Marlana Orloff, MDAssistant ProfessorThomas Jefferson UniversityDepartment of Medical Oncology
Looking Beyond 2020: The Next Decade of Melanoma Treatment
Melanoma Research AlliancePatient and Advocate Forum
Why We Haven't Won … YET
• Not all melanomas are created equal• Rare subtypes behave and respond differently to current
available treatments• Even in cutaneous melanoma not all patients respond• And if they do respond, resistance can develop• Other difficult to treat populations/scenarios• Brain metastases• Liver metastases
Cutaneous ≠ Uveal ≠ Conjunctival ≠ Mucosal
3Click to edit Author Name
CutaneousMelanoma
UvealMelanoma
ConjunctivalMelanoma
Mucosal Melanoma
IncidencePercent of Melanomas
153.5 per million80-90%
6 per million< 5%
0.24-0.8 per million<1%
2 per million < 2%
Cause UV radiation +/- Not known UV radiation +/- Not Known
Mutations BRAF > NRAS > NF1 > KIT GNAQ/GNA11 > BAP1 > SF3B1 > EIF1AX NF1 ~ BRAF ~ NRAS > KIT BRAF ~ NRAS ~ KIT ~ NF1
Primary Management Surgical excision +/- sentinel lymph node mapping and sampling
Plaque radiation, enucleation, external radiation
Surgical excision +/- sentinel lymph node mapping and sampling +/- radiation- Cryotherapy- Topical chemotherapy
Surgical excision +/- sentinel lymph node mapping and sampling +/-radiation
Risk Prognostication StageLymph node involvementGene Profile
Gene ProfileStage
StageLymph node involvement
Stage*No applicable stage for all subtypes(head and neck, sinus, anorectal, vaginal etc)
% Metastatic at PresentationPatterns
5%Lymph nodes > lung, soft tissues > bone > liver > brain
5%Liver >>> lung > bone > other soft tissues
UnkLymph nodes > lung > liver, soft tissues > bone, brain
23%Varied dependent on subtype
Treatment Over 9 drug regimens FDA approvedClinical trials
No official standard of careLiver directed therapy, immunotherapy, and clinical trials
No official standard of care Immunotherapy and targeted therapy available
No official standard of care Immunotherapy and targeted therapy available
Overall survival stratified by melanoma subtype in patients with metastatic disease.
Deborah Kuk et al. The Oncologist 2016;21:848-854
©2016 by AlphaMed Press
We Can Do Better!
Best Responses To IO in MUM
1. Algazi AP et al. Cancer. 2016 Nov 15;122(21):3344-3353.2. Rodriquez et al ESMO 20183. Najar et al SMR 2018
Drug Line Patients ORR Median PFS Median OS
Algazi, 2016 PD-1 inhibition case series >1st line 56 3.6% 2.6 months 7.6 months
Rodriguez, 2018 Ipilimumab + Nivolumab Phase 2 1st line 50 12% 3.27 months 12.7 month
Najar, 2018 Ipilimumab + Nivolumab retrospective >2nd line 85 9% 2.7 months 15 months
Marlana Orloff, MD
Targeted Attempts in Uveal Melanoma
Graphic Adapted from Krantz et al 2017Yang et al 2018
PKC Inhibition4
AEB071ORR: 3%PFS: 15.2 weeks
MEK Inhibition5-7
Selumetinib Phase 2ORR: 14%PFS: 15.9 weeksSelumetinib Phase 3ORR: 3%PFS: 2.8 monthsTrametinibORR: 0%PFS: 7.8 weeks
MEK + AKT3
Trametinib + GSK795ORR: 5%PFS: 15.7 weeks
MEK + PI3K1
AEB071 + BYL719ORR: 0%PFS: 7.6 weeks
RAF2
SorafenibORR: 0%24 Week PFS: 31%
1. Komatsubara et al presented SMR 20172. Mouriax et al BJC 20163. Shoustari et al JCO suppl 20164. Piperno-Neumann et al JCO suppl 2014
5. Carvajal et al JAMA 20146. Carvajal et al JCO 20187. Falchook et al Lancet 2012 Marlana Orloff, MD
IO for Mucosal
• Pooled analysis of 86 patients with mucosal melanoma patients receiving immune checkpoint inhibitor therapy
101. D’Angelo et al JCO 2017Marlana Orloff, MD
Targeted Therapy
• BRAF and KIT mutation type and rate vary between mucosal melanoma subtypes
• Heterogeneity especially of KIT mutations has made targeting difficult
11
Melanoma Subtype
KIT Mutation Status
BRAF Mutation Status
NRASMutation Status
Ref
Vulvo-vaginal
12%-27% 7% 27% 1,2
Sino-Nasal 22% 8% 22% 3
Ano-Rectal 35% 6% 6% 4, 5
Other mutations seen: SF3B1 and NF1
1. Aulmann Mod Path 20142. Rouzbahman JLGTD 20153. Wroblewska Am J Surg Path 20194. Santi J Clin Path 2015
Marlana Orloff, MD
Brain Metastases: STILL HIGH UNMET NEED
• Close to half of all patients with metastatic melanoma will encounter brain metastases at some point during their disease course
• Remains major cause of morbidity and mortality• Need for steroids for swelling can impact ability to give
immunotherapy• Intracranial response to treatments, notably for symptomatic
brain mets, is inferior to extracranial responses
Tawbi et al ASCO 2019
Liver Metastases
• Management of liver metastases major issue in uveal melanoma but issue in other subtypes
• Liver metastases may have less response to immunotherapy regardless of melanoma subtype
• Liver directed therapies and combination systemic and liver directed therapies are an option
Panel
Dr. Georgia BeasleyDuke University
Dr. Kenneth GrossmanUniversity of Utah
Dr. Stephanie GoffNational Cancer Institute
Dr. James MoonUniversity of Michigan
Dr. Antoni RibasUCLA
To Ask a Question• Microphones are circulating
• Email [email protected]• Text 202.670.9169 with questions