Part II – Melanoma: Novel Pathways and Agents Tuesday, June 21, 2011 7:30 PM – 8:30 PM ET RTP...

Part II – Melanoma: Novel Pathways and AgentsTuesday, June 21, 20117:30 PM – 8:30 PM ET

RTP TV: An 8-Part Live CME Webcast Series

Keith T Flaherty, MDAssociate ProfessorHarvard Medical SchoolDirector of Developmental TherapeuticsMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Jeffrey Weber, MD, PhDSenior Member, H Lee Moffitt Cancer Center Director, Donald A Adam Comprehensive Melanoma Research Center Tampa, Florida

Neil Love, MDResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium — The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics.

Disclosures for Keith T Flaherty, MD

Advisory CommitteeBristol-Myers Squibb Company, Eisai Inc, Genentech BioOncology

Consulting Agreements Cephalon Inc, GlaxoSmithKline

Disclosures for Jeffrey Weber MD, PhD

Advisory Committee

Bristol-Myers Squibb Company, Celldex Inc, Genentech BioOncology, Novartis Pharmaceuticals Corporation

Consulting Agreement Bristol-Myers Squibb Company

Stock Ownership Celldex Inc

Pathology Video Primer Adriano Piris, MD

Dermatopathologist, Massachusetts General HospitalDirector, Quality and Safety Division, MGH DermatopathologyInstructor of Pathology, Harvard Medical SchoolBoston, Massachusetts

No financial interests or affiliations to disclose

Agenda

• Overview: Melanoma in current practice

• ASCO 2011 plenary/NEJM

– Dacarbazine + ipilimumab

– Vemurafenib vs dacarbazine

• Faculty cases

• Adjuvant update

– Pathology video primer (Adriano Piris, MD)

Survey of 100 Practicing Oncologists April 15-28, 2011

• 5 — Median number of new patients with melanoma

evaluated in the past year

• Fraction of oncologists who in the past year…

– Referred a melanoma patient to tertiary center: 76%

– Enrolled a melanoma patient on a clinical trial: 57%

– Had melanoma patients tested for BRAF mutation: 47%

1. What is your usual preferred first-line therapy

off protocol for a younger, otherwise healthy patient with metastatic melanoma?

6%

26%

6%

38%

24%

0% 5% 10% 15% 20% 25% 30% 35% 40%

Other

Ipilimumab

Paclitaxel/carboplatin

High-doseinterleukin-2

Dacarbazine ortemozolomide

Survey of 100 Practicing Oncologists April 15-28, 2011

First-line systemic treatment for metastatic melanoma?

• Temozolomide (alone or in combination): 49%

• Dacarbazine (alone or in combination): 20%

• High-dose interleukin-2: 14%

• Paclitaxel/carboplatin: 11%

• Other: 6% (Ipilimumab: 2%)

• I do not treat patients with metastatic melanoma: 12%

Survey of 100 Practicing Oncologists

Where are you most likely to use ipilimumab in the treatment algorithm for metastatic melanoma?

• Front line single agent — 41%• Second line single agent — 29%• Front line in combination with chemotherapy — 5%• Second line in combination with chemotherapy — 1%

• I don’t know — 24%

RTP TV – Year of Melanoma: Two Landmark Trials

Key Topics

ASCO 2011 PlenaryWolchok et al. Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.

N Engl J Med 2011Robert et al. Ipilimumab plus dacarbazine for previouslyuntreated metastatic melanoma

Chapman et al. Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.

Chapman et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation

Margolin et al. Melanoma therapy great news...and new challenges

Ernstoff. Been there, not done that — Melanoma in the age of molecular therapy

2. For how many patients with melanoma have you used ipilimumab off study?

3%

0%

0%

8%

89%

0% 20% 40% 60% 80% 100%

More than 10

Six to 10

Three to five

One to two

None

Wolchok J et al.

Proc ASCO 2011;Abstract LBA5.

Phase 3 Randomized Study of Ipilimumab (IPI) Plus Dacarbazine (DTIC) vs DTIC Alone as First-Line Treatment in Patients With Unresectable Stage III or IV Melanoma

Robert C et al. N Engl J Med 2011 Jun 5;[Epub ahead of print].

Hodi FS et al. N Engl J Med 2010;363(8):711-23. Hwu P. N Engl J Med 2010;363(8):779-81.

ASCO: June 5, 2010Published: Aug 19, 2010

With permission from Wolchok J et al. Proc ASCO 2011;Abstract LBA5.

T-cellActivation

T-cellInactivation

T-cell Remains Active

resting

T-cell

T-cellT-cell

CTLA-4

HLA B7

APC APC APC

Ipilimumab

Ipilimumab, a CTLA-4 Blocking Monoclonal Antibody, Augments T-Cell Activation

CTLA-4

CTLA-4

Wolchok J et al. Proc ASCO 2011;Abstract LBA5.

Study 024: Phase III Placebo-Controlled Trial of First-line DTIC ± IPI (10 mg/kg)

SCREENING INDUCTION MAINTENANCE

Previously untreated

metastatic melanoma(N = 502)

Previously untreated

metastatic melanoma(N = 502)

Ipilimumab 10 mg/kgq3w x4

Ipilimumab 10 mg/kgq3w x4

Placebo q3w x4Placebo q3w x4

Ipilimumab 10 mg/kgq12w

Ipilimumab 10 mg/kgq12w

Placeboq12w

Placeboq12w

Week 1Week 1

Dacarbazine 850 mg/m2

q3s x8Dacarbazine 850 mg/m2

q3s x8

Dacarbazine 850 mg/m2

q3s x8Dacarbazine 850 mg/m2

q3s x8

Week 12Week 12 Week 24Week 24

Baseline tumor assessment

First scheduledTumor assessment

R

Study 024: Overall Survival


Ipilimumab + Dacarbazine versus Placebo + Dacarbazine

HR (95% CI)Median OSp-value

0.72 (0.59-0.87)11.2 vs 9.1 months0.0009

Pro

po

rtio

n A

live

Years

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4

Ipilimumab + dacarbazinePlacebo + dacarbazine

Years

Study 024: Overall Survival


Pro

po

rtio

n A

live

Estimated Survival Rate

1 year 2 year 3 year*

Ipilimumab + dacarbazinen = 250

47.3 28.5 20.8

Placebo + dacarbazinen = 252

36.3 17.9 12.2


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4

*3-year survival was a post-hoc analysis

Study 024: Progression-Free Survival



HR (95% CI)Median PFSp-value

0.76 (0.63-0.93)2.8 vs 2.6 months0.006


1st tumor assessment(per protocol)

Pro

po

rtio

n w

ith

ou

t D

isea

se P

rog

ress

ion

Years

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2

Study 024: Duration of Response (DoR)



Pro

po

rtio

n w

ith

CR

or

PR

Years

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2

Data shown for patients with a confirmed complete response (CR) or partial response (PR)


DoR 19.3 vs 8.1 months

Study 024: Safety Summary

• Types of adverse events associated with IPI consistent with previous studies

– Mainly affect skin, GI tract, liver, endocrine system

• Mechanism (immune)-based:

– Managed with established guidelines

– Generally response to dose interruptions/discontinuation, corticosteroids and/or other immunosuppressants

• Rates of high-grade events different from observed in Phase II

– Elevated AST and ALT rates – higher

– Diarrhea and colitis rates – lower

– No GI perforations

Wolchok J et al. Proc ASCO 2011;Abstract LBA5.

How Should IPI Be Studied Next?

• Single agent questions– Dose and duration of therapy– Biomarkers of activity and of toxicity– Predictive immuno-molecular markers

• Combinations, sequences (ongoing or planned)– Cytotoxic agents– Molecularly targeted agents including vemurafenib– Immunomodulators– VEGF receptor blockade (Hodi et al. Proc ASCO

2011, Abstract 8511.)• Multi-checkpoint blockade (e.g. PD-1 axis)

Margolin K et al. Proc ASCO 2011; Discussant.

3. Have you ordered a BRAF mutation assay for a patient with melanoma?

76%

24%

0% 10% 20% 30% 40% 50% 60% 70% 80%

No

Yes

Long GV et al. J Clin Oncol 2011;29(10):1239-46. Flaherty KT. J Clin Oncol 2011;9(10):1229-30.

BRAF Mutations in Melanoma

• Roughly 40-60% of cutaneous melanomas are positive for mutations in the BRAF gene1,2.

• BRAF V600E mutation comprises approximately 90% of BRAF mutations3.

1Davies H et al. Nature 2002;417(6892):949-54; 2Curtin JA et al. N Engl J Med 2005;353(20):2135-47; 3Chapman PB et al. N Engl J Med 2011;[Epub ahead of print];

Vemurafenib Inhibits BRAFV600E Kinase

RTK

VEMURAFENIB(PLX4032, RO5185426)

RAS BRAFV600E MEK ERKGene

transcription

40-60% of melanomas

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

Cellular proliferation

Chapman PB et al.

Proc ASCO 2011;Abstract LBA4.

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

Chapman PB et al. N Engl J Med 2011 Jun 5;[Epub ahead of print].

BRIM2: An Open-Label, Multicenter Phase II Study of Vemurafenib (PLX4032, RG7204) in Previously Treated Patients with BRAFV600E Mutation-Positive Metastatic Melanoma

Ribas A et al. Proc ASCO 2011;Abstract 8509.

Assessment of Primary Endpoint: Tumor Responses by IRC

• ORR 53% by IRC• ORR 57% by investigator assessments (INV)• RR, including unconfirmed, 69% (INV)• PR in 5 of 10 BRAFV600K patients

Response Rate (%)

70

60

50

40

30

20

10

0CR+PRn = 70

SDn = 38

PDn = 18

53% CR + PR

5% CR

29%

14%

Error bars represent 95% confidence intervals

Ribas A et al. Proc ASCO 2011;Abstract 8509.

Changes in the Sum of Diameters from Baseline by Disease Stage

60

40

20

0

-20

-40

-60

-80

-100Individual Patients Treated with Vemurafenib

Per

cen

t C

han

ge

fro

m B

asel

ine

in D

iam

eter

of

Tar

get

Les

ion

Disease Stage

M1aM1bM1c

7 confirmed CRs

With permission from Ribas A et al. Proc ASCO 2011;Abstract 8509.

BRIM3: Phase III Study Design

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

Screening

BRAFV600E mutation

Stratification

• Stage• ECOG PS (0 vs 1)• LDH level (vs nl)• Geographic region

R

Vemurafenib

960 mg po bid

(N = 337)

Dacarbazine

1,000 mg/m2 iv q3w

(N = 338)

Coprimary endpoints: Overall and progression-free survival rates

BRIM3: Select Adverse Events


Adverse Event, %

DTIC (n = 282)Vemurafenib

(n = 336)

All Gr 3 All Gr 3

Arthralgia 3% <1% 49% 3%

Rash 1% – 36% 8%

LFTs 5% 1% 18% 7%

Cutaneous SCC <1% <1% 12% 12%

Keratoacanthoma – – 8% 6%

Skin papilloma – – 18% <1%

• ≥Gr 4 adverse events in vemurafenib arm: Neutropenia (<1%), LFTs (<1%)• Discontinuations due to adverse events: 6% vemurafenib, 4% DTIC

BRIM3: Efficacy Results


Clinical Parameter

DTIC(n = 336)

Vemurafenib(n = 336) HR p-value

ORR CR PR

5.5%0

5.5%

48.4%0.9%

47.5%– –

Estimated 6-month OS rate 64% 84% 0.37 <0.0001

ORR = overall response rate; CR = complete response; PR = partial response

BRIM3: Maximal Tumor Response

Chapman PB et al. N Engl J Med 2011. Jun 5 [Epub ahead of print]. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Vemurafenib

Dacarbazine

Per

cen

t C

han

ge

fro

m B

ase

lin

e in

Su

m o

f T

um

or

Dia

met

ers

>100

50

0

-50

100

>100

50

0

-50

100

BRIM3: Efficacy Results

Clinical Parameter

DTIC(n = 336)

Vemurafenib(n = 336) HR p-value

ORR CR PR

5.5%0

5.5%

48.4%0.9%

47.5%– –

Estimated 6-month OS rate 64% 84% 0.37 <0.0001

ORR = overall response rate; CR = complete response; PR = partial response


BRIM3: Maximal Tumor Response


Vemurafenib

Dacarbazine

Per

cen

t C

han

ge

fro

m B

ase

lin

e in

Su

m o

f T

um

or

Dia

met

ers

>100

50

0

-50

100

>100

50

0

-50

100

Progression-Free Survival (Dec 30, 2010 cutoff)

Pro

gre

ssio

n-f

ree

surv

ival

(%)

Months

Hazard ratio 0.26(95% CI; 0.20 - 0.33)Log-rank p < 0.0001Vemurafenib (N = 275)

Decarbazine (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



Overall Survival(December 30, 2010 cutoff)

4. If vemurafenib were available, what would be your usual first-line therapy for a younger, otherwise healthy patient with asymptomatic BRAF V600E-mutant melanoma?

59%

9%

2%

23%

2%

5%

0%

0% 10% 20% 30% 40% 50% 60% 70%

Other

Vemurafenib

Ipilimumab

Paclitaxel/carboplatin

High-doseinterleukin-2

Temozolomide

Dacarbazine

Future Research Directions with Vemurafenib

• Biomarkers of resistance/escape

• Predictors of toxicity/management

• Combinations and sequences

– MEK inhibitors

– PI3K and mTOR inhibitors

– IGFR inhibitors

– Immunomodulators

– Cytotoxic agents

Margolin K et al. Proc ASCO 2011; Discussant.

Case 1 (Dr Weber)

• 55 yo man with bulky, unresectable left lower extremity and para-aortic disease

– Treated with the BRAF inhibitor vemurafenib (PLX4032)

– Rapid disease regression, near CR after 16 weeks

– On therapy 12 more months

• Relapses with subcutaneous lesion in involved left leg

– Resected

– PET/CT and MRI: NED

– Remains on vemurafenib

– Alive and disease-free 12 months later

MRI (Case 1)

Pretreatment Post-Treatment – 8 weeks

Case 2 (Dr Flaherty)

• 62 yo man with T4, N1b melanoma resected in 2008 with primary on right arm and involved palpable lymph node in right axilla– Received one year of high-dose interferon

• May 2011: Palpable right supraclavicular lymph node – FNA: Melanoma

• Staging CT scans – Several enlarged right supraclavicular and mediastinal

lymph nodes– Lung and liver lesions– LDH 2x upper limit of normal

• Tumor block from 2008 lymphadenectomy– V600E mutation present

Case 2 (Dr Flaherty): Primary Melanoma, Ulcerated, Measuring at Least 1.5 mm in Thickness

Case 3 (Dr Weber)

• 72 yo man with lung, liver and bony disease

– Failed carbo/paclitaxel/sorafenib on protocol

– Failed high-dose IL2

– Failed PD-1 antibody

• Ipilimumab off protocol

– Develops itchy rash and hypothyroidism (corrected)

– Continues therapy and has SD at week 12 evaluation

– Slow regression over next 12 months with 90% PR

– Tapered off synthroid with minimal disease via CT

CT Scans (Case 3)

Pretreatment 12 weeks Post-treatment

24 weeks Post-treatment

CT Scans (Case 3)

Pretreatment 12 weeksPost-treatment

24 weeks Post-treatment


• 54 yo man with 2.0 mm, at least level IV, non-ulcerated, melanoma

– 4 mitoses/mm2 on scalp

– Two palpable lymph nodes, total of 10 out of 77 necks nodes positive for melanoma

• Received one year of high-dose interferon

• June 2011: Seizure

– Brain MRI: Two dominant brain metastases and several smaller ones

• Tumor block from 2010 lymphadenectomy

– BRAF mutation testing requested

Ipilimumab in Stable, Asymptomatic Brain Metastases: Overall Survival

With permission from Heller KN et al. ASCO 2011;Abstract 8581.

X = censored deaths

Overall survival for 51-patient cohortRx with 10 mg/kg x4 plus maintenance

Case 5 (Dr Weber)

• 32 yo man with lung and intra-abdominal disease

– Treated with biochemotherapy, but increased intra-abdominal disease

– Receives ipilimumab

– Acute abdomen with evidence of free air

– Perforation: Area repaired, with no real disease observed by the surgeon

• Disease regresses at first evaluation

– Patient continues to have diminution of disease

– CR after one year

• Patient is alive and well 8 years later

1Agarwala SS et al. ASCO 2011;Abstract 8505. 2Chiarion-Sileni V et al. ASCO 2011;Abstract 8506.

Study IFN DosingNo. Pts Outcome

ECOG

E16971

HD IFN x 1 mo

vs

observation

1150 Stopped for futility

• Median RFS: 7.3y vs 7.8y

• 5y OS: 82% vs 85%

Italian

Melanoma

Intergroup2

Intensified HD IFN

vs

Kirkwood regimen

330 No differences

• Median RFS: 4y vs 3.3y

• 5y OS: 59.5% vs 53.2%

Adjuvant Interferon: Randomized Trials Testing Changes in the Kirkwood HD IFN Regimen

EORTC 18991 Phase III Trial: Long-Term Adjuvant Pegylated Interferon-α2b (PEG-IFN) versus Observation in Resected Stage III Melanoma: Long-Term Results at 7.6-Years Follow-Up

Eggermont AM et al. Proc ASCO 2011;Abstract 8506b.

Eggermont AM et al. ASCO 2011;Abstract 8506b.

RFS DMFS OS

All patients

(N = 1,256)

Obs PEG-IFN Obs PEG-IFN

Obs PEG-IFN

7-year rates 35% 39% 40% 42% 46% 48%

Median, years 2.2 3.0 3.2 3.9 5.6 6.2

Hazard ratiop-value

HR = 0.87

p = 0.05

HR = 0.93

p = 0.33

HR = 0.96

p = 0.57

N1+, ulcerated

(n = 186)

HR = 0.72

p = 0.06

HR = 0.65

p = 0.02

HR = 0.59

p = 0.006

Survival Benefits of PEG-IFN in Resected Stage III Melanoma

Schedule of Events

Tuesday, June 28 Non-Small Cell Lung CancerLucian R Chirieac, MD Thomas J Lynch Jr, MDLecia V Sequist, MD, MPH

Tuesday, July 5Multiple MyelomaNikhil C Munshi, MDA Keith Stewart, MBChB

Tuesday, July 12Gastric CancerCharles S Fuchs, MD, MPHDavid H Ilson, MD, PhDLaura H Tang, MD, PhD

Tuesday, July 19Triple-Negative Breast Cancer: Current Clinical Management

Harold J Burstein, MD, PhDCharles E Geyer Jr, MD

Tuesday, July 26Non-Hodgkin’s Lymphoma/Chronic Lymphocytic LeukemiaStephanie A Gregory, MDJohn P Leonard, MD

Tuesday, August 2Chronic Myeloid LeukemiaSusan M O’Brien, MDNeil P Shah, MD, PhD

Part II – Melanoma: Novel Pathways and Agents Tuesday, June 21, 2011 7:30 PM – 8:30 PM ET RTP...

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Transcript of Part II – Melanoma: Novel Pathways and Agents Tuesday, June 21, 2011 7:30 PM – 8:30 PM ET RTP...