi.org/10.1186/s12885-025-15066-z
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