This is a patient oriented translational research project aiming to improve clinical outcomes for patients with BRAF and NRAS wild-type unresectable Stage III or Stage IV metastatic melanoma who have progressed on, or are unable to receive standard therapy (in general, immunotherapy). Consecutive patients seen at three major clinics and fitting the broad eligibility criteria will be invited to participate.

The approach is designed to test the impact of different targeted drugs on different mutations in a single type of cancer. In this project, patients will have tumour tissue genetically profiled to determine which mutation(s) are present, and will then be assigned to receive a matched drug expected to target the mutation(s) in the tumour. Where multiple targets are identified in one patient, or where multiple potential therapies would be appropriate for a single tumour mutation, the treating clinician may determine the appropriate therapeutic approach after consultation with the study team, using the latest version of library of matched therapies.

Current standard of care testing covers mutations in the BRAF and NRAS genes. The comprehensive gene testing platform to be used in this project is designed to interrogate the entire coding sequence of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. These genes are known to be somatically altered in solid cancers based on recent scientific and clinical literature. The test panel will be used on melanoma tissue from patients pre-screened as having BRAF and NRAS wild-type melanoma. The extent of testing will be updated to reflect new discoveries in melanoma tumourigenesis and availability of new therapies as the project proceeds. Testing will be performed on formalin-fixed and paraffin-embedded samples of metastatic tissue. Archival tissue from primary or regional recurrent melanoma may be considered if no recent sample is available or possible.

All new patients with unresectable Stage III or IV melanoma seen at each participating site will be invited to participate. Following written consent, all patients will undergo the standard testing for BRAF and NRAS mutations. Patients found to have mutations in either gene will receive standard treatment with dabrafenib and / or trametinib and no further molecular testing.

Patients with wild type versions of BRAF and NRAS genes will have tumour tissue sent for the extended gene testing platform. These patients will first receive standard of care therapy for wild type BRAF / NRAS melanoma, where possible. Once standard therapies have been exhausted (because of disease progression or intolerable adverse events), patients will then receive a targeted therapy matched for their genetic result, if applicable. The selection of targeted therapy will be based on clinical evidence of activity in other solid tumours harbouring similar mutations and / or in at least Phase I testing in melanoma. The table of matched therapies will be modified and extended as new findings from clinical research become available. Patients may be included in specific clinical trials of targeted therapies if available, e.g. a MEK inhibitor combined with an MDM2 inhibitor (AMG232) for BRAF and TP53 wild-type melanoma or a MEK inhibitor combined with a CDK4/6 inhibitor for BRAF wild-type melanoma.

The extensive molecular profiling platform is fully validated and will be conducted by an external provider accredited by an authority with the responsibility to award Laboratory Accreditation at private and public facilities.

Inclusion criteria for Part 1:

1. Written informed consent for Part 1
2. Newly diagnosed, histologically confirmedand , unresectable Stage IIIB, IIIC or Stage IV melanoma including cutaneous (including acral, ungual subtypes), ocular (including uveal and extra-uveal), mucosal, and unknown primary).
3. Treatment-naïve for unresectable advanced orf metastatic melanoma (systemic treatment given in the neoadjuvant and adjuvant settings are acceptable).
4. Tumour tissue available from advanced or metastatic disease. Archival tissue from primary or regional recurrent melanoma may be considered if no recent sample is available.
5. Male or female patients aged 18 or over.
6. Standard of care molecular tumour testing which has identified NRAS wild type, and either BRAF wild type or non-V600 BRAF mutant melanoma.
7. Adequate tissue available for the Molecular Testing Platform.

Eligibility Criteria for NGS Molecular Testing Platform (Part 1)

1. Standard of care molecular tumour testing which has identified non V600 BRAF or BRAF wild type, or NRAS wild type melanoma (NRAS mutant patients are eligible for Part 2, but will not undergo NGS testing).
2. Adequate tissue available per NGS specimen preparation instructions.

Inclusion Criteria for Part 2:

1. Written informed consent to receive targeted therapy (if applicable) and clinical follow up.

2. Patient has undergone NGS tumour testing or has NRAS or ALKati mutant melanoma on routine testing

3. Histologically confirmed melanoma of any sub type with measurable disease per RECIST criteria.

4. Received available standard therapies or clinical trial agents for unrectable metastatic melanoma that has progressed, unable to tolerate standard therapy, or standard therapy is contraindicated.

5. Patient has an 'actionable' genetic aberration and matched targeted therapy is available. Patients with no genetic aberration or where no matched targeted therapy is available, patients will be offered trametinib

6. ECOG status 0 - 2.

7. Adequate haematological, hepatic and renal organ function as defined by:

   1. White cell count ≥ 2.0 × 109/L
   2. Neutrophil count ≥ 1.5 × 109/L
   3. Haemoglobin ≥ 90 g/L
   4. Platelet count ≥ 100 x 109/L
   5. Total bilirubin ≤ 3.0 x ULN
   6. Alanine transaminase ≤ 3.0 x ULN
   7. Aspartate aminotransferase ≤ 3.0 x ULN
   8. Serum creatinine ≤ 1.5 x the upper limit of normal (ULN).

8. Life expectancy > 30 days.

9. Women of child bearing potential (WOCBP) to use contraception to avoid pregnancy.

10. Non sterile men with female partners of CBP to use contraception to avoid pregnancy.

Exclusion criteria for Matched Targeted Therapy:

1. An expectation for the need for concurrent radiotherapy (unless safety has been established with the matched drug regimen and is directed at one anatomical region for symptom control).
2. Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug.
3. Any investigational drug or other systemic drug therapy for melanoma within 14 days or 5 half-lives from baseline, whichever is shorter.
4. Pregnant or breast feeding females.
5. Drug specific exclusions as detailed in the TGA Product Information for each drug.