Stereotactic Ablative Radiotherapy (XRT) and Immunotherapy for Oligometastatic Extracranial Melanoma (AXIOM)

A Phase II, Multicentre, Non-Comparative, Randomised Controlled Trial of Stereotactic Ablative Body Radiotherapy and Immunotherapy Versus Immunotherapy Alone in Patients With Treatment Naïve Oligometastatic Extracranial Melanoma

The purpose of this research is to evaluate the addition of radiotherapy to the standard immunotherapy drugs that are given to patients with advanced or metastatic melanoma that has spread to other parts of the body. Radiotherapy uses x-rays to target and kill melanoma cells and immunotherapy works by activating the body's own immune system to seek out and fight melanoma cells. Both of these treatments are commonly given to patients with advanced melanoma and other cancers. Both treatments are usually given separately but can also be given together. The aim of this research is to find out if giving radiotherapy and immunotherapy together is better than giving immunotherapy alone.

The type of radiotherapy to be used in this project is known as 'stereotactic' body radiotherapy or SBRT (also known as stereotactic body ablative radiotherapy, SABR). SBRT targets the radiation very precisely at the metastatic deposits in the body. This method protects the healthy areas near the melanoma. SBRT works by delivering a high dose of radiation precisely to the areas of melanoma which causes the melanoma cells to break apart and eventually die. SBRT is given in 'fractions' which means the high dose is given in small measures over several days, depending on the number and size of metastases.

Study Overview

• Status: Recruiting
• Conditions: Melanoma Metastatic
• Intervention / Treatment: Drug: Immunotherapy alone; Other: Stereotactic Body Radiotherapy (extracranial) concurrent with Immunotherapy

Detailed Description

One of the promising treatment combinations for metastatic melanoma is the use of radiotherapy with immune checkpoint inhibitors. There have been multiple reports of the synergy between radiation and immunotherapy in preclinical studies and early phase clinical trials. This combination improves response rates compared to immunotherapy alone and without worsening the toxicity associated with each agent alone. Radiation has the potential to convert tumours considered immunologically "cold" into "warm" through the combination of three processes: 1) Changes in the balance of cytokines by increasing the production of immunostimulatory cytokines which overcome the immunosuppressive tumour microenvironment, 2) Recruitment, of antigen-presenting cells and immune effector cells in the tumour microenvironment, 3) Positive regulation of antigen expression, antigen processing, histocompatibility molecules, and costimulatory signals, thereby increasing tumour immunogenicity.

There is a significant body of data to suggest a reproducible clinical benefit can be achieved when stereotactic body radiotherapy (SBRT) is used with immunotherapy in a tightly sequenced treatment combination, in contrast to independently timed use of either treatment alone, for the management of a variety of malignancies. In metastatic non-small cell lung cancer, a pooled analysis of two randomised trials showed that the addition of radiotherapy improved the out-of-field response rate, progression-free survival, and the overall survival. In the Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Tumors trial (SABR-COMET - NCT01446744) of 1-5 oligo metastases in all tumour histologies, the 8-year overall survival was 27.2% in the experimental SBRT arm versus 13.6% in the palliative radiotherapy control arm (with the goal of alleviating symptoms) (hazard ratio, 0.50; 95% confidence interval, 0.30-0.84; P = 0.008). The eight-year progression free survival estimates were 21.3% versus 0.0%, respectively (hazard ratio, 0.45; 95% confidence interval, 0.28-0.72; P <0.001) (Harrow, Palma et al. 2022). There are two ongoing phase 3 randomised trials of SABR with standard of care (palliative radiotherapy with or without systemic anti-cancer therapy) vs standard of care alone for patients with 1-3 solid cancer metastases (SABR-COMET 3) and 4-10 metastases (SABR- COMET 10).

At present, patients with metastatic melanoma receive various treatment modalities in different combinations and sequencing, including a drug alone approach, palliative radiotherapy for symptom control, SBRT to persistent disease as salvage therapy if all or some metastases do not respond to initial drug therapy, and surgery. There is an ongoing randomised trial examining the role of upfront stereotactic radiosurgery to asymptomatic melanoma brain metastases in patients receiving concurrent combination of ipilimumab and nivolumab (Clinical Trials.gov Identifier: NCT03340129). However, there is no prospective randomised trial on the role of SBRT with immunotherapy in patients with extracranial melanoma oligometastases.

The AXIOM trial seeks to determine the role of upfront SBRT in patients with 1-5 extracranial melanoma oligometastases treated with concurrent immunotherapy. The efficacy of immunotherapy in this patient population is well established and therefore this randomised controlled study design is non-comparable with the control group. The randomisation ratio of 2:1 will provide more information on the response and safety of SBRT and immunotherapy, whilst limiting the number of patients randomised to the 'control' group, in order to provide minimum but contemporary immunotherapy efficacy and safety data.

The hypothesis is that for patients with extracranial melanoma oligometastases, concurrent stereotactic body radiotherapy with immunotherapy is safe and prolongs survival through enhanced anti-tumour immunity due to the potential synergy of the combination therapies, than immunotherapy alone.

• Study Type: Interventional
• Enrollment (Estimated): 129
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Monica Osorio; Phone Number: +61 2 9911 7296; Email: monica.osorio@melanoma.org.au

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital
      • Principal Investigator: Tim Wang
    • Wollstonecraft, New South Wales, Australia, 2065
      • Recruiting
      • Melanoma Institute Australia
      • Contact: Maria Gonzalez; Phone Number: +612 9911 7200; Email: maria.gonzalez@melanoma.org.au
      • Principal Investigator: Angela Hong
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Principal Investigator: Mark Pinkham
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • The Alfred Hospital
      • Principal Investigator: Jeremy Ruben
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Recruiting
      • Princess Margaret Cancer Centre
      • Principal Investigator: Philip Wong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female or male patients, age 18 or older
• Willing to provide signed informed consent
• Life expectancy > 6 months
• First presentation of AJCC Stage IV (any N, M1a, M1b, M1c), histologically confirmed cutaneous, acral or unknown primary melanoma with one to five extracranial metastases detected on CT and whole body PET-CT, and considered unresectable
• A primary lesion and / or up to 4 in-transit metastases(is) (ITM) in addition to distant metastases(is) are permitted and will be counted in the maximum number of permitted baseline lesions
• Prior surgery for symptomatic disease (e.g. small bowel obstruction) for this first presentation of Stage IV melanoma is permitted, provided the total number of remaining extracranial metastases is ≤ 5 (NOT including the resected lesion). No more than one excised metastatic lesion is permitted
• At least one metastasis should be measurable as a target lesion per RECIST version 1.1
• No evidence of cerebral metastases on MRI brain (CT brain is acceptable if there is contraindication to MRI)
• All lesions can be treated with a minimum SBRT biologically effective dose (BED) of 48Gy
• Able to tolerate treatment with immunotherapy as determined by the medical oncologist
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of randomisation

Exclusion Criteria:

• Ocular or mucosal melanoma
• Serious or unstable medical co-morbidities or other conditions that could interfere with the patient's safety, consent, or compliance
• Patients for whom there is a definite and immediate indication for radiotherapy (e.g., spinal cord compression, rapidly progressing disease associated with clinical signs and symptoms)
• Prior radiotherapy for Stage IV disease (prior adjuvant radiotherapy to primary site or nodal field (Stage I-III disease) is permitted, however adjuvant-treated sites must not be included in the baseline lesions
• Inability to treat all disease sites with SBRT as determined by radiation oncologist
• Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting for Stage I-III disease
• Any contraindication to the planned standard of care immunotherapy regimen per regulatory approved product information
• For patients with liver metastases - moderate/severe liver dysfunction
• A known history of another malignancy or concurrent malignancy unless the patient is disease-free for a minimum of 1 year, is completely treated and is at low risk of recurrence
• Pregnant or breastfeeding females

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm B: Immune checkpoint inhibitor(s); Immunotherapy alone Standard of care 1st line immunotherapy, as decided by the treating clinician and in accordance with the current listing on the Australian Register of Therapeutic Goods (ARTG) or applicable international regulatory agency will be administered alone.	Drug: Immunotherapy alone; All patients will receive standard of care 1st line immunotherapy as decided by the treating clinician and in accordance with the current listing on the Australian Register of Therapeutic Goods (ARTG) or applicable international regulatory agency.; Other Names: Immune checkpoint inhibitor; First line treatment; Standard of care immunotherapy
Experimental: Arm A: Concurrent stereotactic body radiotherapy + Immune checkpoint inhibitor(s); Concurrent stereotactic body radiotherapy (SBRT) with standard of care immune checkpoint inhibitor(s) (ICI). Patients will receive a minimum SBRT biologically effective dose (BED) of 48Gy10 to all sites of metastatic disease between cycle 1 and cycle 3 of immunotherapy. The interval between cycles 1 and 3 will depend on the prescribed immunotherapy regimen that is standard of care at each participating site. Standard of care 1st line immunotherapy, as decided by the treating clinician and in accordance with the current listing on the Australian Register of Therapeutic Goods (ARTG) or applicable international regulatory agency will be administered concurrently	Radiation: Stereotactic Body Radiotherapy (extracranial) concurrent with immunotherapy; A minimum SBRT biologically effective dose (BED) of 48Gy10 to all sites of extracranial metastatic disease should be administered between cycle 1 and cycle 3 of standard of care immunotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Proportion of patients alive at 6 months 1, 2, 3 and 5 years from the time of randomization	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall progression-free survival	Proportion of patients alive and with no evidence of disease progression or new melanoma lesions as assessed by RECIST 1.1 criteria	5 years
Progression-free survival related to new lesions only	Proportion of patients alive and with no evidence of new melanoma lesions as assessed by RECIST 1.1 criteria	5 years
Overall response rate	Overall response rate from the time of randomization to the best response as assessed by RECIST 1.1	5 years
Safety and tolerability of each treatment arm and study procedures	Proportion of patients with adverse events related to SBRT alone, combined SBRT and immunotherapy, immunotherapy-related Suspected Unexpected Serious Adverse Reaction (SUSAR), or related to study specific procedures with causality determined by the investigator and described per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Only AEs greater than CTCAE grade 1 will be recorded.	5 years
The requirement for immunosuppressive agents to treat adverse events	Proportion of patients receiving corticosteroids or other immunosuppressive agents to treat each adverse event including duration and maximum dose.	5 years
Patient reported quality of life	The mean change from baseline quality of life scores [EuroQol Group Association ED-5Q-5L and European Organisation for Research and Treatment of Cancer QLQ-C30] from randomization to best and lowest scores for each instrument.	5 years
Salvage radiotherapy in the immunotherapy alone arm	The incidence of salvage radiotherapy for symptomatic control or progressing baseline lesions or new metastasis(es) in the immunotherapy arm.	5 years
Local control of the initial oligometastases	The proportion of patients with local control of all baseline metastases: complete response, partial response or stable disease) as assessed per RECIST 1.1 criteria	5 years

Collaborators and Investigators

• Sponsor: Melanoma Institute Australia
• Investigators: Study Chair: Angela Hong, Melanoma Institute Australia

Publications and helpful links

General Publications

• Hong AM, Wang T, Carlino MS, Lo SN, Menzies AM, da Silva IP, Long GV. 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. 2025 Oct 21;25(1):1615. doi: 10.1186/s12885-025-15066-z.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2025
• Primary Completion (Estimated): April 1, 2033
• Study Completion (Estimated): April 1, 2033

Study Registration Dates

• First Submitted: January 4, 2025
• First Submitted That Met QC Criteria: January 8, 2025
• First Posted (Actual): January 9, 2025

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 3, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Quality of life; Immunotherapy; Immune Checkpoint Inhibitors; Biomarkers; stereotactic body radiotherapy; Oligometastases; SABR; Stereotactic Ablative Body Radiotherapy; SABRT; Extracranial
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Biological Therapy; Immunomodulation; Immune Checkpoint Inhibitors; Radiosurgery; Immunotherapy
• Other Study ID Numbers: MIA2024/508

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No