DISCLAIMERDISCLAIMERThis 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 thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US

Food and Drug Administration and off-label uses of approved products. Readersshould 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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DISCLAIMERDISCLAIMERParticipants 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 USEDISCLOSURE OF UNLABELED USEThis 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.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestAntoni Ribas, MD, PhDAntoni 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.

IntroductionIntroduction

Antoni Ribas, MD, PhDUniversity of California, Los Angeles (UCLA)

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to: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

Activity AgendaActivity 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)

Oncogenic cell proliferation and survival

BRAF

MEK

ERK

cKitNRAS

Antitumor immune response

IL-2IFN-aAnti-CD40Anti-CD137Anti-OX40

Anti-CTLA4

Anti-PD1

Kit inhibitors

BRAF inhibitors

MEK inhibitors

Therapeutic Targets in MelanomaTherapeutic Targets in Melanoma

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.

Relevance of Immunotherapy for the Relevance of Immunotherapy for the Treatment of Melanoma 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.

Active immunotherapy

Passive immunotherapy

IL-2IFNIL-15IL-21

PD1CTLA4

Peptide vaccineDC vaccineGenetic vaccine

OX40

CD137

CD40

T-cell cloningTCR or CAR

genetic engineering

Active and Passive ImmunotherapyActive and Passive Immunotherapy

TCR = T-cell receptor; CAR = chimeric antigen receptor.Courtesy of Antoni Ribas, MD, PhD.

CTLA4 BlockadeCTLA4 BlockadeT-cell

inactivation

APC

CTLA-4T cell

APC

T cellT cell

APC

CD28CD28

B7

TCR

HLA

CTLA-4

HLA = human leukocyte antigen; APC = antigen presenting cell.Adapted from Weber, 2009.

T-cell activation

T-cell activation

OS = overall survival; ORR = overall response rater; DOR = duration of response;gp100 = glycoprotein 100; PFS = progression-free survival.Hodi et al, 2010.

Ipilimumab + gp100(n = 403)

gp100 + Placebo(n = 136)

RANDOMIZE

Pretreated Metastatic Melanoma (N = 676)

Ipilimumab + Placebo(n = 137)

Phase III Trial of Ipilimumab ± gp100 Vaccine Phase III Trial of Ipilimumab ± gp100 Vaccine Vs. gp100 Vaccine Alone: MDX010-20Vs. gp100 Vaccine Alone: MDX010-20

Primary end point: OS

Secondary end points: ORR, DOR, PFS

Phase III Trial of Ipilimumab Plus Dacarbazine Phase III Trial of Ipilimumab Plus Dacarbazine Vs. Dacarbazine Alone: Study 024Vs. Dacarbazine Alone: Study 024

Scheduled tumor assessments at baseline, 12 wks, and 24 wks

Primary end point: OS

Ipilimumab 10 mg/kgq3wks x 4

Dacarbazine 850 mg/m2

q3wks x 8(n = 250)

Dacarbazine 850 mg/m2

q3wks x 8Placebo(n = 252)

RANDOMIZE

Previously Untreated Metastatic Melanoma(N = 502)

Ipilimumab 10 mg/kgq12wks

Placeboq12wks

Robert et al, 2011.

Improved Survival With IpilimumabImproved Survival With Ipilimumab

3 mg/kg x 4 doses q3wks with or without gp100

10 mg/kg x 4 doses q3wks, then q3mos + dacarbazine

Hodi et al, 2010; Robert et al, 2011.

Week 20: Regression Week 36: Still Regressing

Screening Week 12: Progression

Reproduced with permission from Wolchok et al, 2008.

Objective Response to Ipilimumab After Significant Objective Response to Ipilimumab After Significant Progression With Tumor Volume IncreaseProgression With Tumor Volume Increase

ScreeningWeek 12: Swelling and Progression Week 12: Improved

Week 16: Continued Improvement

Week 72: Complete Remission

Week 108: Complete Remission

Images courtesy of Jedd D. Wolchok, MD.

Unique Kinetics of Response in Unique Kinetics of Response in Patients Treated With IpilimumabPatients Treated With Ipilimumab

WHO = World Health Organization.Wolchok et al, 2009; Ribas et al, 2009.WHO = World Health Organization.Wolchok et al, 2009; Ribas et al, 2009.

The patterns of tumor response with

ipilimumab are different from responses to

cytotoxic therapies due to the immune

mechanism of action

Tumor responses usually take time (1–4

months) to declare, and may go through a

period of uncertainty about response or

progression

A modified WHO tumor resposne criteria

has been proposed to more adequately

assess tumor responses to ipilimumab and

other tumor immunotherapy agents

The patterns of tumor response with

ipilimumab are different from responses to

cytotoxic therapies due to the immune

mechanism of action

Tumor responses usually take time (1–4

months) to declare, and may go through a

period of uncertainty about response or

progression

A modified WHO tumor resposne criteria

has been proposed to more adequately

assess tumor responses to ipilimumab and

other tumor immunotherapy agents

Mechanism of the Differential Kinetics Mechanism of the Differential Kinetics of Tumor Response With Ipilimumabof Tumor Response With Ipilimumab

TumorImmunotherapy

TumorImmunotherapy

Response by WHO or RECIST

Response by WHO or RECIST

ProgressionProgression

irRC?irRC?

Cancer Cell

Lymphocyte

Macrophage

Cancer Cell

Lymphocyte

Macrophage

Ipilimumab Treatment and irAEsIpilimumab 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.

Gl irAEs: OverviewGl 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.

Endocrinopathies: IrAEs (Overview)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.

Beck et al, 2006; Agarwala, 2009; Weber, 2009.

Management of irAEs 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

Other Combinations With Other Combinations With Anti-CTLA4 AntibodiesAnti-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 VEGFImmune Effects of VEGF

VEGF = vascular endothelial growth factor.Tartour et al, 2011.

+

+

hypoxia Immunosuppressivemechanisms

angiogenesis

HIF-1

VEGF

COX-2

PGE2

CXCL12

VEGF

Foxp3+ T cell

VEGFbFGF

macrophage

Stat3

MDSC

arginase

IL-17

IL-6

24

CD8 CD4 CD163Pre-Treatment

Post-Treatment

CD3

Hodi et al, 2011.

Immune Cell Infiltration in TumorsImmune Cell Infiltration in TumorsWith Ipilimumab + BevacizumabWith Ipilimumab + Bevacizumab

Differences Between Blocking CTLA4/B7 Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1and Blocking PD-1/PD-L1

Dendritic cell

T cellMHC TCR

CD28

B7 CTLA4

Ribas, 2012.

Differences Between Blocking CTLA4/B7 Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1 (cont.)and Blocking PD-1/PD-L1 (cont.)

Dendritic cell

MHC

B7

TCR

CD28

CTLA4

T cell

Ribas, 2012.

Differences Between Blocking CTLA4/B7 Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1 (cont.)and Blocking PD-1/PD-L1 (cont.)

Melanoma cell

T cellMHCTCR

PD-L1(B7-H1)

PD-1

Ribas, 2012.

Differences Between Blocking CTLA4/B7 Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1and Blocking PD-1/PD-L1

Melanoma cell

T cellMHCTCR

PD-1

Ribas, 2012.

Induced Expression of PD-L1 (B7-H1) on Induced Expression of PD-L1 (B7-H1) on Melanoma Cells by Infiltrating T Cells 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

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.

Differences Between Blocking Differences Between Blocking CTLA4/B7 and Blocking PD-1/PD-L1CTLA4/B7 and Blocking PD-1/PD-L1

Ribas, 2012.

Clinical Activity and Safety of Anti-PD-1 (BMS-Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients With Advanced 936558, MDX-1106) in Patients With Advanced

MelanomaMelanoma 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.

Changes in Target Lesions Over Time Changes in Target Lesions Over Time in Melanoma Patientsin Melanoma Patients

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

1 mg/kg 10 mg/kg

Hodi et al, 2012.

Summary of ACT Therapies Summary of ACT Therapies for for MelanomaMelanoma

ACT of TIL results in reproducible and durable clinical responses in ~ 20% of 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 of Patients With Metastatic Melanoma Treated With Autologous TILs and IL-2

ACT = adoptive cell therapy; TILs = tumor infiltrating lymphocytes.Rosenberg et al, 2011; Hunder et al, 2008; Morgan et al, 2006; Johnson et al, 2009.

Survival Time (months)

Oncogenic cell proliferation and survival

BRAF

MEK

ERK

cKitNRAS

Melanoma Molecular Profiling: Melanoma Molecular Profiling: Driver Oncogenic Mutations Driver Oncogenic Mutations Define Clinically Relevant Melanoma Molecular SubsetsDefine Clinically Relevant Melanoma Molecular Subsets

Adapted from Fecher et al, 2007; Xing, 2010; Curtin et al, 2005, 2006; Van Raamsdonk et al, 2010.

< 5% melanomas (mucosal, acral)

20% melanomas (> age)

50% melanomas (< age)

Kit inhibitors: imatinib, nilotinib, dasatinib

BRAF inhibitors: vemurafenib, dabrafenib

MEK inhibitors

Usually mutually exclusive Noted in ~70% of melanomas

Key Takeaways:Key Takeaways:FDA Approvals for the TreatmentFDA Approvals for the Treatment

of Metastatic Melanoma 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.

Clinical Debates:Clinical Debates:Interactive Thought Interactive Thought

Leader/Group DiscussionLeader/Group Discussion

Clinical Debates: Clinical Debates:

What Is the Optimal Frontline What Is the Optimal Frontline Treatment for Patients Who Treatment for Patients Who

Present With Metastatic Present With Metastatic Melanoma?Melanoma?

Treatment of Advanced Melanoma in 2012Treatment of Advanced Melanoma in 2012

BRAFV600

+

SOC Experimental

Vemurafenib

Ipilimumab

BRAFV600

Negative

SOC Experimental

HD IL-2

Ipilimumab

HD IL-2

GSK BRAFi+MEKi

Anti-PD1

TIL ACT

Open Questions- Immunotherapy vs. BRAFi first-line?- Immunotherapy + BRAFi?- Treatment of BRAFi resistance?- Prevention of BRAFi resistance?- Role of MTKis?- Role of chemotherapy?

Anti-PD1

TIL ACT

Special Considerations- Uncommon BRAF mutations- NRAS mutants with MAPK dependency

GSK = GlaxoSmithKline; BRAFi = BRAF inhibitor; MEKi = MEK inhibitor; SOC = standard of care.NCCN, 2012; US NIH, 2012a–g.

Targeted Therapy

Per

cen

t A

live

1 2 30Time (yrs)Time (yrs)

Immunotherapy

Per

cen

t A

live

1 2 30

Different Clinical Benefits of Immunotherapy and Different Clinical Benefits of Immunotherapy and Targeted Therapy for Metastatic Melanoma Targeted Therapy for Metastatic Melanoma

Chapman et al, 2011; Hodi et al, 2010.Adapted from Ribas et al, 2012.

Baseline characteristics

OR

R (

%)

30

40

50

70

60

80

ORR by Pre-Defined Subgroups in BRIM2ORR by Pre-Defined Subgroups in BRIM2

20

0

Age

< 65 65Alltreatedpatients

Alltreatedpatients

Sex

F M

LDH at enrollment

1.0–1.5xULN

>1.5xULN

Normal

ECOG PS

0 1

Stage

M1a/M1b

M1c

# priortherapies

1 >1

Previous IL-2

Yes No

10

Overall ORR of 53% (IRC)

RR (size proportional to the number of patients in the subgroup)

95% CI

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.

Subgroup Analyses for OS Subgroup Analyses for OS With Vemurafenib (BRIM3)With Vemurafenib (BRIM3)

Chapman et al, 2011.

Subgroup Analyses for OS Subgroup Analyses for OS With Ipilimumab With Ipilimumab

Hodi et al, 2010.

Subgroup Analyses for OS Subgroup Analyses for OS With Ipilimumab With Ipilimumab

Robert et al, 2011.

Clinical Debates: Clinical Debates:

Should All Patients Get Tested for Should All Patients Get Tested for BRAF Mutations Upfront?BRAF Mutations Upfront?

How Do You Treat Patients How Do You Treat Patients

With BRAF Mutations? With BRAF Mutations?

Cancer growth and survival

BRAF

MEK

ERK

BRAF Inhibitors, Targeted Therapy to BRAF Inhibitors, Targeted Therapy to Block the Driver Oncogenic SignalingBlock the Driver Oncogenic Signaling

Adapted from Fecher et al, 2007; Xing, 2010; Weber, 2011.

Ras GTP

Baseline

pERK

cyclin D

Ki67

Day 15

Cyclin D

BRAFV600

MEK

ERK

P

P

Cell cycle

(Ki67)

PLX4032

RTK

Y-PY-P

GF

Inhibition of MAPK Signaling in Biopsies of BRAFV600 Inhibition of MAPK Signaling in Biopsies of BRAFV600 Melanoma From Patients Treated With VemurafenibMelanoma From Patients Treated With Vemurafenib

MAPK = mitogen-activated protein kinase; pERK = phosphorylated extracellurar signal-regulated kinase.Adapted from Smalley et al, 2010; Flaherty et al, 2010b.

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

Comparison of Maximum Response With Comparison of Maximum Response With Vemurafenib and DabrafenibVemurafenib and Dabrafenib

> 100

50

0

-50

-100

Vemurafenib

Dabrafenib

BRIM3Chapman et al, 2011

BREAK3Hauschild et al, 2012

Chapman et al, 2011; Hauschild et al, 2012.

Early Analysis of the Phase III Trial Early Analysis of the Phase III Trial Comparing Vemurafenib and DacarbazineComparing Vemurafenib and Dacarbazine

OS: HR = 0.37

PFS: HR = 0.26

1,000 mg/m2 iv q3w (n = 338)

Dacarbazine

960 mg po bid (n = 337)

Vemurafenib

RandomizationN = 675

BRAFV600E mutation

Stratification:• Stage• ECOG PS (0 vs. 1)• LDH (elevated vs. normal)• Geographic region

Screening

Chapman et al, 2011.

Improved Survival With VemurafenibImproved Survival With Vemurafenib

Chapman et al, 2011.

338

337

211

280

136

178

34

44

0

1

255

326

173

231

81

109

6

7

No. at risk

Update of the Overall Survival Update of the Overall Survival in BRIM3 in BRIM3 (not (not censored at crossover)censored at crossover)

Dacarbazine

Vemurafenib

Chapman et al, 2012.

100908070605040302010

0

Ove

rall

Su

rviv

al (

%)

0 6 12 18 24

10.3 13.6

Vemurafenib (n = 337)

Median F/U 12.5 months

Dacarbazine (n = 338)

Median F/U 9.5 months

Time (months)

HR 0.76 (95% CI: 0.63–0.93)p < .01 (post-hoc)

BREAK-3: Comparison of PFS With Dabrafenib BREAK-3: Comparison of PFS With Dabrafenib and Dacarbazineand Dacarbazine

ScreenedN = 733

Dabrafenib150 mg bid

n = 187

DTIC1,000 mg/m2 IV

q3w n = 63

Enrolledn = 250

3:1 randomizationDabrafenib150 mg bid

n = 28(68% of PD patients)

Cross over allowed at radiological PD

187 184 173 113 100 41 31 5 3 063 53 31 14 11 6 4 2 0 0

At risk

Hauschild et al, 2012.

Pro

por

tion

Aliv

e W

ithou

t P

rog

ress

ion

(%)

Time from Randomization (Months)

0 1 2 3 4 5 6 7 8 90.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS HR 0.30Dabrafenib median PFS 5.1 months

DTIC: median PFS 2.7 months

Two-Cohort Open-Label Study of Dabrafenib Two-Cohort Open-Label Study of Dabrafenib in Patients With Brain Metastasesin Patients With Brain Metastases

Cohort A (n = 89)(no prior brain treatment)

Cohort B (n = 83)(prior brain treatment)

Dabrafenib 150 mg bid

Screened (N = 325)Enrolled (n = 172)

Metastatic melanoma

Centrally confirmed BRAFV600E/K mutation

Asymptomatic brain metastases

No prior treatment with MEK or BRAF inhibitors

Ma

xim

um p

erce

nt c

ha

ng

e fr

om

ba

selin

e in

tra

cra

nia

l me

asu

rem

ent

OIRR: 31%ORR: 31%Intracranial DCR: 89%Overall DCR: 83%

Ma

xim

um p

erce

nt c

ha

ng

e fr

om

ba

selin

e in

tra

cra

nia

l me

asu

rem

ent

OIRR: 39%ORR: 38%Intracranial DCR: 81%Overall DCR: 80%

Prior brain treatment: Cohort BNo prior brain treatment: Cohort A

Kirkwood et al, 2012.

Examples of Brain Metastases Responses to DabrafenibExamples of Brain Metastases Responses to Dabrafenib

Baseline Week 8

Baseline Week 32

Kirkwood et al, 2012.

BRIM2: Toxicities With VemurafenibBRIM2: Toxicities With Vemurafenib

All grades n (%)

Grade 3n (%)

Grade 4n (%)

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)¶

Includes AEs reported in ≥ 20 patients

†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.

cuSCC/KAs With cuSCC/KAs With VemurafenibVemurafenib

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

0 5 10 15 20 25 3530 40

Time on Vemurafenib (wks)

Median

Ribas et al, 2011.

Acquired Resistance to Vemurafenib: Acquired Resistance to Vemurafenib: Time to Response and ProgressionTime to Response and Progression

16140

Approx timing of CT

assessments

Approx timing of CT

assessments

Continued response

Progressive diseaseProgressive disease

Time to responseTime to response

Time (mos)4 6 8 10 122

Time on studyTime on study

Median DOR = 6.7 mos (95% CI 5.6, 9.8; range 1.3–12.7)CT = computed tomography.Ribas et al, 2011.

Phase III Trial Comparing Trametinib (MEK inhibitor) Phase III Trial Comparing Trametinib (MEK inhibitor) and Dacarbazine in Metastatic Melanomaand Dacarbazine in Metastatic Melanoma

METRIC PFS – Primary Efficacy PopulationMETRIC PFS – Primary Efficacy Population

V600E/K mutation (n = 322)

V600E/K mutation (n = 322)

Chemotherapy(n = 108)

Chemotherapy(n = 108)

Trametinib 2 mg QD (n = 214)

Trametinib 2 mg QD (n = 214)

Trametinib 2 mg QD

Trametinib 2 mg QD

PFSPFS

FSFV: Dec 2010, LSFV: July 2011

Cross-over*

Screened (N = 1,059)Screened (N = 1,059)

Pro

po

rtio

n A

live

an

d P

rog

ress

ion

-Fre

e

Time From Randomization (Months)0 1 2 3 4 5 6 7 8 9

Number at risk

INV – Trametinib 178 170 130 79 69 22 18 4 0 0INV – Chemotherapy 95 77 38 20 17 8 5 1 0 0

INV – Trametinib

IRC – Trametinib

INV – Chemotherapy

IRC – Chemotherapy 0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 Events n (%)

Median (months)

HR (95%CI)p Value

Trametinib 96 (54) 4.8 0.44 (0.31, 0.64)< .0001

Chemotherapy 68 (72) 1.4

Robert et al, 2012; Flaherty et al, 2012.Robert et al, 2012; Flaherty et al, 2012.

Conclusion: Trametinib is the first MEKi to show statistically significant PFS, RR, and OS benefit in a randomized trial compared to chemotherapyConclusion: Trametinib is the first MEKi to show statistically significant PFS, RR, and OS benefit in a randomized trial compared to chemotherapy

Clinical Debates:Clinical Debates:

Should Therapies Be Used Should Therapies Be Used in Combination? in Combination?

Mechanisms of Resistance to BRAF InhibitorsMechanisms of Resistance to BRAF Inhibitors

Survival

BRAFV600E

MEK

ERK

P

P

BRAF inh

PDGFRb or IGF1R

PI3K

AKT

MEK-independentprogression

NRASQ61

COT

CRAF

MEK-dependentprogression

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.

MEKi

PI3Ki or AKTi

Treating Resistance to BRAFi Treating Resistance to BRAFi

BRAFi MEKi No activity(Kim et al, 2011)

BRAFi Local Tx + BRAFiOccasional prolonged responses(Kim et al, 2011)

BRAFi BRAFi ORR 19%(Flaherty et al, 2011)MEKi

BRAFi ORR 50%–74%, increased PFS?(Infante et al, 2011)

MEKi

Progression of melanoma

BRAFi = vemurafenib, dabrafenib (GSK2118436); MEKi = trametinib (GSK1120212).

• Clinical activity

Drug–drug interactionDrug–drug interaction

Dabrafenib + Trametinib Study DesignDabrafenib + Trametinib Study Designand Objectivesand Objectives

Dose escalation

Expansion cohorts

Randomized Phase II trial

Colorectal BRAF+ Prior BRAF inhibitor

Part A

Part B

Part C

• Trametinib effects on dabrafenib PK

• Trametinib effects on dabrafenib PK

• Safety/tolerability• Determine phase II dose• Steady-state PK• Clinical activity

• Safety/tolerability• Determine phase II dose• Steady-state PK• Clinical activity

• Clinical activity

Bridging Studydabrafenib (HPMC) +

trametinib

Part D

• Safety/tolerability• Characterize PK of dabrafenib

HPMC capsules

• Safety/tolerability• Characterize PK of dabrafenib

HPMC capsules

• Clinical activity (RR, PFS) of combo vs dabrafenib

• Assess safety/tolerability

• Clinical activity (RR, PFS) of combo vs dabrafenib

• Assess safety/tolerability

Objective/sObjective/s

N = 77 BRAFi-naïve melanoma patients across 4

dose levels

N = 77 BRAFi-naïve melanoma patients across 4

dose levels

Part A

Part C Randomized phase II trial

Part D Bridging studydabrafenib (HPMC) +

trametinib

Objective/s

• Trametinib effects on dabrafenib PK

• Clinical activity (RR, PFS) of combo vs. dabrafenib

• Assess safety/tolerability

• Safety/tolerability• Characterize PK of dabrafenib

HPMC capsules

PFS = progression-free survival; PK = pharmacokinetics; HPMC = hydroxypropyl methylcellulose.Weber et al, 2012.

Investigator-Assessed Maximum Tumor Reduction Investigator-Assessed Maximum Tumor Reduction Part B BRAFi-Naïve Melanoma Patients Part B BRAFi-Naïve Melanoma Patients (N = 77) (N = 77)

K

KKK

KK

Dose level: dabrafenib/trametinib (mg bid/mg QD)

75/1

150/1

150/1.5

150/2

RR 44%–67%

Median DOR 11.3 months (95% CI: 9.2, NR)

Median PFS 7.4 months, PFS at the highest dose 10.8 months

RR 44%–67%

Median DOR 11.3 months (95% CI: 9.2, NR)

Median PFS 7.4 months, PFS at the highest dose 10.8 months

K = BRAFV600K mutation-positive patients.Weber et al, 2012.

Best Confirmed Response Rate Best Confirmed Response Rate Part B BRAFi-Naïve Melanoma Patients Part B BRAFi-Naïve Melanoma Patients

(N = 77)(N = 77)

Dose-Level of Dabrafenib/Trametinib

Re

sp

on

se

Ra

te (

%)

75/1(n = 6)

150/1(n = 22)

150/1.5(n = 25)

150/2(n = 24)

All doses(n = 77)

67%63%

44%

64%57%

18% CR

8% CR 8% CR

Median DOR 11.3 months (95% CI: 9.2, NR)

Weber et al, 2012.

CR+PR

CR+PR+SD

Treatment Duration Treatment Duration Part B BRAFi-Naïve Melanoma Patients (N = 77) Part B BRAFi-Naïve Melanoma Patients (N = 77)

Treatment Duration (months)

Ongoing

Discontinued/progressed

38% of patients are ongoing

Median Duration of Treatment = 10.7 months

Weber et al, 2012.

Time (yrs)

Immunotherapy Targeted Therapy

Pe

rce

nt

Aliv

e

Pe

rce

nt

Aliv

e

1 2 30 1 2 30Time (yrs)

Combination?

Pe

rce

nt

Aliv

e

1 2 30Time (yrs)

Chapman et al, 2011; Hodi et al, 2010.Adapted from Ribas et al, 2012.

Combining Immunotherapy and Combining Immunotherapy and Targeted Therapy for Melanoma?Targeted Therapy for Melanoma?

Can BRAF Inhibitors Be Combined Can BRAF Inhibitors Be Combined With Tumor Immunotherapy?With Tumor Immunotherapy?

Comin-Anduix et al, 2010; Boni et al, 2010; Wilmott et al, 2011.

Author Title Journal

Comin-Anduix et al, 2010 The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affectthe Viability or Function of Human Lymphocytes across a Wide Rangeof Concentrations

Clinical Cancer Research

Boni et al, 2010 Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma Without Affecting Lymphocyte Function

Cancer Research

Wilmott et al, 2012 Selective BRAF Inhibitors Induce Marked T-cell Infiltration Into Human Metastatic Melanoma

Clinical Cancer Research

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

Systemic Therapies for Advanced Systemic Therapies for Advanced or Metastatic Melanomaor 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.

Guidance in Therapy Decisions 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.

Case Study 1 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

Case Study 1 (cont.) Case Study 1 (cont.)

Should this patient receive:

– Ipilimumab 3 mg/kg x 4 doses

– Vemurafenib 960 mg po BID

– Clinical trial

– Surgery

Case Study 1 (cont.) Case Study 1 (cont.)

The patient received vemurafenib 960 mg po BID within the PLX4032 phase I trial (BRIM1) and continues with a sustained tumor response over 2 yrs later

Case Study 2 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

Case Study 2 (cont.) 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

Before Ipilimumab04/22/11

After Ipilimumab08/05/11

Case by Antoni Ribas, MD, PhD.

Metastatic Melanoma Response to IpilimumabMetastatic Melanoma Response to Ipilimumab

Key TakeawaysKey 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