Knocking out melanoma with targeted therapy

Ravi Amaravadi, MD Associate Professor of Medicine Co-Leader Cancer Therapeutics Program Abramson Cancer Center University of Pennsylvania

2000’s: Age of targeted therapy began with the drug Gleevec for leukemia

1 genetic mistake is “easy” to target 2000: Treatment of Stage IV Melanoma: No standard 1st Line therapy identified

Interferon Interleukin-2 Cisplatin, Vincristine, Dacarbazine Temozolomide v. Dacarbazine High dose temozolomide Tamoxifen

NO major improvement for patients BRAF is frequently (50%) mutated in melanoma And was identified as an unlikely driver of cancer

Ibrahim and Haluska Ann rev. pathology mech. Disease 2009 How do DNA mutations cause cancer?

CML has 1 mutation; Melanoma: 10-30,000 DNA mutations!!! Can it be targeted? Vemurafenib an ultra-selective mutant BRAF Inhibitor Phase I trial of vemurafenib was the most important trial and many patients on this trial benefited Dramatic and rapid tumor shrinkage (50%) and improved survival in phase II and III with vemurafenib leads to FDA approval Day 0 Day 15 Most common side effects of Vemurafenib

Common Rash KA- SCC(20-25%) Arthritis Fatigue Hair changes Liver test changes Kidney blood test change EKG changes Eye problems Colon polyps

In most cases, side effects are easily managed

Sosman NEJM 2012; Chu J Am Ac Derm 2012; Choe Am J. Opthalomology, 2014; Amaravadi Clin Can Research 2015 Resistance to BRAF inhibitors: Cancer can evade even the most effective inhibitor

Baseline Single agent BRAF inhibitor may be okay for some patients with small amount of tumor that responds completely: 25% patients from the phase I trial are still alive with no other treatment (Kim et al Eur. J Cancer 2015)

2 months PR Reactivation of the MAPK pathway is one of many possible mechanisms of resistance to BRAF inhibitors.

Necrotic tumor

4 months PD Combined BRAF and MEK inhibition is superior (75% RR) in some cases to BRAF inhibitor alone

Ribas et al. Lancet Oncology 2014 Vemurafenib and cobimetinib BRAF + MEK inhibitor combinations: • Less skin rash • More fever Current known resistance mechanisms (selected) and drug partners for BRAF mutant melanoma Resistance Add to BRAF Trial mechanism inhibitor ERK MEK inhibitor FDA approved activation PI3K PX866 Phase I activation Autophagy Hydroxychloroquine Phase I HSP90 HSP90 inhibitor Phase I CDK4 CDK4 inhibitor Phase I VEGF Avastin Phase I HCQ trials in BRAF mutant melanoma

N Therapeutic Sites/ Disease Progress DLT (accrued/ Efficacy agents Funding Target) Vemurafenib + Penn/ Rash, Melanoma Phase I 6/6 6/6 Responders HCQ Genentech LFTs PENN, Rutgers, Dabrafenib, Northwestern, 7/8 Response trametinib + Melanoma Phase I/II None 8/47 Wash 5/8 100% response HCQ U/Novartis

Pre V+H

Pre D+T+H Large scale genetic studies have identified 4 genetic categories of melanoma of the skin

Non-skin melanoma subtypes have different genetics Acral Lentiginous: CKIT mutations imatinib Mucosal melanoma: More studies needed, cKIT amplifications Uveal melanoma: GNA11, GNAQ mutations  MEK inhibitors TCGA investigators Cell 2015 We now routinely test for 47 genes in melanoma samples

ABL1 EGFR GNAS MLH1 RET

AKT1 ERBB2 HNF1A MPL SMAD4

ALK ERBB4 HRAS NOTCH1 SMARCB1

APC FBXW7 IDH1 NPM1 SMO

ATM FGFR1 JAK2 NRAS SRC

BRAF FGFR2 JAK3 PDGFRA STK11

CDH1 FGFR3 KDR PIK3CA TP53

CDKN2A FLT3 KIT PTEN VHL

CSF1R GNA11 KRAS PTPN11

CTNNB1 GNAQ MET RB1 Thank you to all of the patients and families who have participated in clinical research

FDA approvals for melanoma in last 5 years Vemurafenib Ipilimumab Dabrafenib Pembrolizumab Trametinib Nivolumab Cobimetinib Pegylated interferon TVEC Coming soon: MEK inhibitors for NRAS mutant melanoma