What’s New in Immunotherapy and Targeted Therapy?

18th Focus on Melanoma 2021 Conference

Justine V. Cohen, DO Clinical Assistant Professor of Medicine Abramson Cancer Center 2 Old Model of Cancer Care

One size fits all

3 Precision Medicine

Precision Medicine Personalized Medicine Precision Oncology

New approach that takes into account individual variability in genes, environment and lifestyle to allow doctors and researchers to predict more accurately which treatment and prevention strategy will work in which groups of patients.

4 One Size Does Not Fit All!

5 Distinct Genetic Changes in Melanoma

Superficial Lentigo Maligna Acral Lentiginous Spreading Melanoma Melanoma Melanoma Abnormal gene: Abnormal Gene: Abnormal gene: C-kit-2% C-kit-15% BRAF- 50% BRAF- 10% BRAF- 15% NRAS- 20% NRAS- 10% NRAS- 15%

6 Distinct Genetic Changes in Melanoma

Ocular Melanoma Mucosal Melanoma Abnormal gene: Abnormal Gene: GNA11- 32% C-kit- 20% GNAQ- 50% NRAS- 15% BRAF < 1% BRAF- 5%

7 Many mutations in melanoma

 Difficult to predict which mutations will be present in a particular tumor

 Molecular profiling can help clinicians: • Enroll patients in clinical trials • Make informed therapeutic choices

Adapted from mycancergenome.org 8 Timeline of approvals

Encorafenib + Binimetinib Cobimetinib + V Vemurafenib (V) Dabafenib (D), Nivolumab Trametinib (T) High-dose Cobimetinib + V IL-2 Pembrolizumab D + T Ipi + DTIC Ipilimumab Nivo

1980 2011 2013 2015 2020

9 Immunotherapy Targeted Therapy

.Interferon .Dabrafenib (Tafinlar)

.IL-2 .Trametinib (Mekinist)

.Ipilimumab (Yervoy) .Vemurafenib (Zelboraf)

.Pembrolizumab (Keytruda) .Cobimetinib (Cotellic)

.Nivolumab (Optivo) .Encorafenib (Braftovi)

.Ipilimumab + Nivolumab .Binimetinib (Mektovi) .Talimogene laherparevec, TVEC (imlygic)

.Atezolizumab + Cobimetinib + Vemurafenib

10 How we got here

Pembrolizumab Nivolumab

Ipilimumab

Atezolizumab

11 How we got here

12 Tumor Cell APC Inactive T cells are T Cell activated and Tumor antigens proliferate released by tumor Activated T Cell cells

Tumor antigens Tumor presented to T Activated Cell T Cell cells

T cells recognize tumor antigens Tumor Cell

T cells kill tumor cells 13 Immunotherapy

14 Immune checkpoint inhibitors

15 Precision Immunotherapy

“Mutational Burden” High numbers of mutations correlate with strong response to immunotherapy

PD-L1 expression on tumor cells

16 Neoantigens are more likely to occur in highly mutated tumors

Lee et al Trends in Immunology May 2018 17 Updates in immunotherapy stage IV melanoma

18 Toxicity

19 BRAF/MEK inhibitor combinations

Encorafenib + Binimetinib Cobimetinib + Vemurafenib

Dabrafenib + Trametinib

1980 2014 2015 2018

20 BRAF mutations differ

p.G469E p.L597S p.G464E 2% 2% AMP 3% p.L597R 3% 2% p.G469R 2% p.K601D 2% AMP p.G464E p.V600K p.G469E 10% p.G469R p.K601E p.K601D 12% p.K601E p.K601N p.K601N 2% p.V600E p.V600K p.L597R p.V600E p.L597S 60%

Even mutations in commonly mutated genes vary between individuals

21 Targeted therapy toxicity

 Pyrexia  Rash  Photosensitivity  Nausea  Arthralgias  Abnormalities in liver enzymes  Cardiac toxicities  Increase in cuSCCs

ALL REVERSIBLE!!!

22 Triplet Therapy

23 Triplet Therapy Trials

Vem/Cobi/Atezo vs Vem/Cobi IMSpire150

Dab/Tram/Pembro vs Dab/Tram Keynote-022

Dab/Tram/Sparta vs Dab/Tram COMBI-i

24 What’s on the horizon

Combination Trials • Combinations with radiation • Combinations with hydroxychloroquine New Targets: “Next Generation” • LAG-3, TIM-3, TIGIT Adoptive T Cell Therapy CAR T Cell Therapy Cancer Vaccines

25 26 What’s on the horizon

Combination Trials • Combinations with radiation • Combinations with hydroxychloroquine New Targets: “Next Generation” • LAG-3, TIM-3, TIGIT Adoptive T Cell Therapy CAR T Cell Therapy Cancer Vaccines

27 Penn Trials for Metastatic Melanoma

RADVAX • Ipilimumab, nivolumab and radiation trial

LIMIT trial • Nivolumab and hydroxychloroquine

Umbrella • Includes rotating new drugs combined with trial pembrolizumab (TIGIT, CTLA-4, Lenvatanib)

• Dabrafenib, trametinib and BAMM trial hydroxychloroquine

28 In Summary

• Precision Medicine approach to cancer treatment

• Clinical Trials

• Biomarker research

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