1. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation 1 Phase III Randomized, Open-Label, Multicenter Trial (BRIM3) Comparing BRAF Inhibitor Vemurafenib with Dacarbazine in Patients with BRAF V600E -Mutated Melanoma 2 1 Chapman PB et al. N Engl J Med 2011;364(26):2507-16. 2 Chapman PB et al. Proc ASCO 2011;Abstract LBA4.

2. RTK Vemurafenib (PLX4032, RO5185426) RAS BRAF V600E MEK ERK Gene 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 BRAF V600E Kinase

3. 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 R DTIC (n = 338) 1,000 mg/m 2 IV q3wk BRIM3: A Phase III Trial of Vemurafenib vs Dacarbazine (DTIC)

4. 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 2Gr 3Gr 2Gr 3 Arthralgia<1% 18%3% Rash0010%8% Fatigue12%2%11%2% Cutaneous SCC—<1%—12% Keratoacanthoma002%6%

5. Progression-free survival(%) Months Hazard ratio 0.26 (95% CI; 0.20–0.33) Log-rank p < 0.001 Vemurafenib (N = 275) Dacarbazine (N = 274) Median 5.3 moMedian 1.6 mo 100 90 80 70 60 50 40 30 20 10 0 0 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)

6. 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

7. 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 Percent Change from Baseline in Sum of Tumor Diameters >100 50 0 -50 100 >100 50 0 -50 100

8. 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.

9. Investigator Commentary: Vemurafenib for the Treatment of BRAF V600E -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