What should patients with BRAF mutant melanoma receive as front line therapy?

Antoni Ribas, M.D.

Professor of Medicine Professor of Surgery Professor of Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC) University of California Los Angeles (UCLA) Chair, Melanoma Committee at SWOG

Discuss melanoma treatments with Mike Atkins… Let’s stick to the facts of melanoma treatment

The hard fact

After >40 years of modern medical oncology and >3,000 clinical trials, only 3 agents have improved overall survival (OS) in melanoma: – ipilimumab – vemurafenib – trametinib Data collected using PubMed; search criteria ‘melanoma clinical trial’

Vemurafenib, an on target therapy to block the driver cancer signal

BRAF MEK ERK

Cancer growth and survival

Vemurafenib, an on target therapy to block the driver cancer signal

BRAF MEK ERK

Cancer growth and survival

Vemurafenib, an on target therapy to block the driver cancer signal

BRAF MEK ERK

ipilimumab Cancer growth and survival

ipi and vem in phase 2 testing as second line therapy for metastatic melanoma No. patients Response rate Median OS Toxic deaths Journal publication Ipi phase 2 155 Vem phase 2 132 5.8% 53%

10 times higher

10.2 months 15.9 months

6 months longer

5 patients O’Day et al. 2010 Annals Oncology (IF 6.45) 0 patients Sosman et al. 2012 NEJM (IF 53.48)

10 times higher

OS

Time to results HR = 0.66

> 3 years HR = 0.72

> 3 years HR = 0.37

1 month

PFS HR = 0.64

HR = 0.76

HR = 0.26

Time to response and progression according to baseline LDH Less aggressive melanomas, more frequent durable responses

Time on study by LDH level at baseline Normal 1.0-1.5 x ULN

More aggressive melanomas, unlikely to respond to ipi but had benefit with vem

0 Approx timing of CT assessments 2 4 6 8 Time (months) 10 12 14 Median duration of response = 6.7 months (95% CI: 5.6, 9.8; range 1.3

–12.7) 16

Let me think about this?

Eureka!! Je le trouve To vem or not to vem? this is the question

Conclusions

• Only 3 agents have improved OS in metastatic melanoma after >3000 clinical trials • In patients with

BRAF V600

mutant metastatic melanoma, BRAF inhibitors should be the first line choice of therapy