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

What should patients with BRAF mutant melanoma

receive as front line therapy?

Antoni Ribas, M.D.Professor of MedicineProfessor of Surgery

Professor of Molecular and Medical PharmacologyDirector, 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 factAfter >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’

Cancer growth and survival

BRAF

MEK

ERK

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

Cancer growth and survival

BRAF

MEK

ERK

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

Cancer growth and survival

BRAF

MEK

ERK

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

ipilimumab

ipi and vem in phase 2 testing as second line therapy for metastatic melanoma

Ipi phase 2 Vem phase 2

No. patients 155 132

Response rate 5.8% 53%

Median OS 10.2 months 15.9 months

Toxic deaths 5 patients 0 patients

Journal publication

O’Day et al. 2010

Annals Oncology

(IF 6.45)

Sosman et al. 2012

NEJM

(IF 53.48)

10 times higher10 times higher

10 times higher10 times higher

6 months longer6 months longer

OS

HR = 0.66 HR = 0.72 HR = 0.37

Time to results

> 3 years > 3 years 1 month

PFS

HR = 0.64 HR = 0.76 HR = 0.26

Time to response and progression according to baseline LDH

16140

Approx timing of CT assessments

Approx timing of CT assessments

Continued response

Progressive diseaseProgressive disease

Time to responseTime to response

Time (months)4 6 8 10 122

Time on studyTime on study

Median duration of response = 6.7 months (95% CI: 5.6, 9.8; range 1.3–12.7)

Time on study byLDH level at baseline

Continued response

Time to responseTime to response

1.0-1.5 x ULN>1.5 x ULN

Progressive diseaseProgressive disease

Normal

Less aggressive melanomas, more frequent durable responses

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

Let me think about this?

To vem or not to vem? this is the question

Eureka!! Je le trouve

Conclusions

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

• In patients with BRAFV600 mutant metastatic melanoma, BRAF inhibitors should be the first line choice of therapy