Clinical Trial Finder

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

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.#46;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.

Arms

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.

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.

Interventions

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.

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.