Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation1

Phase III Randomized, Open-Label, Multicenter Trial (BRIM3) Comparing BRAF Inhibitor Vemurafenib with Dacarbazine in Patients with BRAFV600E-Mutated Melanoma2

1Chapman PB et al.N Engl J Med 2011;364(26):2507-16.

2Chapman PB et al.Proc ASCO 2011;Abstract LBA4.

RTK

Vemurafenib(PLX4032, RO5185426)

RAS BRAFV600E MEK ERKGene

transcription

40-60% of cutaneous melanomas are positive for mutations in the BRAF gene

Adapted from Chapman PB et al. Proc ASCO 2011;Abstract LBA4.

Cellular proliferation

BRAF V600E mutation comprises approximately 90% of BRAF mutations

Vemurafenib Inhibits BRAFV600E Kinase

Chapman PB et al. N Engl J Med 2011;364(26):2507-16.

Vemurafenib (n = 337)960 mg PO BID

Coprimary endpoints: Overall and progression-free survival rates

Screening

BRAFV600E mutation

Stratification

•Stage

•ECOG PS (0 vs 1)

•LDH level ( vs nl)

•Geographic region

RDTIC (n = 338)1,000 mg/m2 IV q3wk

BRIM3: A Phase III Trial of Vemurafenib vs Dacarbazine (DTIC)

Select Adverse Events

SCC = squamous cell carcinoma

Chapman PB et al. N Engl J Med 2011;364(26):2507-16.

38% of patients receiving vemurafenib required dose modification due to toxicities.

Adverse event

DTIC (n = 282)Vemurafenib

(n = 336)

Gr 2 Gr 3 Gr 2 Gr 3

Arthralgia <1% <1% 18% 3%

Rash 0 0 10% 8%

Fatigue 12% 2% 11% 2%

Cutaneous SCC — <1% — 12%

Keratoacanthoma 0 0 2% 6%

Pro

gre

ssio

n-f

ree

su

rviv

al(

%)

Months

Hazard ratio 0.26(95% CI; 0.20–0.33)Log-rank p < 0.001Vemurafenib (N = 275)

Dacarbazine (N = 274)

Median 5.3 moMedian 1.6 mo

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10 11 12

Chapman PB et al. N Engl J Med 2011;364(26):2507-16. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Progression-Free Survival (December 30, 2010 Cutoff)

Months

Vemurafenib (N = 336)Est 6-mo survival 84%

Dacarbazine (N = 336)Est 6-mo survival 64%

Overall Survival (%)

0

10

20

30

40

50

60

70

80

90

100

10 2 3 4 5 6 7 8 9 10 11 12

Overall Survival(December 30, 2010 Cutoff)

Chapman PB et al. N Engl J Med 2011;364(26):2507-16. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Hazard ratio 0.37(95% CI; 0.26–0.55)Log-rank p < 0.001

Maximal Tumor Response

Chapman PB et al. N Engl J Med 2011;364(26):2507-16. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Vemurafenib

Dacarbazine

Per

cen

t C

han

ge

fro

m B

ase

lin

e i

n S

um

of

Tu

mo

r D

iam

eter

s

>100

50

0

-50

100

>100

50

0

-50

100

Conclusions

Vemurafenib is associated with a 63% decrease in the hazard of death (p < 0.001).

74% decrease in the hazard of tumor progression was observed (p < 0.001).

48% of patients in the vemurafenib arm had a confirmed objective tumor response compared to 5% of patients in the DTIC arm (data not shown).

Patients receiving vemurafenib reported relatively few Grade 3 or worse adverse events.

Chapman PB et al. N Engl J Med 2011;364(26):2507-16.

Investigator Commentary: Vemurafenib for the Treatment of BRAFV600E-Mutated Melanoma

The progression-free and overall survival curves from BRIM3 indicate that vemurafenib provides a clear improvement in early outcomes. A melanoma treatment algorithm that has been discussed is that for patients who need a quick response due to burdensome disease that is rapidly growing, vemurafenib should be considered. For patients who are asymptomatic with slowly progressing disease, the goal of therapy often is to obtain a long-term effect. For these patients, it is reasonable to withhold the BRAF inhibitor to second line and try to obtain that immune response as early as possible with ipilimumab or high-dose IL-2.

Treatment with vemurafenib is associated with the development of squamous cell carcinomas and keratoacanthomas. These are generally solitary, nonpigmented skin lesions arising early in the course of treatment. They are excised, and therapy can continue. Rash, arthralgias and photosensitivity are also observed. These are the toxicities that will affect quality of life. Moving forward, ongoing trials are exploring combinations of vemurafenib with other immune-based therapies. These trials could help provide answers on how to sequence these agents.

Keith T Flaherty, MD