Where next with the next targeted therapies ?
Principles of advances
Combining laboratory with clinical research
Braf is mutated in 45 % in melanoma
Remarkable responses but relapses are coming
resistance mechanisms that are not completely understood
PAN RAF inhibitors overcoming this resistence and are now in trials tested
Circulating tumour DNA to be evaluated -to measure what the tumour is doing and how the disease progressing , monitoring the disease.
Good study cases
To understand the disease and to send then the patient to the scan
then you look to the mutations
The case of a lady with mucosal melanoma
-DNA sequences in circulating DNA
- she had in two tumours kind -one with kit mutations responding to imatinib
Circulating Tumours DNA trials
Patient derived xenografts - close relationship with pathologists
Problem is timing to take Braf inhibitors -is important for the time of progression
Rare Braf mutations + HRAS mutation
By DNA sequences in circulating DNA paclitaxel + trametinib = effective
They did not put the patient on it because of randomisation-
they decided to treat him with immunotherapy -patient died.
over 600 000 mutations - trametinib alone, crisotinib alone did not work
Trametinib+ crizotinib - discovered to be good in patient xenograft tumours
This combination -to be given to the patient when progress is arising
Immuno offers long survival
Clinical biomarker signature - orients the selection of patients
PD-L1 expression level to select treatment for the patients? Better not.
Consider an integrative approach
Gene expression and tumour burden at baseline- that means before patients start the treatment:
Neoepitope signature and mutational load
Combinations and rationale for combinations
Braf inhibitors could induce T cells infiltrations in melanoma metastasis, facilitating further the action of immunotherapies