latest developments in melanoma management...latest developments in melanoma management dr heather...
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Latest Developments in Melanoma Management
Dr Heather Shaw
University College London Hospital and Mount Vernon Cancer Centre
Melanoma Focus Oct 2019
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Disclosures
• Consulting/advisory
– Novartis, BMS, MSD, Immunocore, Idera, Iovance, Genmab, Sanofi/Regeneron, Macrogenics, Roche
• Speakers bureau
– Novartis, BMS, MSD, Sanofi
Melanoma Focus Oct 2019
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Objectives
• What are we currently using?
• Who benefits (most)?
• What else is out there?
• Can we influence response in other ways?
Melanoma Focus Oct 2019
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Immunotherapy –CheckMate 067
Melanoma Focus Oct 2019 Larkin et al, NEJM 2019
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Targeted therapy –Combi-D and Combi-V
Melanoma Focus Oct 2019
Robert et al, NEJM 2019
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BUT…..!
Melanoma Focus Oct 2019 Larkin et al, NEJM 2019
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AND….!
Melanoma Focus Oct 2019
Robert et al, NEJM 2019
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Positive prognostic features –normal LDH
Melanoma Focus Oct 2019Larkin et al, NEJM 2019
Immunotherapy
52%
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Positive prognostic features –normal LDH
Melanoma Focus Oct 2019
Robert et al, NEJM 2019
BRAF Directed Therapy
34%
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Positive prognostic features –≤3 sites of disease and normal LDH
Melanoma Focus Oct 2019Larkin et al, NEJM 2019
Immunotherapy
52%
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Positive prognostic features –≤3 sites of disease and normal LDH
Melanoma Focus Oct 2019
Robert et al, NEJM 2019
BRAF Directed Therapy
34%
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Biomarkers?
Melanoma Focus Oct 2019
Tarhini and Kudchadkar, Cancer Treat Rev. 2018
Depth of response to Rx
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Gin and tonic plus a garnish of your favourite anti-PD1/PDL1?
• Current active clinical trial combinations include:
– IO – IO– IO – metabolic therapy– IO – targeted therapy – IO – chemotherapy– IO – radiotherapy– IO – endocrine therapy– IO – epigenetic therapy– IO – viral therapy– IO – vaccine therapy– IO – surgery– IO – cellular therapy– IO – and every therapeutic modality not mentioned above!
Melanoma Focus Oct 2019
Approx. 1500 active IO clinical trials for adults
> 1100 active IO clinical trials from FIH to phase II
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Improving the tumour immune environment in BRAF mutant patients
• BRAF directed therapy can potentiate a favourable tumour microenvironment for immune responses prior to resistance developing to targeted treatment
• Increased T cell infiltrate
• Improved melanoma antigen recognition
• Reduction in suppressive cytokine production
• ?reduced tumour burden/lower LDH adding to beneficial effect
Melanoma Focus Oct 2019
Boni et al; Cancer Res. 2010 Frederick et al; Clin Cancer Res. 2013
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Sequential Therapeutic Options for BRAF Mutant Patients
• CAcTUS (and EBIN)– Circulating Tumour DNA Guided Switch– First line therapy: BRAF mutant metastatic/advanced patients
• BRAF directed therapy as first treatment followed by immunotherapy at a predetermined change in ctDNA
– BRAF mutant variant allele frequency ≧ 5% in circulating tumour DNA to enter study
– Decrease of ≧ 80% ctDNA BRAF VAF to initiate a switch to immunotherapy
– Practicality of testing ctDNA to guide therapy– Appropriate cut offs?– Benefit in progression free and overall survival?– Awaiting results of SECOMBIT
Melanoma Focus Oct 2019
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Concurrent Therapeutic Options for BRAF Mutant Patients
• COMBI – I (and Trilogy)– Dabrafenib & trametinib +/- spartalizumab– First line therapy: BRAF mutant metastatic/advanced
patients– Results from safety and biomarker cohort (36 pts)
• Objective response rate 75% (all patients had triple Rx)• Complete response rate 33%• Patients with elevated LDH (15 pts) still appear to have a
high ORR (67%) and CR (20%) rate
– Randomised part III data not yet available– Toxicity rate will be important in tolerability vs
outcome
Melanoma Focus Oct 2019
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Novel Combinations – all patients
• PLATFORM (and others: IMCgp100 combo, HyPeR etc)– Second (third) line therapy in any
metastatic/advanced patient with prior anti PD1/PDL1
– Spartalizumab in combination with either LAG3, CDK4/6 inhibitor, MET inhibitor or anti-IL1 beta• Overcome resistance mechanisms
• Encourage favourable immune environment
• Flexible study design with arms added/on hold
Melanoma Focus Oct 2019
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Intratumoural therapy combination• Direct modulation of immune environment to more
favourable profile
• Illuminate 301 (tilsotolimod)– AntiPD1 resistant patients
– Ipilimumab vs ipilimumab/TLR9 agonist intratumourally
– Phase II data suggests a 38% response rate for combination (Diab et al, ASCO 2018)
• T-VEC (Chesney et al, JCO 2018)– In combination with ipi - 39% ORR vs 18%
• Masterkey 265 results awaited – T-VEC and pembro
• Masterkey 115 pending recruitment - for pts with prior progression on PD1
Melanoma Focus Oct 2019
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Vaccine combinations
• RO7198457 – personalised cancer vaccine– Created to stimulate the immune system to “see” the
patient’s tumour– Selection of tumour antigens within patient’s tumour from
paraffin sections– mRNA based – taken up, expressed as a protein and
presented via MHC on antigen presenting cells– Aim to induce specific T cell response against cancer cells
which have those antigens
• Given in combination with atezolizumab in certain cohorts
• First and subsequent (post anti PD1) line cohorts
Melanoma Focus Oct 2019
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Adoptive Cell Transfer
• LN144 Iovance (and Achilles)– Tumour harvest to obtain tumour infiltrating
lymphocytes which are expanded in vitro
– Lymphodepletion chemotherapy
– Cell transfer
– Infusional IL-2 for engraftment
• Pretreated patients (prior anti PD1, BRAF/MEKi)– 38% ORR, 78% DCR
Melanoma Focus Oct 2019
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Are there other considerations??
Melanoma Focus Oct 2019
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You are not entirely human….
Melanoma Focus Oct 2019
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The Microbiome
Melanoma Focus Oct 2019
The Human Genome Project
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Immunotherapy and the microbiome
Melanoma Focus Oct 2019 Science. 2018 Jan 5; 359(6371): 97–103.
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Well, how does that happen??
Melanoma Focus Oct 2019
Germ-free mice receiving FMT from a responding donor were able to mount response to ⍺-PD1An increased density of CD8+ cells within the tumours in responding mice was seen
Science. 2018 Jan 5; 359(6371): 97–103.
Anti-PD1 admin
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Antibiotic stewardship is vital
Melanoma Focus Oct 2019
Science; Vol. 359, Issue 6371, pp. 91-97
(JAMA Oncol. September 2019. doi:10.1001/jamaoncol.2019.2785)
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Probiotics, fibre and diet?
• Probiotics narrow the diversity of the biome and were associated with reduced responses
• High dietary soluble fibre increased population groups of microbiota associated with response
• Processed meats and refined sugars also correlated negatively
• Maybe you are what you eat??
Melanoma Focus Oct 2019Spencer et al, AACR 2019
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Body Composition
Melanoma Focus Oct 2019
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Reconciling “bad” fat with good outcomes to anti PD1….
Melanoma Focus Oct 2019
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We still have more questions than answers!!!
Melanoma Focus Oct 2019
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Melanoma Focus Oct 2019