Novel Combination therapies in Melanoma

Paolo Ascierto


Progress in Melanoma has been enormous

Review on the therapeutic progresses made in Melanoma
https://www.ncbi.nlm.nih.gov/pubmed/28756137

but we still loose too many patients, so further options are needed and combinations likely to provide additional benefit.



READ

Elements of cancer immunity and the cancer-immune set point. 

https://www.ncbi.nlm.nih.gov/pubmed/28102259

Interesting question- is there still a role for IDO inhibitors? Remember the trial with Epacadostat and Pembro failed recently- now it remains to understand why the Ph2 looked promising but the Ph3 failed.


Possible combinations

LAG3 with PD1s

efficacy in combination with PD1 in patients who failed PD1

Big question now- why now a first-line trial?!


Other options- 

Entinostat (HDACi) plus pembro for patients who progressed on PD1

Johnson ASCO2017 poster

check also out- Hamm AACR 2018


CD122 agonist with PD1

NKTR-214 - Diab et al


Read up - how to target metabolism
Morella 2017

CD73 
AZAR
CD73 and A2AR inhibition
https://www.cell.com/cancer-cell/pdfExtended/S1535-6108(16)30388-9



Novel targets in Melanoma therapy
Keith Flaherty

BRAF, NRAS, NF1 and triple-WT Melanoma
(remember- absence of a marker does not suggest homogeneity)

CDKN2A biological important node in Melanoma


Remember
MEKi in NRAS mutant does not work as well as BRAFi + MEKi in BRAF mutant Melanoma

MITF low, Axl high predicts lack of response to BRAFi, unfortunately also the 'immunologically cold' tumours, so also not likely to correspond to immune therapy

Tirosh Science 2016

BUT high transcriptional heterogeneity within a tumour



Yuan PNAS 2013

Phenformin to target the metabolic state of persisting cells to add it to BRAF/MEK combination to prevent resistance 

Now tested in a clinical trial
https://clinicaltrials.gov/ct2/show/NCT03026517


Zhang JCI 2017 HSP


TILs


can work in patients who progressed on Ipi, PD1s and combinations

Schachter 2017 Lancet