To evaluate the best sequencing approach with the combination of target agents (LGX818 plus
MEK162) and the combination of immunomodulatory antibodies (ipilimumab plus nivolumab) in
patients with metastatic melanoma and BRAF V600 mutation.
The combination BRAF (B-raf murine sarcoma viral oncogene homolog B1) inhibitor plus
mitogen-activated protein kinase (MEK) inhibitor seems to be more effective in the V600 BRAF
mutated advanced melanoma patients compared to treatment with the BRAF inhibitors alone. In
fact, a phase I-II study showed a better overall response rate (ORR) and progression-free
survival (PFS) in the combination arm (dabrafenib plus trametinib) respect to the single
agent treatment (dabrafenib): 76% and 9.4 months versus 54% and 5.8 months respectively.
Another phase I study with a similar combination (vemurafenib plus cobimetinib) showed an ORR
of 85% in vemurafenib-naïve patients.
Recently, the results of a phase I study about the combination ipilimumab plus nivolumab have
been reported. In this study at the selected schedule (ipilimumab 3 mg/kg and nivolumab 1
mg/kg), 53% of patients had an objective response, all with tumor reduction of 80% or more.
Reponses were durable, although longer follow-up is needed.
A recent phase I study has shown a high rate of liver toxicity with the combo ipilimumab plus
vemurafenib . which makes difficult a combination with these two different drugs. Moreover, a
better efficacy of the sequencing treatment BRAF inhibitors/ipilimumab vs. the single agent
treatment was also observed; for this reason it was also suggested to start immunotherapy
treatment in the BRAF V600 mutated melanoma population as first option, in order to increase
the percentage of patients who can benefit from the sequencing, considering the possibility
of a fast progression of the disease after the BRAF inhibitors treatment.
Taking into account these considerations, it seems impossible to think to combine all the
four compounds (the target agents and immunomodulating monoclonal antibodies). The risk of a
high rate of toxicity is realistic and would render this approach inapplicable.
Sequencing with these different combinations seems to be more feasible. However, also in this
case it would be important to start with the best combination in order to give to the
patients the best chance to increase the overall survival.
The aim of this prospective randomized phase II study is to evaluate the sequencing of these
two different combinations and evaluate which is the best of these approaches.
Inclusion Criteria:
1. Patients of either sex aged ≥ 18 years;
2. Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF
V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are
eligible for study participation;
3. Treatment naïve for metastatic disease patients. Previous adjuvant treatment, included
checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed, except for stage IV (if
completed at least 6 weeks prior to randomization, and all related adverse events have
either returned to baseline or stabilized). BRAF inhibitor treatment in adjuvant
setting is not permitted.
4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per
RECIST 1.1 criteria;
5. Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment;
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1;
7. Tumor tissue from an unresectable or metastatic site of disease must be provided for
biomarker analyses. An archive sample is mandatory at the screening visit; however, a
new sample collection would be preferable;
8. Female subjects of childbearing potential must have a negative pregnancy test result
at baseline and must practice two highly effective methods of contraception for the
total study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab
to undergo five half lives) after the last dose of nivolumab and ipilimumab and 30
days after the last dose of binimetinib and encorafenib for female subjects.
Additional pregnancy testing must be performed every 6 weeks during the treatment
Combo-Immuno and every 4 weeks during the treatment Combo-Target, as well as at the
end of the systemic exposure;
9. Men who are sexually active with women of childbearing potential must practice a
reliable method of contraception for the total study duration plus 31 weeks (i.e. 80
days plus the time required for nivolumab to undergo five half lives) after the last
dose of nivolumab and ipilimumab and 90 days after the last dose of binimetinib and
encorafenib;
10. Adequate bone marrow haematological function: absolute neutrophil count (ANC) ≥ 1.5 x
109/L AND platelet count ≥ 100 x 109/L AND haemoglobin ≥ 9 g/dL;
11. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) AND
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X ULN (< 5 x ULN
if liver metastases);
12. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60
mL/min in males and ≥ 50 mL/min in females (calculated according to Cockroft-Gault
formula);
13. Serum calcium levels, international normalised ratio (INR) and partial thromboplastin
time were within normal limits;
14. Life expectancy of at least 3 months;
15. Ability to understand study-related patient information and provision of written
informed consent for participation in the study.
16. Adequate electrolytes at Baseline, defined as serum potassium and magnesium levels
within institutional normal limits (Note: replacement treatment to achieve adequate
electrolytes will be allowed).
17. Adequate cardiac function:
- left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated
--acquisition (MUGA) scan or echocardiogram,
- QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs)
Exclusion Criteria:
1. Active brain metastases. Subjects with brain metastases are eligible if these have
been treated and there is no magnetic resonance imaging (MRI) evidence of progression
for at least 4 weeks after treatment is complete and within 28 days prior to first
dose of study drug administration. There must also be no requirement for
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone
equivalents) for at least 2 weeks prior to study drug administration;
2. Subjects with active, known or suspected autoimmune disease;
3. Subjects with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of treatment;
4. Prior treatment for stage III (unresectable) or stage IV melanoma with an
anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1),
anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4)
antibody;
5. Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are
of childbearing potential and not practicing a reliable method of birth control;
6. Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the investigator's opinion makes it undesirable for the patient to participate in
the study, or which would jeopardize compliance with the protocol, or would interfere
with the results of the study;
7. Patients with a history of uncontrolled cardiovascular or interstitial lung disease
and evidence or risk of retinal vein occlusion or central serous retinopathy (patients
with a history of cardiovascular or interstitial lung disease and evidence or risk of
retinal vein occlusion or central serous retinopathy (past or present evidence of
rethinophaty central serous retinopathy - CSR -, occlusion of retinal - RVOo retinal
degenerative disease) or ophthalmopathy, which according to the ophthalmologic
evaluation at baseline could be considered a risk factor for CSR / RVO ( eg. cupping
of the optic disc, visual field defect, intraocular pressure - (eg: central IOP - > 21
mmHg);
8. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or
squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and
without evidence of recurrence for at least 3 years prior to study entry; or other
solid tumor treated curatively, and without evidence of recurrence for at least 3
years prior to study entry
9. History of Gilbert's syndrome;
10. Inability to regularly access centre facilities for logistical or other reasons;
11. History of poor co-operation, non-compliance with medical treatment, or unreliability;
12. Participation in any interventional drug or medical device study within 30 days prior
to treatment start.
13. Positive test for human immunodeficiency virus (HIV), hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection;
14. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
15. Receipt of live vaccine within 30 days prior to study drug administration.
16. History of severe or life-threatening skin adverse events or reactions to drugs.
