Latest Developments in Melanoma Management

Dr Heather Shaw

University College London Hospital and Mount Vernon Cancer Centre

Melanoma Focus Oct 2019

Disclosures

• Consulting/advisory

– Novartis, BMS, MSD, Immunocore, Idera, Iovance, Genmab, Sanofi/Regeneron, Macrogenics, Roche

• Speakers bureau

– Novartis, BMS, MSD, Sanofi

Melanoma Focus Oct 2019

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

Immunotherapy –CheckMate 067

Melanoma Focus Oct 2019 Larkin et al, NEJM 2019

Targeted therapy –Combi-D and Combi-V

Melanoma Focus Oct 2019

Robert et al, NEJM 2019

BUT…..!

Melanoma Focus Oct 2019 Larkin et al, NEJM 2019

AND….!

Melanoma Focus Oct 2019

Robert et al, NEJM 2019

Positive prognostic features –normal LDH

Melanoma Focus Oct 2019Larkin et al, NEJM 2019

Immunotherapy

52%

Positive prognostic features –normal LDH

Melanoma Focus Oct 2019

Robert et al, NEJM 2019

BRAF Directed Therapy

34%

Positive prognostic features –≤3 sites of disease and normal LDH

Melanoma Focus Oct 2019Larkin et al, NEJM 2019

Immunotherapy

52%

Positive prognostic features –≤3 sites of disease and normal LDH

Melanoma Focus Oct 2019

Robert et al, NEJM 2019

BRAF Directed Therapy

34%

Biomarkers?

Melanoma Focus Oct 2019

Tarhini and Kudchadkar, Cancer Treat Rev. 2018

Depth of response to Rx

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

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

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

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

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

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

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

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

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Are there other considerations??

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You are not entirely human….

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The Microbiome

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The Human Genome Project

Immunotherapy and the microbiome

Melanoma Focus Oct 2019 Science. 2018 Jan 5; 359(6371): 97–103.

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

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)

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

Body Composition

Melanoma Focus Oct 2019

Reconciling “bad” fat with good outcomes to anti PD1….

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We still have more questions than answers!!!

Melanoma Focus Oct 2019

Melanoma Focus Oct 2019