Community Oncology Clinical Debates: Advanced Melanoma Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge. Review a downloadable slide deck by Antoni Ribas, MD, PhD, covering the most clinically relevant new data reported from Community Oncology Clinical Debates: Advanced Melanoma. Target Audience This educational activity has been designed to meet the unique learning needs of oncologists involved in the treatment of patients with advanced melanoma. Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of June 2012. All materials contained herein reflect the views of the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readers
should not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
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3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. PIM and IMER do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not
necessarily represent the views of PIM and IMER. Please refer to the official
prescribing information for each product for discussion of approved indications,
contraindications, and warnings.

4. Disclosure of Conflicts of Interest
D
A
Antoni Ribas, MD, PhD
Reported a financial interest/relationship or affiliation in
the form of: Consultant, Amgen, Inc., Celgene
Corporation, Genentech BioOncology, GlaxoSmithKline
plc., Millennium Pharmaceuticals, Inc.

5. Introduction
Antoni Ribas, MD, PhD
University of California, Los Angeles (UCLA)

6. Learning Objectives
Upon completion of this activity,
participants should be better able to:
 Assess the results of clinical studies evaluating the safety
and efficacy of BRAF and CTLA4 inhibitors
 Identify the role of genetic testing in selecting treatment for
frontline therapy
 Determine optimal treatment regimens for frontline therapy
 Discuss implications of frontline therapy selection for
second- and third-line settings

7. Activity Agenda
 Introduction (10 mins)
 Clinical Debates: Interactive Thought Leader/Group
Discussion (45 mins)
– What is the optimal frontline treatment for patients who present
with metastatic melanoma?
• Should all patients get tested for BRAF mutations upfront?
• How do you treat patients with BRAF mutations?
• Should therapies be used in combination?
• What affect does the choice of first-line treatment have on
subsequent treatment?
 Questions and Answers (5 mins)

8. Therapeutic Targets in Melanoma
Kit inhibitors cKit
NRAS
BRAF inhibitors BRAF
MEK inhibitors MEK
ERK
IL-2
IFN-a
Anti-CD40
Anti-CD137
Anti-OX40
Antitumor immune Oncogenic cell
response proliferation
Anti-CTLA4 and survival
Anti-PD1
MEK = MAPK/ERK kinase; CTLA4 = cytotoxic T-lymphocyte antigen-4; PD1 = programmed death-1;
IL-2 = interleukin-2; IFN-a = interferon alfa-2b.
Adapted from Fecher et al, 2007; Xing, 2010.

9. Relevance of Immunotherapy for the
Treatment of Melanoma
 FDA-approved immunotherapies for melanoma
– Adjuvant treatment
• High-dose IFN-a
• Pegylated IFN-a
– Metastatic melanoma
• High-dose IL-2
• Ipilimumab
 Immunotherapy has been demonstrated to reproducibly
result in long-term responses (not immediate) in (few)
patients with metastatic melanoma
YervoyTM prescribing information, 2012; Proleukin® prescribing information, 2012; Sylatron® prescribing information, 2012;
Intron-A® prescribing information, 2012; NCCN, 2012.

10. Active and Passive Immunotherapy
Peptide vaccine CD40
DC vaccine
Genetic vaccine
CD137
IL-2 OX40
IFN
IL-15
IL-21 CTLA4
PD1
Active immunotherapy
Passive immunotherapy
TCR or CAR
T-cell cloning genetic engineering
TCR = T-cell receptor; CAR = chimeric antigen receptor.
Courtesy of Antoni Ribas, MD, PhD.

11. CTLA4 Blockade
T-cell T-cell T-cell
activation inactivation activation
CTLA-4
CTLA-4
T cell T cell
T cell
TCR CD28
HLA B7
APC
APC APC
HLA = human leukocyte antigen; APC = antigen presenting cell.
Adapted from Weber, 2009.

12. Phase III Trial of Ipilimumab ± gp100 Vaccine
Vs. gp100 Vaccine Alone: MDX010-20
Ipilimumab + gp100
R (n = 403)
A
Pretreated N
Metastatic D Ipilimumab + Placebo
Melanoma O (n = 137)
(N = 676) M
I
gp100 + Placebo
Z
(n = 136)
E
 Primary end point: OS
 Secondary end points: ORR, DOR, PFS
OS = overall survival; ORR = overall response rater; DOR = duration of response;
gp100 = glycoprotein 100; PFS = progression-free survival.
Hodi et al, 2010.

13. Phase III Trial of Ipilimumab Plus Dacarbazine
Vs. Dacarbazine Alone: Study 024
Ipilimumab 10 mg/kg
R q3wks x 4
Ipilimumab
A Dacarbazine 850 mg/m2
10 mg/kg
Previously N q3wks x 8
q12wks
Untreated D (n = 250)
Metastatic O
Melanoma M
(N = 502) I
Dacarbazine 850 mg/m2
Z
E q3wks x 8
Placebo
Placebo
q12wks
(n = 252)
 Scheduled tumor assessments at baseline, 12 wks, and 24 wks
 Primary end point: OS
Robert et al, 2011.

14. Improved Survival With Ipilimumab
10 mg/kg x 4 doses q3wks,
3 mg/kg x 4 doses q3wks then q3mos + dacarbazine
with or without gp100
Hodi et al, 2010; Robert et al, 2011.

15. Objective Response to Ipilimumab After Significant
Progression With Tumor Volume Increase
Screening Week 12: Progression
Week 20: Regression Week 36: Still Regressing
Reproduced with permission from Wolchok et al, 2008.

16. Unique Kinetics of Response in
Patients Treated With Ipilimumab
Week 12: Swelling
Screening and Progression Week 12: Improved
Week 16: Continued Week 72: Complete Week 108: Complete
Improvement Remission Remission
Images courtesy of Jedd D. Wolchok, MD.

17. Mechanism of the Differential Kinetics
of Tumor Response With Ipilimumab
Tumor Response by
Immunotherapy WHO or RECIST
Progression
The patterns of tumor response with
ipilimumab are different from responses to
cytotoxic therapies due to the immune Cancer Cell
Lymphocyte
mechanism of action Macrophage irRC?
Tumor responses usually take time (1–4
months) to declare, and may go through a
period of uncertainty about response or
progression
WHO = World Health Organization.
Wolchok et al, 2009; Ribas et al, 2009.

18. Ipilimumab Treatment and irAEs
 Blockade of CTLA-4 can lead to the development of irAEs
 Treatment results in T cells losing tolerance to self-antigens
 Preclinical melanoma tumor models utilizing CTLA-4 blockade
have demonstrated enhanced immune-mediated tumor rejection
and irAEs such as depigmentation
 Common autoimmunities in patients treated with anti–CTLA-4
– Dermatitis
– Enterocolitis
– Endocrinopathies
 Toxicity does not always equal response, but there does appear to
be an association
Attia et al, 2005; Downey et al, 2007; Lutzky et al, 2009; van Elsas et al, 1999; Weber et al, 2008.

19. Gl irAEs: Overview
 Diarrhea is a frequent irAE
– Most cases are mild or moderate
– May be severe (> 7 stools/day and hematochezia)
– Biopsy demonstrates inflammatory colitis,T cell infiltrates
– Most cases respond to either symptomatic treatment or
steroids, may need anti-TNF Rx
– Can rarely lead to GI perforation (< 1%) requiring surgery
GI = gastrointestinal.
Attia et al, 2005; Beck et al, 2006.

20. Endocrinopathies: IrAEs (Overview)
 Symptoms: Fatigue, weakness, nausea, amenorrhea, impotence,
hypotension, hyponatremia, hypoglycemia, eosinophilia
– If strong suspicion for adrenal crisis (dehydration, hypotension) start
stress dose steroids
 Laboratory evaluation: ACTH, cortisol, TSH
– Closely follow; if grade 2 toxicity, continue ipilimumab
– Hormone replacement; consider trial of high-dose steroids prn
– If suspect hypophysitis, head MRI with pituitary cuts; visual field
testing
Beck et al, 2006.

21. Management of irAEs
 Patient education for early recognition of irAEs
 Aggressive work-up and management for
moderate/severe events
 Non-specific complaints might reflect endocrine
(eg, pituitary) toxicity
 Corticosteroids might be effective
 Algorithms established for the management of
irAEs
Beck et al, 2006; Agarwala, 2009; Weber, 2009.

22. Other Combinations With
Anti-CTLA4 Antibodies
mAb = monoclonal antibody; CR = complete response; PR = partial response; OR = objective response.
Maker et al, 2005; Ribas et al, 2009; Tarhini et al, 2012.

23. Immune Effects of VEGF
hypoxia Immunosuppressive
mechanisms
COX-2
HIF-1 CXCL12
arginase
PGE2
MDSC
VEGF
VEGF
Foxp3+ T cell
IL-17 +
macrophage
Stat3
IL-6
angiogenesis +
VEGF
bFGF
23
VEGF = vascular endothelial growth factor.
Tartour et al, 2011.

24. Immune Cell Infiltration in Tumors
With Ipilimumab + Bevacizumab
Pre-Treatment CD3 CD8 CD4 CD163
Post-Treatment
24
Hodi et al, 2011.

25. Differences Between Blocking CTLA4/B7
and Blocking PD-1/PD-L1
T cell
MHC TCR
Dendritic
cell CD28
B7 CTLA4
Ribas, 2012.

26. Differences Between Blocking CTLA4/B7
and Blocking PD-1/PD-L1 (cont.)
T cell
MHC TCR
Dendritic
cell B7 CD28
CTLA4
Ribas, 2012.

27. Differences Between Blocking CTLA4/B7
and Blocking PD-1/PD-L1 (cont.)
T cell
TCR MHC
Melanoma
cell
PD-1 PD-L1
(B7-H1)
Ribas, 2012.

28. Differences Between Blocking CTLA4/B7
and Blocking PD-1/PD-L1
T cell
TCR MHC
Melanoma
cell
PD-1
Ribas, 2012.

29. Induced Expression of PD-L1 (B7-H1) on
Melanoma Cells by Infiltrating T Cells
Induction of the B7-
H1/PD-1 pathway may
represent an adaptive
immune resistance
mechanism exerted by
tumor cells in response
to endogenous antitumor
activity and may explain
how melanomas escape
immune destruction
despite endogenous
antitumor immune
responses
Taube et al, 2012.

30. Differences Between Blocking
CTLA4/B7 and Blocking PD-1/PD-L1
Ribas, 2012.

31. Clinical Activity and Safety of Anti-PD-1
(BMS-936558, MDX-1106) in Patients With
Advanced Melanoma
 Grade 3/4 drug-related AEs
– 20% of patients
– Most common lymphopenia, fatigue, diarrhea, abdominal pain,
and lipase
 Among 94 evaluable patients
– 20%–40% objective responses
– Approximately 2/3 being durable responses (> 1 year)
 The durable responses compares favorably to prior
melanoma immunotherapies with HD IL-2, anti-CTLA4,
dendritic cell vaccines, etc.
Hodi et al, 2012; Ribas, 2012.

32. Changes in Target Lesions Over Time
in Melanoma Patients
1 mg/kg 10 mg/kg
 Of 26 patients with OR
– 18 were treated ≥ 1 year (before 2/24/12) and 13 had responses of ≥ 1 year
– 8 were treated < 1 year and 6 had responses ranging from 1.9–5.6 months
Hodi et al, 2012.

33. Summary of ACT Therapies
for Melanoma
 ACT of TIL results in Survival of Patients With
reproducible and durable Metastatic Melanoma Treated
clinical responses in ~ 20% of With Autologous TILs and IL-2
patients refractory to other
therapies
 ACT of cloned peripheral blood
T cells can result in responses
in patients
 ACT of TCR engineered
lymphocytes can result in
responses in patients
Survival Time (months)
ACT = adoptive cell therapy; TILs = tumor infiltrating lymphocytes.
Rosenberg et al, 2011; Hunder et al, 2008; Morgan et al, 2006; Johnson et al, 2009.

34. Melanoma Molecular Profiling: Driver Oncogenic Mutations
Define Clinically Relevant Melanoma Molecular Subsets
Usually mutually exclusive
Noted in ~70% of melanomas
< 5% melanomas (mucosal, acral) Kit inhibitors: imatinib, nilotinib, dasatinib
cKit
20% melanomas (> age) NRAS
50% melanomas (< age) BRAF BRAF inhibitors: vemurafenib, dabrafenib
MEK MEK inhibitors
ERK
Oncogenic cell
proliferation
and survival
Adapted from Fecher et al, 2007; Xing, 2010; Curtin et al, 2005, 2006; Van Raamsdonk et al, 2010.

35. Key Takeaways:
FDA Approvals for the Treatment
of Metastatic Melanoma
 2 therapies approved based on OS improvement in
randomized trials
– Ipilimumab (2011)
– Vemurafenib (2011)
 2 therapies approved based on RR in single arm trials
– Dacarbazine (1975)
– IL-2 (1998)
RR = response rate.
YervoyTM prescribing information, 2012; Zelboraf® prescribing information, 2012; NCCN, 2012; Bhatia et al, 2009.

36. Clinical Debates:
Interactive Thought
Leader/Group Discussion

37. Clinical Debates:
What Is the Optimal Frontline
Treatment for Patients Who
Present With Metastatic
Melanoma?

38. Treatment of Advanced Melanoma in 2012
V600 V600
BRAF + BRAF Negative
SOC Experimental SOC Experimental
Vemurafenib GSK BRAFi+MEKi Ipilimumab Anti-PD1
Ipilimumab Anti-PD1 HD IL-2 TIL ACT
HD IL-2 TIL ACT
Open Questions Special Considerations
- Immunotherapy vs. BRAFi first-line? - Uncommon BRAF mutations
- Immunotherapy + BRAFi? - NRAS mutants with MAPK dependency
- Treatment of BRAFi resistance?
- Prevention of BRAFi resistance?
- Role of MTKis?
- Role of chemotherapy?
GSK = GlaxoSmithKline; BRAFi = BRAF inhibitor; MEKi = MEK inhibitor; SOC = standard of care.
NCCN, 2012; US NIH, 2012a–g.

39. Different Clinical Benefits of Immunotherapy and
Targeted Therapy for Metastatic Melanoma
Immunotherapy Targeted Therapy
Percent Alive
Percent Alive
0 1 2 3 0 1 2 3
Time (yrs) Time (yrs)
Chapman et al, 2011; Hodi et al, 2010.
Adapted from Ribas et al, 2012.

40. ORR by Pre-Defined Subgroups in BRIM2
80
70
60
ORR (%)
50
40
30
20
Overall ORR of 53% (IRC)
10 RR (size proportional to the number of patients in the subgroup)
95% CI
0
All < 65 ≥ 65 F M 0 1 M1a/ M1c 1 >1 Yes No Normal 1.0–1.5x >1.5x
treated M1b ULN ULN
Age Sex ECOG PS # prior Previous IL-2
patients Stage therapies LDH at enrollment
Baseline characteristics
ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase;
ORR = overall response rate; CI = confidence interval; ULN = upper limit of normal.
Ribas et al, 2011.

41. Subgroup Analyses for OS
With Vemurafenib (BRIM3)
Chapman et al, 2011.

42. Subgroup Analyses for OS
With Ipilimumab
Hodi et al, 2010.

43. Subgroup Analyses for OS
With Ipilimumab
Robert et al, 2011.

44. Clinical Debates:
Should All Patients Get Tested for
BRAF Mutations Upfront?
How Do You Treat Patients
With BRAF Mutations?

45. BRAF Inhibitors, Targeted Therapy to
Block the Driver Oncogenic Signaling
BRAF
MEK
ERK
Cancer
growth and
Adapted from Fecher et al, 2007; Xing, 2010; Weber, 2011.
survival

46. Inhibition of MAPK Signaling in Biopsies of BRAFV600
Melanoma From Patients Treated With Vemurafenib
GF
Baseline Day 15
RTK
V600
BRAF
Y-P Y-P pERK
Ras
GTP
PLX4032
MEK
P
ERK
P cyclin D
Cyclin D
Cell cycle
(Ki67)
Ki67
MAPK = mitogen-activated protein kinase;
pERK = phosphorylated extracellurar signal-regulated kinase.
Adapted from Smalley et al, 2010; Flaherty et al, 2010b.

47. Flaherty et al, 2010; Chapman et al, 2011; Sosman et al, 2012.

48. Comparison of Maximum Response With
Vemurafenib and Dabrafenib
> 100 BRIM3
Vemurafenib Chapman et al, 2011
5
0
0
-5
0
-10
0
BREAK3
Dabrafenib Hauschild et al, 2012
Chapman et al, 2011; Hauschild et al, 2012.

49. Early Analysis of the Phase III Trial
Comparing Vemurafenib and Dacarbazine
OS: HR = 0.37
Screening Vemurafenib
960 mg po bid
PFS: HR = 0.26
BRAFV600E mutation (n = 337)
Stratification: Randomization
• Stage N = 675
• ECOG PS (0 vs. 1) Dacarbazine
• LDH (elevated
vs. normal) 1,000 mg/m2 iv q3w
• Geographic region (n = 338)
Chapman et al, 2011.

50. Improved Survival With Vemurafenib
Chapman et al, 2011.

51. Update of the Overall Survival in BRIM3
(not censored at crossover)
100 Vemurafenib (n = 337)
90 Median F/U 12.5 months
Overall Survival (%)
80
HR 0.76
70 (95% CI: 0.63–0.93)
60 p < .01 (post-hoc)
50 Dacarbazine (n = 338)
40 Median F/U 9.5 months
30
20
10
10.3 13.6
0
0 6 12 18 24
Time (months)
No. at risk
Dacarbazine 338 255 211 173 136 81 34 6 0
Vemurafenib 337 326 280 231 178 109 44 7 1
Chapman et al, 2012.

52. BREAK-3: Comparison of PFS With Dabrafenib
and Dacarbazine
Screened Dabrafenib
N = 733 150 mg bid
n = 187
3:1 randomization Cross over
allowed at Dabrafenib
Enrolled
DTIC radiological PD 150 mg bid
n = 250
1,000 mg/m2 IV n = 28
q3w
Proportion Alive Without Progression (%)
(68% of PD
n = 63 patients)
1.0
0.9
0.8
0.7
PFS HR 0.30
0.6 Dabrafenib median PFS 5.1 months
0.5
0.4
DTIC:
0.3
median PFS 2.7 months
0.2
0.1
0.0
0 1 2 3 4 5 6 7 8 9
Time from Randomization (Months)
At risk 187 184 173 113 100 41 31 5 3 0
63 53 31 14 11 6 4 2 0 0
Hauschild et al, 2012.

53. Two-Cohort Open-Label Study of Dabrafenib
in Patients With Brain Metastases
Screened (N = 325)
Enrolled (n = 172) Cohort A (n = 89)
(no prior brain treatment)
Metastatic melanoma
Dabrafenib
Centrally confirmed BRAF V600E/K
mutation 150 mg bid
Asymptomatic brain metastases Cohort B (n = 83)
No prior treatment with MEK or BRAF (prior brain treatment)
inhibitors
No prior brain treatment: Cohort A Prior brain treatment: Cohort B
OIRR: 39% OIRR: 31%
ORR: 38% ORR: 31%
Maximum percent change from
baseline intracranial measurement
Maximum percent change from
baseline intracranial measurement
Intracranial DCR: 81% Intracranial DCR: 89%
Overall DCR: 80% Overall DCR: 83%
Kirkwood et al, 2012.

54. Examples of Brain Metastases Responses to Dabrafenib
Baseline Week 8
Baseline Week 32
Kirkwood et al, 2012.

55. BRIM2: Toxicities With Vemurafenib
Includes AEs reported in ≥ 20 patients
All grades Grade 3 Grade 4
n (%) n (%) n (%)
Overall 130 (99) 79 (60) 5 (4)†
Arthralgia 78 (59) 8 (6) –
Rash 69 (52) 9 (7) –
Photosensitivity reaction 69 (52) 4 (3) –
Fatigue 56 (42) 2 (2) –
Alopecia 48 (36) – –
Pruritus 38 (29) 3 (2) –
Skin papilloma 38 (29) – –
cuSCC / KA‡ 34 (26) 34 (26) –
Nausea 30 (23) 2 (2) –
Elevated liver enzymes 23 (17) 8 (6) § 4 (3)¶
†One patient with 2 grade 4 AEs.
‡Cases of cuSCC/KA were managed with simple excision and did not require dose modification.
§Managed with dose reduction; one removed from study.
¶Led to discontinuation of therapy.
cuSCC = cutaneous squamous cell carcinoma; KA = keratoacanthomas; AEs = adverse events.
Ribas et al, 2011.

56. cuSCC/KAs With Vemurafenib
Median
0 5 10 15 20 25 30 35 40
Time on Vemurafenib (wks)
 cuSCCs
– Incidence: 26%
– Median time: 8 wks (2–36)
– Median number of cuSCC/KAs per patient: 1 (range 1–7)
– Each dot represents wks to development of first cuSCC/KA
lesion
Ribas et al, 2011.

57. Acquired Resistance to Vemurafenib:
Time to Response and Progression
Time on study
Time to response
Progressive disease
Continued response
0 2 4 6 8 10 12 14 16
Approx timing Time (mos)
of CT
assessments
Median DOR = 6.7 mos (95% CI 5.6, 9.8; range 1.3–12.7)
CT = computed tomography.
Ribas et al, 2011.

58. Phase III Trial Comparing Trametinib (MEK inhibitor)
and Dacarbazine in Metastatic Melanoma
METRIC PFS – Primary Efficacy Population
1.0 Events Median HR (95%CI)
n (%) (months) p Value
Screened 0.9
(N = 1,059) Trametinib 96 (54) 4.8 0.44 (0.31, 0.64)
Proportion Alive and Progression-Free
0.8 < .0001
Chemotherapy 68 (72) 1.4
V600E/K 0.7
mutation
(n = 322) 0.6
Trametinib 0.5
Chemotherapy
2 mg QD
(n = 108) 0.4
(n = 214)
0.3
PFS Cross-over*
INV – Trametinib
0.2
IRC – Trametinib
Trametinib
FSFV: Dec 0.1 INV – Chemotherapy
2 mg QD
2010, LSFV:
0.0 IRC – Chemotherapy
July 2011
0 1 2 3 4 5 6 7 8 9
Time From Randomization (Months)
Number at risk
INV –
INV – Trametinib 178 170 130 79 69 22 18 4 0 0
Chemotherapy 95 77 38 20 17 8 5 1 0 0
Conclusion: Trametinib is the first MEKi to show statistically significant PFS, RR,
and OS benefit in a randomized trial compared to chemotherapy
Robert et al, 2012; Flaherty et al, 2012.

59. Clinical Debates:
Should Therapies Be Used
in Combination?

60. Mechanisms of Resistance to BRAF Inhibitors
PDGFRb or IGF1R
NRASQ61
BRAF inh PI3K
CRAF
PI3Ki or AKTi
COT BRAFV600E
AKT
MEK-independent
MEK progression
PMEKi
MEK-dependent
progression
ERK
P
Survival
Adapted from Poulikakos et al, 2011; Shi et al, 2012; Nazarian et al, 2010;
Villanueva et al, 2010; Johannessen et al, 2010; Wagle et al, 2011.

61. Treating Resistance to BRAFi
Occasional prolonged
BRAFi Local Tx + BRAFi responses
(Kim et al, 2011)
BRAFi MEKi No activity
(Kim et al, 2011)
BRAFi BRAFi
ORR 19%
MEKi (Flaherty et al, 2011)
BRAFi ORR 50%–74%, increased PFS?
(Infante et al, 2011)
MEKi
Progression of melanoma
BRAFi = vemurafenib, dabrafenib (GSK2118436); MEKi = trametinib (GSK1120212).

62. Dabrafenib + Trametinib Study Design
and Objectives Objective/s
• Trametinib effects on
Part A Drug–drug interaction
dabrafenib PK
Dose escalation N = 77
BRAFi-naïve
• Safety/tolerability
melanoma • Determine phase II dose
patients • Steady-state PK
Part B across 4 • Clinical activity
Expansion cohorts dose levels
• Clinical activity
Colorectal BRAF+ Prior BRAF inhibitor
• Clinical activity (RR, PFS) of
combo vs. dabrafenib
vs dabrafenib
• Assess safety/tolerability
Part C Randomized Phase II trial
phase
• Safety/tolerability
• Characterize PK of dabrafenib
Bridging Study
study
Part D dabrafenib (HPMC) +
HPMC capsules
trametinib
Weber et al, 2012.
PFS = progression-free survival; PK = pharmacokinetics; HPMC = hydroxypropyl methylcellulose.

63. Investigator-Assessed Maximum Tumor Reduction
Part B BRAFi-Naïve Melanoma Patients (N = 77)
RR 44%–67%
Median DOR 11.3 months (95% CI: 9.2, NR)
Dose level:
dabrafenib/trametinib (mg bid/mg QD)
Median PFS 7.4 months, PFS at the highest dose 10.8 months
75/1
150/1
150/1.5
150/2
KK
K K
K
K
K = BRAFV600K mutation-positive patients.
Weber et al, 2012.

64. Best Confirmed Response Rate
Part B BRAFi-Naïve Melanoma Patients
(N = 77)
Median DOR 11.3 months (95% CI: 9.2, NR)
CR+PR
CR+PR+SD
Response Rate (%)
67% 64% 63%
57%
44%
18% CR
8% CR 8% CR
75/1 150/1 150/1.5 150/2 All doses
(n = 6) (n = 22) (n = 25) (n = 24) (n = 77)
Dose-Level of Dabrafenib/Trametinib
Weber et al, 2012.

65. Treatment Duration
Part B BRAFi-Naïve Melanoma Patients (N = 77)
Median Duration of Treatment = 10.7 months
38% of patients are ongoing
Ongoing
Discontinued/progressed
Treatment Duration (months)
Weber et al, 2012.

66. Combining Immunotherapy and
Targeted Therapy for Melanoma?
Immunotherapy Targeted Therapy Combination?
Percent Alive
Percent Alive
Percent Alive
0 1 2 3 0 1 2 3 0 1 2 3
Time (yrs) Time (yrs) Time (yrs)
Chapman et al, 2011; Hodi et al, 2010.
Adapted from Ribas et al, 2012.

67. Can BRAF Inhibitors Be Combined
With Tumor Immunotherapy?
Author Title Journal
Comin-Anduix et al, 2010 The Oncogenic BRAF Kinase Inhibitor Clinical
PLX4032/RG7204 Does Not Affect Cancer
the Viability or Function of Human Research
Lymphocytes across a Wide Range
of Concentrations
Boni et al, 2010 Selective BRAFV600E Inhibition Enhances Cancer
T-Cell Recognition of Melanoma Without Research
Affecting Lymphocyte Function
Wilmott et al, 2012 Selective BRAF Inhibitors Induce Marked Clinical
T-cell Infiltration Into Human Metastatic Cancer
Melanoma Research
Comin-Anduix et al, 2010; Boni et al, 2010; Wilmott et al, 2011.

68. Clinical Debates:
What Effect Does the Choice
of First-Line Treatment Have
on Subsequent Treatment?

69. Systemic Therapies for Advanced
or Metastatic Melanoma
 Clinical trial
 Ipilimumab, HD IL-2, vemurafenib (BRAFV600E)
 Paclitaxel, carboplatin, cisplatin
 Dacarbazine, temozolomide
Patients who progress after initial therapy may
be offered subsequent therapy if they maintain
ECOG PS 0–2 or Karnofsky score ≥ 60
NCCN, 2012.

70. Guidance in Therapy Decisions
 Recommendation for first-line systemic therapy of melanoma based on:
– BRAF mutation status
– Tempo of disease
– Presence or absence of cancer-related symptoms
 Patients with low-volume, asymptomatic metastatic melanoma may be good
candidates for immunotherapy (ipilimumab or IL-2; unless contraindicated)
– May be time for an antitumor immune response
 Patients with BRAF-mutant melanoma who have symptomatic disease or who
have progressed despite immunotherapy should be considered for vemurafenib
 Clinical trials underway to address unanswered questions regarding optimal
sequencing and/or combination
 Patients who are intolerant to, or relapsing after first-line systemic therapy,
additional systemic therapy may be indicated if the patient has ECOG PS 0–2
or Karnofsky score ≥ 60
 Options for second-line therapy include clinical trial (preferred) or treatment with
a different agent from the list of first-line options
NCCN, 2012.

71. Case Study 1
 65-yr-old woman with BRAFV600 positive metastatic
melanoma
 Progression on prior experimental therapy with a
dendritic cell vaccine
 M1a
– Metastases to lymph nodes to the axilla and subpectoral area
– LDH within normal limits

72. Case Study 1 (cont.)
 Should this patient receive:
– Ipilimumab 3 mg/kg x 4 doses
– Vemurafenib 960 mg po BID
– Clinical trial
– Surgery

73. Case Study 1 (cont.)
 Thepatient received vemurafenib 960 mg po
BID within the PLX4032 phase I trial (BRIM1)
and continues with a sustained tumor
response over 2 yrs later

74. Case Study 2
 64-yr-old with a BRAFV600 negative metastatic melanoma
 Progression on prior therapy with:
– Dacarbazine
– nab-Paclitaxel
– Intra-lesional IL-2 injections
 M1c
– Metastases to liver, spleen, and lymph nodes
– LDH ~ 2x ULN

75. Case Study 2 (cont.)
 Should this patient receive:
– Ipilimumab 3 mg/kg x 4 doses
– Ipilimumab 10 mg/kg in combination with
dacarbazine
– Clinical trial
– Hospice care

76. Metastatic Melanoma Response to Ipilimumab
Before Ipilimumab After Ipilimumab
04/22/11 08/05/11
Case by Antoni Ribas, MD, PhD.

77. Key Takeaways
 Patients with metastatic melanoma should have molecular testing,
at least for the BRAFV600 mutation
– Vemurafenib is a selective BRAFV600E kinase inhibitor
 Immunotherapy has demonstrated long-term responses in patients
with metastatic melanoma
 Ipilimumab and vemurafenib have demonstrated improvements in
OS for the treatment of metastatic melanoma
 The choice of frontline or follow-up therapy in patients with BRAFV600
mutant melanoma includes
– Vemurafenib
– Ipilimumab
– High-dose IL-2
– Dacarbazine
– Clinical trials: BRAF+MEK inhibitors, anti-PD1