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What's New in Immunotherapy and Targeted Therapy?

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What's New in Immunotherapy and Targeted Therapy? 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 29.
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