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!

Long Term Survival Ipilimumab Schadendorf et al. JCO 2015

Reminder: Why so excited!

Not Everyone Responds

43% without response to IPI +NIVO

BRAF/MEK Targeted Therapy

Drummer et al 2018

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 vrami@CureMelanoma.org• Text 202.670.9169 with questions