Inclusion Criteria:
1. Provided written informed consent prior to any trial specific procedures.
2. Aged ≥18 years old.
3. An Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
4. Histologically confirmed Stage IV M1d cutaneous melanoma or unknown primary melanoma
that is metastatic to the brain.
5. Presence of BRAFV600E/K/D/R mutation according to a locally validated BRAF Assay.
6. Candidacy for SRS therapy validated by the radiation oncologist and/or neurosurgeon
at the investigative centre. This should be documented in the patient file.
7. Absence of previous systemic treatment with BRAF inhibitors, MEK inhibitors or
anti-PD-1 for distant metastatic melanoma. Patients having received such treatments
as adjuvant therapy are allowed provided adjuvant treatment has been stopped for 6
months or more.
8. No more than one previous local intracranial therapy for one lesion (e.g.
craniotomy, SRS).
Note: Treatment with stereotactic radiosurgery must have been completed ≥14 days
prior to randomisation and this lesion cannot be target lesion for radiosurgery.
9. Able to undergo gadolinium-enhanced MRI.
10. At least one measurable intracranial lesion for which all of the following criteria
have to be met:
1. Previously untreated (no local therapy including local radiotherapy, resection,
radiosurgery) or progressive after previous local therapy.
2. Longest diameter ≥5 mm as determined by contrast-enhanced MRI. Longest diameter
≥3 mm is acceptable for other IC lesions provided there is at least one lesion
≥5 mm.
3. Cumulative Intracranial Target Volume ≤12 cmᵌ as determined by
contrast-enhanced MRI.
11. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
values) must be resolved or Grade 1 according to NCI-CTCAE v5.0.
12. Able to swallow and retain oral medication and must not have any clinically
significant gastrointestinal abnormalities that may alter absorption (malabsorption
syndrome, major resection of the stomach or bowels).
13. Adequate bone marrow, organ function, and laboratory parameters defined as the
following (all criteria must be met):
1. Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L;
2. Haemoglobin ≥9 g/dL without transfusions;
3. Platelets ≥100 x 10⁹/L without transfusions;
4. Aspartate aminotransferase and alanine aminotransferase ≤2.5 × upper limit of
normal (ULN); ≤5 x ULN is acceptable for patient with liver metastases;
5. Total bilirubin ≤2 x ULN;
6. Creatinine ≤1.5 mg/dL, or calculated creatinine clearance ≥50 mL/min (as
determined using the MDRD method).
14. Adequate cardiac function, defined as the following (all criteria must be met):
- - Left ventricular ejection fraction (LVEF) ≥ local lower normal limit (LLN) as
determined by a multigated acquisition (MUGA) scan or echocardiogram;
- Baseline QT interval corrected for heart rate QTc ≤ 480 ms according to local
standard formula.
15. Women of childbearing potential (WOCBP) or men must agree to refrain from sexual
activity or use adequate contraception for the duration of study treatment and for
120 days after completing treatment. Male participants must agree to refrain from
donating sperm during this period.
16. Patient affiliated to or a beneficiary of the local social security system or
equivalent.
17. Patient is willing and able to comply with the protocol for the duration of the
trial including undergoing treatment and scheduled visits, and examinations
including follow-up.
Exclusion Criteria:
1. More than 10 intracranial metastases.
2. Presence of neurological symptoms related to intracranial metastases which induce
alteration of the ECOG performance status to 2 or more or require immediate
radiation treatment.
3. Ocular melanoma.
4. Brain metastases which necessitate immediate neurosurgery.
5. Any previous treatment with whole-brain radiation.
6. Presence of leptomeningeal disease or any parenchymal brain metastasis >30 mm in
longest diameter.
Note: On MRI, the most common finding of leptomeningeal disease is pial enhancement
and nodularity, typically over the cerebral convexities, in the basal cisterns, on
the tentorium, or in the ventricular ependymal surfaces.
7. Current or expected use of a strong inhibitor of CYP3A4.
8. History of malignancy other than disease under study occurring within 3 years of
study enrolment with the exception of: completely resected non-melanoma skin cancer
or indolent second malignancies.
9. Any serious or unstable pre-existing medical conditions (aside from malignancy
exceptions specified above), psychiatric disorders, or other conditions that, in the
opinion of the investigator, could interfere with the patient's safety, obtaining
informed consent, or compliance with study procedures.
10. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
Virus (HCV) infection (patients with laboratory evidence of cured HBV and/or HCV
will be permitted).
11. A history or evidence of cardiovascular risk including any of the following:
1. Left ventricular ejection fraction < local LLN as determined by a MUGA scan or
echocardiogram;
2. A QT interval corrected for heart rate QTc > 480 ms according to local standard
formula;
3. A history or evidence of current clinically significant uncontrolled
arrhythmias.
Note: Patients with atrial fibrillation controlled for >30 days prior to
randomisation are eligible.
4. A history or evidence of current >Class II congestive heart failure as defined
by the New York Heart Association guidelines;
5. Treatment refractory hypertension defined as a systolic blood pressure of >140
mmHg and/or diastolic blood pressure >90 mmHg, which cannot be controlled by
antihypertensive therapy;
6. Patients with intra-cardiac defibrillators;
7. A history of acute coronary syndromes (including myocardial infarction or
unstable angina), coronary angioplasty, or stenting less than 6 months prior to
enrolment.
12. A history or current evidence of retinal vein occlusion.
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study treatments, and their excipients.
14. Hereditary problems of galactose intolerance, total lactase deficiency or
glucose-galactose malabsorption. 15. Participation in another therapeutic trial within the 30 days prior to randomization. 16. Pregnant or breastfeeding female. Note: WOCBP must have a negative serum pregnancy
test within 14 days prior to enrolment.
17. History of, or active interstitial lung disease or (non-infectious) pneumonitis.
18. Active, known or suspected autoimmune disease or a documented history of autoimmune
disease, including ulcerative colitis and Crohn's disease (Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll).
19. Diagnosis of immunodeficiency or systemic chronic steroid therapy (≥ 10mg/day
prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned
date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic
steroids are allowed.
20. Has received a live vaccine within 30 days prior to the first dose of study drug.
21. Active infection requiring systemic therapy.
22. Known history of active TB (Bacillus Tuberculosis).
23. Allogenic tissue/solid organ transplant.
24. Person deprived of their liberty or under protective custody or guardianship.
25. Patient unwilling or unable to comply with the medical follow-up required by the
trial because of geographic, social or psychological reasons
