updates in community oncology 2011: a focus on melanoma this program is supported by educational...

Updates in Community Oncology 2011:A Focus on Melanoma

This program is supported by educational grants fromBristol-Myers Squibb, Genentech BioOncology, and Merck.

Updates in Community Oncology 2011: Melanoma

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Faculty

Keith T. Flaherty, MDDirector of Developmental TherapeuticsMassachusetts General Hospital Cancer CenterBoston, Massachusetts

John M. Kirkwood, MDProfessor, Medicine, Dermatology, and Translational ScienceDirector, Melanoma and Skin Cancer ProgramUniversity of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania

Jedd D. Wolchok, MD, PhDDirector, Immunotherapy Clinical Trials Department of Medicine Associate Attending Physician Department of Medicine, Melanoma/Sacroma Services Memorial Sloan-Kettering Cancer Center New York, New York


Disclosures

Keith T. Flaherty, MD, has disclosed that he has received consulting fees from GlaxoSmithKline and Roche-Genentech BioOncology.

John M. Kirkwood, MD, has disclosed that he has received consulting fees from GlaxoSmithKline, Merck, and Roche-Genentech BioOncology.

Jedd D. Wolchok, MD, PhD, has disclosed that he has received consulting fees from Bristol-Myers Squibb.

Adjuvant Therapy for Melanoma


E1684, E1690, and E1694: Durable Impact on RFS and OS All trials of IFNα with durable benefit in terms of RFS and

OS used IV induction at 20 MU/m2 (Cmax > 10,000 µ/mL)

Cooperative Group/PI

Eligibility nN Treatment Agent/Dosage/Duration

Impact on

RFS OS

ECOG 1684[1] T4, N1 287 IFNα2b 20 MU/m2/day IV x 1 mo 10 MU/m2 SC TIW x 11 mos

+ +

at 6.9-12.6 yrs

ECOG 1690[2] T4, N1 642 IFNα2b 20 MU/m2/day IV x 1 mo 10 MU/m2 SC TIW x 11 mos vs 3 MU/D SC

TIW x 2 yrs

+ -

at 4.3-6.6 yrs

ECOG 1694[3] T4, N1 880 IFNα2b 20 MU/m2/day IV x 1 mo 10 MU/m2 SC TIW x 11 mos vs

GMK vaccine x 96 wks

+ +

at 1.3-2.1 yrs

1. Kirkwood JM, et al. J Clin Oncol. 1996;14:7-17. 2. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 3. Kirkwood JM, et al. J Clin Oncol. 2001;19:1430-1436.


3 Meta-analyses of All Trials of IFN-alfa Confirm RFS, OS ImpactMeta-analysis

RCT, n

RFS OS Comment

Ives[1] 18 + -/+ Did not include E1694

↑benefit with ↑IFN dose

Wheatley[2] 13 +OR: 0.87;

95% CI: 0.81-0.93; P = .00006

+OR: 0.9;

95% CI: 0.84-0.97; P = .008

OS translates into absolute benefit of 3% (CI: 1% to 5%) at 5 yrs

Mocellin[3] 14 +HR: 0.82

95% CI: 0.77-0.87; P < .001

+HR: 0.89;

95% CI: 0.83-0.96; P = .002

18% risk reduction in DFS 11% risk reduction in OS

1. Ives NJ, et al. J Clin Oncol. 2007;25:5426-5434. 2. Wheatley K, et al. ASCO 2007. Abstract 8526. 3. Mocellin S, et al. J Natl Cancer Inst. 2010;102:493-501.


STRATIFICATION

Pathologic Lymph Node StatusKnownUnknown

Lymph Node Staging ProcedureSentinel lymph node procedure; elective lymph node dissection; no lymphadenectomy

Breslow Depth1.5-3.0 mm3.1-4.0 mm > 4 mm

Ulceration of Primary LesionYesNo

Disease StageLymph node positiveLymph node negative

Arm B:

4-wk high-dose IFN alfa-2b

20 MU/m2/day QD IV for 5 consecutive days out of 7 (M-F) every wk x 4 wks

Hypothesis: 1-month induction IV IFN is necessary and sufficient to achieve durable adjuvant benefit in intermediate-risk melanoma patients

E1697: 4 Wks of High-Dose IFN alfa-2b in Stage T3-T4 or N1 Melanoma

Arm A:

Observation

R

A

N

D

O

M

I

Z

E

Agarwala SS, et al. ASCO 2011. Abstract 8505.


Median RFS

HDI (n = 425)

6.8 yrs, 95% CI: 5.1-9.0

Observation (n = 413)

7.3 yrs, 95% CI: 5.3-9.8

Efficacy analysis

P value from stratified log-rank test = .962

No significant difference

Futility analysis

HR: 1.01, 95% CI: 0.71-1.43

Conditional power: 3%

E1697: 3rd Interim Analysis—RFS (N = 838)

Pro

bab

ilit

y

1.00.90.80.70.60.50.40.30.20.1

00 111 2 3 4 5 6 7 8 9 10

Yrs

TreatmentObservationHDI

Total413425

Failed111123

Censored302302

Median7.36.8

Agarwala SS, et al. ASCO 2011. Abstract 8505.


E1697: Current Assessment

No benefit from 1 mo of IFN in stage IIB/IIIA disease

Patients with IIB/IIIA melanoma require 1 year of standard therapy (E1684, E1690, E1694)

Analysis of mortality and role of salvage therapy indicate that

– Crossover has confounded both adjuvant and advanced disease therapy

– IFN from observation in E1690[1]

– Anti-CTLA4 abstract: tremelimumab phase III trial[2]

– BRAF inhibitor trials?

Potential predictive biomarkers of immunotherapy?

– Autoimmunity[3]

– Cytokine profile pretreatment[4]

1. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 2. Ribas A, et al. ASCO 2008. Abstract LBA9011. 3. Gogas H, et al. N Engl J Med. 2006;354:708-718. 4. Yurkovetsky ZR, et al. Clin Cancer Res. 2007;13:2422-2428.


Patients with autoimmunity (n = 52)

Patients with autoimmunity (n = 52)

Patients without autoimmunity (n = 148)Patients without autoimmunity (n = 148)

Time to Progression OS

Multivariate Analysis of High-Risk Melanoma Patients Receiving HDI

Positive Autoimmunity Status RFS OS

HR (95% CI) P Value HR (95% CI) P Value

At 3 mos 0.15 (0.06-0.37) < .001 0.07 (0.02-0.28) < .001

At 12 mos 0.08 (0.03-0.22) < .001 0.02 (<0.01-0.15) < .001

1.0

0.5

0

Pro

bab

ilit

y

Mos0 20 40 60 80 100

1.0

0.5

0

Pro

bab

ilit

y

Mos0 20 40 60 80 100

Gogas H, et al. N Engl J Med. 2006;354:709-718.


Stratified by:

Microscopic (N1) vs palpable (N2)

1 vs 2-4 vs 5+ nodes

Breslow

Ulceration

Gender and site

Observation

Peg-IFN alfa-2b

Induction (8 wks) 6 µg/kg/wk

Maintenance (5 years or distant metastasis) 3 µg/kg/wk

Dose reduction to 3, 2, 1 to maintain performance status

Primary Endpoints:

Relapse-free survival

Distant metastasis-free survival

Patients (N = 1256): Resected TxN1-2M0 melanoma, within 7 wks of lymphadenectomy

Randomization

Eggermont AM, et al. Lancet. 2008;372:117-126.

EORTC 18991: Peg-IFN alfa-2b vs Observation


EORTC 18991 (2011 Update): Outcome at 7.6 Yrs of Follow-up RFS benefit with pegIFN alfa-2b still significant at 7.6 yrs,

but eroded 2007 2009

No change in DMFS or OS

Outcome (ITT)

2007 2011

HR (95% CI) P Value HR (95% CI) P Value

RFS 0.82 (0.71-0.96) .01 0.87 (0.76-1.00) .05

DMFS 0.88 (0.75-1.03) .11 0.93 (0.81-1.07) .33

OS 0.98 (0.82-1.16) .78 0.96 (0.82-1.11) .57

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


EORTC 18991 (2011 Update): RFS by Subgroup RFS 2011

HR (99% CI) P Value

Stage III N1 0.82 (0.61-1.10) .08*

Stage III N2 0.89 (0.71-1.13) .21

Ulcerated 0.81 (0.58-1.14) .11*

Not ulcerated 1.05 (0.79-1.41) .64

*Statistically significant vs observation in 2007, but not in 2011



EORTC 18991 (2011 Update): Stage III N1, Ulcerated Disease Stage III N1 and ulcerated primary tumors showed

significant benefit for multiple endpoints, including OS

– Median OS pegIFN vs observation: > 9.0 vs 3.7 yrs

EORTC 18081 plans comparison of pegIFN x 2 yrs vs observation in ulcerated primary tumors > 1 mm

Outcome in Patients WithStage III N1, Ulcerated Primary

HR (99% CI) P Value

RFS 0.72 (0.46-1.13) .06

DMFS 0.65 (0.41-1.04) .02

OS 0.59 (0.35-0.97) .006



Adverse Event Summary and Treatment Compliance

Treatment compliance Median induction duration: 8 wks Median maintenance duration: 14.9 mos 31% of patients discontinued treatment due to AEs; 23% remain on

treatment in Yrs 4-5

Grade 3/4 Adverse Event, % PegIFN(n = 627)

Observation(n = 629)

Any 47 16

Events occurring in > 5% of patients (grade 3/4)

Fatigue 14/1 1/0

Liver toxicity 10/< 1 1/< 1

Depression 6/< 1 < 1/< 1



Summary: Adjuvant Modalities Evaluated to DateIFN alfa-2b, 2a; PegIFN alfa-2b HDI has only confirmed, significant, durable OS and

RFS benefit (ITT) at > 10 yrs (E1684/90/94)

IL-2 Never tested, too toxic

Cellular Vaccines Ganglioside VaccineProtein MAGE A3

Canvaxin detrimental in phase III trialsGMK inactive: neither of benefit, nor detriment

Pending

GM-CSF, Peptide Vaccine Neither GM-CSF nor peptide vaccination achieved objectives of significant improvement in OS or DFSSuggests effects of GM-CSF on DFS and OS are largest among stage IV subjects

Anti-CTLA4 Blocking mAbs PendingEORTC 18071US Intergroup E1609

Molecularly Targeted BRAFi Pending

Molecularly Targeted Therapies for Metastatic Melanoma


Oncogenes in Melanoma

Year Target Prevalence, % Drug

1984 NRAS 20

2002 BRAF 50 Sorafenib, PD0325901, selumetinib,

GSK1120212, RAF-265, XL281,

vemurafenib, GSK2118436

2005 c-kit 1 Imatinib, dasatinib, nilotinib

2008 GNAQ/GNA11 1*

*80% to 90% of uveal.


Curtin J, et al. J Clin Oncol. 2006;24:4340-4346.

Distribution of Genetic Alterations in BRAF, NRAS, and KIT by Primary Site

100

50

0Non-CSD

Per

cen

t A

ber

ran

t

CSD Acral Mucosal

KITKIT and NRASKIT and BRAFNRASBRAF


BRAF Mutation Location (by Amino Acid Position and Substitution)

% of All BRAF Mutations

V600E 97.3

V600K 1.0

K601E 0.4

G469A 0.4

D594G 0.3

V600R 0.3

L597V 0.2

Flaherty KT, et al. Cancer. 2010;116:4902-4913.

Relative Frequency of BRAF Mutations Submitted to COSMIC Database


BRAF Mutation Testing

BRAF mutations are present throughout melanoma disease progression

– If metastasis biopsy not available, most recent melanoma surgery sample adequate (eg, lymph node)

BRAF mutation testing is commercially available

– FDA-approved method used in vemurafenib clinical trials

– cobas 4800 BRAF V600 Mutation Test


**************Individual Patients Treated With Vemurafenib

60

40

20

0

-20

-40

-60

-80

-100

M1aM1bM1c

Disease stage

Per

cen

t C

han

ge

Fro

m B

asel

ine

in

Dia

met

er o

f T

arg

et L

esio

n

*7 confirmed CRs.*7 confirmed CRs.

Ribas A, et al. ASCO 2011. Abstract 8509.

Change in Tumor Size with Vemurafenib in 132 V600EBRAF-Mutant Patients


Phase III BRIM-3 Study Design

V600EBRAF mutation

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

Screening

960 mg PO BID(n = 337)

1000 mg/m2 IV q3w (n = 338)

Dacarbazine

Vemurafenib

Randomization(N = 675)

Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.


100

90

80

70

60

50

40

30

20

10

0

OS

(%

)

Patients in follow-up, n

Dacarbazine

Vemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

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

Mos

336

336

283

320

192

266

137

210

98

162

64

111

39

80

20

35

1

6

1

1

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

9

14

HR: 0.37 (95% CI: 0.26-0.55; log-rank P < .0001)

Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

Vemurafenib vs Dacarbazine in BRAF V600E–Positive Melanoma: OS


Change in Tumor Size in 26 V600EBRAF Mutant Melanoma Patients (GSK2118436)

Kefford R, et al. Society for Melanoma Research Congress 2010.

Maxim

um

%

Red

ucti

on

Fro

m

Baselin

e

CR

PDPR

SD

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

-100

Isolated kinase IC50 (nM): B-RAF

B-RAF

V600E

WT

0.6

12

C-RAF WT 5


302010

0-10

-20

-30-40-50-60-70-80-90-100

40

Max

imu

m %

C

han

ge

Fro

m B

asel

ine

Patients

403020100

-10-20

-30-40-50-60-70-80-90

-100

*

*V600K.

Long G, et al. ESMO 2010. Abstract 5016.

Response to GSK2118436 in Patients WithV600EBRAF-Positive Brain Lesions (N = 10)


Vemurafenib Adverse Event[1] Patients With Toxicity, %

Rash 68

Arthralgia 48

Photosensitivity 42

Fatigue 32

Cutaneous squamous cell carcinoma (keratoacanthoma)

23/7

GSK2118436 Adverse Event[2] Patients With Toxicity, %

Pyrexia 43

Rash 30

Headache 26

1. Flaherty KT, et al. N Engl J Med. 2010;363:809-819. 2. Kefford R, et al. Society for Melanoma Research Congress 2010. Abstract 100.

Most Common Toxicities With Vemurafenib and GSK2118436


Lacouture ME, et al. ASCO 2010. Abstract 8592.

Timing of Keratoacanthoma/SCC

Wks on PLX4032

0 12 24 36 48 60 72


Subjects

Max

imu

m %

R

edu

ctio

n F

rom

Bas

eli

ne

CR PDPR SD

Preliminary RR is 41% (95% CI: 23% to 61%)

-80

-60

-40

-20

0

20

-100

-80

-60

-40

-20

0

20

-100

40

60

80

100

40

60

80100

Falchook G, et al. ESMO 2010. Abstract 4950.

Tumor Response With MEK Inhibitor (GSK1120212) in BRAF-Mutant Melanoma N = 29; 2 CRs and 10 PRs

~ 90% M1c; 48% history of brain metastases

No previous treatment with a BRAF inhibitor


Events 2 mg QD , %

Grade 1/2 Grade 3 Grade 4

Rash 74 4 0

Diarrhea 53 1 0

Fatigue 39 4 0

Nausea 37 0 0

Peripheral edema 32 0 0

Vomiting 25 1 0

Decreased appetite 21 3 0

Most Common AEs (≥ 20%) for GSK1120212 (N = 68)

Falchook G, et al. ESMO 2010. Abstract 4950.


Guo J, et al. J Clin Oncol. 2011;29:2904-2909.

Phase II Trial of Imatinib in Patients With c-KIT Genetic Aberrations N = 43 patients with metastatic melanoma and c-KIT

aberrations

Treatment: imatinib 400 mg/day continuously unless intolerant toxicities or disease progression occurred

– 15 patients with progression escalated to 800 mg/day

Endpoints: PFS, 6-month PFS, ORR, OS, 1-year OS


Patients (N = 43)

Median age, yrs (range) 57 (27-76)

Sex, male/female 20/23

Primary site, n, acral/mucosal/CSD/NSD/UP 21/11/5/4/2

Previous regimen, n, 0/1/2/≥3 5/18/17/3

Stage, n, M1a/M1b/M1c 10/2/31

KIT status, n, exon 11/13/other 16/6/14

Phase II Trial of Imatinib in Patients With c-KIT Aberrations: Patient Characteristics



M1b

M1cM1a

Phase II Trial of Imatinib in Patients With c-KIT Aberrations: Change in Tumor Size

120

100

80

60

40

30

0

-20

-40

-60

-80

Guo J, et al. ASCO 2010. Abstract 8527.

Ch

ang

e in

tu

mo

r si

ze, %


c-KIT Status, n PR SD PR+SD

c-KIT amplification 1/3 0/3 1/3

c-KIT mutation

Exon 11 6/17 5/17 11/17

Exon 13 3/9 1/9 4/9

Exon 17 0/5 2/5 2/5

Exon 18 0/6 3/6 3/6

Multiple gene aberrations* 3/5 2/5 4/5

*5 patients harbored multiple c-KIT aberrations, one each as follows:K642E (exon 13) + amplification; I653T (exon 13) + T1940C (exon 13); F848L(exon 18) + T2576C (exon 18); L576P (exon 11) + amplification; P577H (exon13) + N486D (exon 9).

68.6%

Phase II Trial of Imatinib: Correlation of Response and c-KIT Aberrations



Conclusions

BRAF inhibitors associated with high response rate and improved survival

– Duration of response highly variable

MEK inhibition is active in BRAF-mutant melanoma

c-KIT mutations present in 10% of mucosal and acral melanomas

– c-KIT inhibitors active in a subset of melanoma patients

Advances in Immunotherapy for Metastatic Melanoma


High-Dose IL-2 Therapy

RR: 16% (43/270)

Durable responses

– Median: 8.9 mos

– CR: not reached

Atkins MB, et al. J Clin Oncol. 1999;17:2105-2116.

0 10 20 30 40 50 60 70 80 90 130

0.8

0.6

0.4

0.2

0.0

1.0

100 110 120

Pro

bab

ility

of

Co

nti

nu

ing

Res

po

nse

Duration of Response (Mos)

0

CR (n = 17)PR (n = 26)CR + PR (n = 43)


IL-2 ± gp100 Peptide Vaccine in Patients With Advanced Melanoma Based on previous phase II studies demonstrating efficacy

– NCI phase II study: OR in 13/31 (42%)[1]

– CWG phase II trials: OR in 20/121 (16%)[2]

Multicenter phase III trial of IL-2 ± gp100, accruing 185 patients from 21 centers over 7 yrs[3]

1. Rosenberg SA, et al. Nat Med. 1998;4:321-327. 2. Sosman JA, et al. J Clin Oncol. 2008;26:2292-2298. 3. Schwartzentruber DJ, et al. N Engl J Med. 2011;364:2119-2127.

Endpoint IL-2 IL-2 + gp100 P Value

Primary ORR, % 6 16 .03

SecondaryMedian PFS, mos 1.6 2.2 .008

Median OS, mos 11.1 17.8 .06


Ipilimumab, CTLA-4 Blocking mAb, Augments T-Cell Activation

T-Cell Remains Active

T-Cell Inactivation

T-Cell Activation

Ipilimumab

APC

CTLA-4

T cell

APC

T cellresting

T cell

APC

B7

CD28TCR

HLA

CTLA-4

CTLA-4

Korman AJ, et al. Adv Immunol. 2006;90:297-339 .


Ipilimumab Pattern of Response

Responses after appearance and subsequent disappearance of new lesions

3 mg/kg ipilimumab

q3w x 4

Pretreatment

Wk 36: Still Regressing

Wk 12: Progression

Wk 20: Regression

New lesions

July 2006

Wolchok JD, et al. ASCO 2008. Abstract 3020.


Ipilimumab Therapy: 4 Patterns of Response 2 conventional

– Response in baseline lesions

– “Stable disease” with slow, steady decline in total tumor volume

2 novel

– Response after initial increase in total tumor volume

– Response in index plus new lesions at or after the appearance of new lesions


Patient Education Tips

Educate patients that a response to ipilimumab is different from a response to chemotherapy

Symptoms that could indicate disease progression may indicate a positive response to ipilimumab

Assure patients that these response patterns are normal


MDX010-20 Study Schema

Hodi FS, et al. N Engl J Med. 2010;363:711-723.

Screening

Ipilimumab + gp100(n = 403)

Ipilimumab alone(n = 137)

gp100 alone(n = 136)

Ipilimumab + gp100

Ipilimumab alone

gp100 alone

≥ 1 Reinduction(eligible patients)

Induction

Previously treated,

HLA-A*0201+ patients with

advanced melanoma

(N = 676)

R

A

N

D

O

M

I

Z

E

Follow- up

PD

PD

PD

3:1:1

Induction: Ipilimumab at 3 mg/kg, with or without gp100, q3w for 4 treatments.Reinduction: Patients with SD for 3 months’ duration from Wk 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PD.


Ipilimumab + gp100 (A)Ipilimumab alone (B)gp100 alone (C)

Comparison HR P Value Arm A vs C 0.68 < .001 Arm B vs C 0.66 .003 Arm A vs B 1.04 .76

MDX010-20: Kaplan-Meier Analysis of OS

Hodi FS, et al. N Engl J Med. 2010;363:711-723.

OS Ipilimumab + gp100 Ipilimumab Alone gp100 Alone

1 yr, % 44 46 25

2 yr, % 22 24 14

Median, mos 10.0 10.1 6.4

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Pro

po

rtio

n A

live

Yrs0 1 2 3 4


irAEs, % Ipilimumab + gp100

(n = 380)

Ipilimumab + Pbo(n = 131)

gp100 + Pbo(n = 132)

Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4

Any 9.7 0.5 12.2 2.3 3.0 0

Dermatologic 2.1 0.3 1.5 0 0 0

GI 5.3 0.5 7.6 0 0.8 0

Endocrine 1.1 0 2.3 1.5 0 0

Hepatic 1.1 0 0 0 2.3 0

Death due to irAE

1.3 1.5 0

Most Common Immune-Related Adverse Events* (Grades 3, 4, and 5)

*Across entire study duration.

Hodi FS, et al. N Engl J Med. 2010;363:711-723. O’Day S, et al. ASCO 2010. Abstract 4.


Baseline Tumor Assessment

First Scheduled Tumor Assessment

Screening

Ipilimumab 10 mg/kgq12w

Ipilimumab 10 mg/kgq3w x 4

Induction Maintenance*

*In absence of progression or dose-limiting toxicity.

PreviouslyuntreatedmetastaticMelanoma

(N = 502)Placebo q3w x 4 Placebo q12w

R = blindedrandomization

(1:1)

Study 024: Design

Robert C, et al. N Engl J Med. 2011;364:2517-2526.

RDacarbazine 850 mg/m2

q3w x 8

Dacarbazine 850 mg/m2

q3w x 8

Wk 12 Wk 24Wk 1


5942

*3-yr survival was a post hoc analysis.


Study 024: Overall Survival

Estimated Survival Rate, % Ipilimumab + Dacarbazine(n = 250)

Placebo + Dacarbazine (n = 252)

Yr 1 47.3 36.3

Yr 2 28.5 17.9

Yr 3* 20.8 12.2

CensoredCensored

100908070605040302010

0

Pa

tie

nts

Su

rviv

ing

(%

)

Ipilimumab + dacarbazine

Placebo + dacarbazine

0 482 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

Months

Ipilimumab + dacarbazinePlacebo + dacarbazine

Patients at Risk, n250252

00

230229

199190

181160

157136

131116

11489

10478

9172

8564

7956

7447

6844

6142

5637

5634

5231

4126

3119

1711

107

45

23


Study 024: Tumor Response

*HR: 0.76; 95% CI: 0.63-0.93; P = .006


Endpoint Ipilimumab + Dacarbazine

(n = 250)

Placebo + Dacarbazine

(n = 252)

Disease progression events, n

203 223*

DCR, n (%) 83 (33.2) 76 (30.2)

BORR (CR + PR), n (%) 38 (15.2) 26 (10.3)

CR 4 (1.6) 2 (0.8)

PR 34 (13.6) 24 (9.5)

SD 45 (18.0) 50 (19.8)

PD 111 (44.4) 131 (52.0)

Duration of response, mos 19.3 8.1


Study 024: Duration of Response


CensoredCensored

100

90

80

70

60

50

40

30

20

10

0

Ipilimumab + dacarbazine

Placebo + dacarbazine

Pat

ien

ts W

ith

CR

or

PR

(%

)

Duration of Response (Mos)

0 282 4 6 8 10 12 14 16 18 20 22 24 26

Patients at Risk, nIpilimumab + dacarbazinePlacebo + dacarbazine

3826

3825

3320

3014

2712

2310

229

208

177

86

11

11

10

00

42


Study 024: Safety Overview

*1 death due to gastrointestinal hemorrhage in placebo + dacarbazine group.

Robert C, et al. N Engl J Med. 2011;364:2517-2526. Wolchok J, et al. ASCO 2011. Abstract LBA5.

Adverse Events, % Ipilimumab + Dacarbazine

(n = 247)


(n = 251)

Total Events

Grade 3/4 Events

Total Events

Grade 3/4 Events

All events 98.8 56.3 94.0 27.5

Drug-related events 89.5 50.6 76.5 11.6

Treatment-related deaths

0 -- 0.4* --


Study 024: Select Adverse Events*

*Select adverse events are shown, regardless of attribution.


Adverse Event, % Ipilimumab + Dacarbazine

(n = 247)


(n = 251)

Total Events Grade 3/4 Events


Dermatologic

Pruritus 29.6 2.0 8.8 0

Rash 24.7 1.2 6.8 0

GI

Diarrhea 36.4 4.0 24.7 0

Immune-related colitis 4.5 2.0 0 0

GI perforation 0 0 0 0


Study 024: Select Adverse Events*

*Select adverse events are shown, regardless of attribution.†1 (0.4%) case of hypophysitis in a patient on maintenance was reported on Day 364.


Adverse Event, % Ipilimumab + Dacarbazine

(n = 247)


(n = 251)



Hepatic

Increased ALT 33.2 21.9 5.6 0.8

Increased AST 29.1 18.2 5.6 1.2

Endocrine

Hypothyroidism 1.6 0 0.4 0

Thyroiditis 0.8 0 0 0

Hyperthyroidism 0.4 0 0.4 0

Hypophysitis† 0 0 0 0


Study 024: Efficacy Summary

Ipilimumab 10 mg/kg + dacarbazine prolongs OS vs dacarbazine alone in previously untreated metastatic melanoma (HR: 0.72; P < .001)

Estimated 1-, 2-, and 3-yr survival rates

– 1 yr: 47.3% vs 36.3%

– 2 yrs: 28.5% vs 17.9%

– 3 yrs: 20.8% vs 12.2%

Durable responses

– Median of 19.3 vs 8.1 mos



Study 024: Safety Summary

Types of ipilimumab AEs consistent with previous studies– Predominantly affect: skin, GI tract, liver, endocrine system

Mechanism (immune) based– Managed with established guidelines

– Generally responsive to dose interruption/discontinuation, corticosteroids, and/or other immunosuppressants

Rates of high-grade events different from those observed in phase II ipilimumab studies– Elevated AST and ALT rates higher

– Diarrhea and colitis rates lower

– No GI perforationsRobert C, et al. N Engl J Med. 2011;364:2517-2526.


Patient Education Tips

Patients should immediately report

– Increased bowel movements/onset of diarrhea

– Black, bloody, or clay stools

– Inability to take fluids by mouth due to nausea or vomiting

– Incontinence of stool

– Awakening at night due to stool urgency

– Abdominal pain, cramping, or bloating


Summary

IL-2 + gp100 significantly prolonged survival vs IL-2 alone

CTLA-4 blockade with ipilimumab resulted in durable responses and prolonged survival

– Immune-related adverse events occur and may be severe, but are generally medically manageable

– Initial response to ipilimumab is different from response to chemotherapy

Other immune modulating antibodies are in development with anti-PD1 showing activity

Next step: combination regimens with targeted therapies to maximize high, early response rate with durability


Targeted:BRAFi MEKiC-KitAkt

Chemotherapy:Dacarbazine

(Temozolomide)& Combinations

Immunological:Interferon alfa-2*

Interleukin 2Anti-CTLA4

Anti-PD1Vaccines

Adjuvant HDIAdjuvant pegIFN

Approved 1976-1998Approved 2011Pending Approval 2011

Evolving Modalities of Systemic Therapy

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