Oncology Highlights from

ASCO 2009

Melanoma

August 1, 2009

Santa Monica, CA

Jeffrey Weber M.D. Ph.D.

Moffitt Cancer Center

Tampa, FL

COI Disclaimers

• Honoraria from Novartis, Roche, Medarex

and BMS, all less than $10,000 dollars in

any year

• I was named on a patent relating to

ipilimumab that was assigned to the Univ

of Southern California and later was

abandoned by the filer

ASCO 2009 Theme:

Melanoma enters the era of

personalized, targeted therapy

Phase I study of PLX4032:Proof of concept for V600E BRAF

mutation as a therapeutic target

in human cancer: abstract #9000

K. Flaherty,1 I. Puzanov2, J. Sosman2, K. Kim3, A. Ribas4, G. McArthur5, R. Lee6, J. Grippo6, K. Nolop7,

P. Chapman8

1University of Pennsylvania 5Peter MacCallum Cancer Centre2Vanderbilt University 6Hoffmann-La Roche Inc3MD Anderson Cancer Center 7Plexxikon Inc4University of Califorinia, Los Angeles 8Memorial Sloan-Kettering Cancer Center

PLX4032: novel, small molecule inhibitor

Selectivity for BRAFV600E in vitro and in vivo

Phospho-ERK IC50 (nM)

A375

COLO829

COLO205

SW620

SKMEL2

20

10

30

>40,000

14,000

Selective in cellular assays

V600E

WT

Selective regression of V600E tumors

Selective for BRAFV600E kinase

among 70 kinases screened

1205Lu

V600E

+ PLX4032

C8161

WT

+ PLX4032

Tumor

Size

100 mm3

10–100

IC50 (nM)

100–1000

1000–10000

PLX4720 co-structure with kinase domain of

BRAFV600E (Tsai J et al. 2008 PNAS)

Kinase domain binding

2006 EORTC-NCI-AACR Molecular Targets & Cancer Therapeutics

BRAF

PLX4032: phase I study

Design:

Open-label, sequential dose escalation study

Intra-patient dose escalation permitted

Primary objectives:

• Evaluate safety and PK of PLX4032 in patients with solid tumors

• Measure activity, including response and symptom improvement

Secondary objectives:

• Measure PD activity of PLX4032 via inhibition of biomarkers

- pMEK, pERK & Ki67 in paired tumor biopsy samples

- 18FDG uptake

Eligibility standard for phase I trials; no requirement for BRAFV600E

3 patients

4 pts

4 pts

3 pts

4 pts4 pts

4 pts

100 200 400 800 1600

Daily Dose (mg) BID

160 240 360Daily Dose (mg)

BID

All Comers

n = 18

Max Dose: 1600 (Bid)

720

100

600

500

400

300

200

shrinkage

stasis

700

PK Bridging

Study

1200

1000

900

1400

1600

1800

2000

2200

2400

2600

2800

AUC ( μM

*hr)

900

1000

800

1100

1200

1300

1400

1500

1600

1700

1800

1900

1120

100

500

400

300

200

600

700 5 pts

7 pts

4 pts

2000

2100

2200

2300

2400

2500

2600

2700

2800

2900

3000

AUC ( μM

*hr)

900

1000

800

1100

1200

1300

1400

1500

1600

1700

1800

1900

500

600

700

2000

2100

2200

2300

2400

2500

2600

2700

2800

2900

3000

960

4 pts

PLX4032 optimized formulation achieves

preclinical target exposure for tumor regression

Initial Formulation Optimized Formulation

1000

2000

3000

AU

C 0

-24

hr

(uM

*hr)

Daily BID dose (mg)

100 200 400 800 1600

Daily BID dose (mg)

160 240 360 720 1120 960

100

400

720 BID

960 BID

1120 BID

Target for regression

1000

2000

3000

AU

C 0

-24 h

r (u

M*h

r)

Target for stasis

400

100

BRAFV600E melanoma patients treated with

PLX4032 > 240 mg BID

% change from baseline (sum of lesion size)

*

100

75

50

25

0

-25

-50

-75

-100

(RECIST cutoff for PR, 30%)

Patients (n=15)*

M1a/M1b patients

M1c patients

* One M1c patient had 55% reduction in target lesions, but PD in non-target lesions;

died before end C2 (not included above)

Conclusions

PLX4032 Phase I dose escalation study

• Twice daily administration tolerable up to 720 mg

• 960 mg BID dose under evaluation as MTD

• Pharmacokinetics show limited variability and exposure adequate to

inhibit target in animal models

• Responses observed in V600E+ melanoma patients > 240 mg BID:

• 9 PRs (7 confirmed 49% - 100%, 2 unconfirmed 31% - 62%)

• Regression of liver, lung and bone lesions

• Symptom improvement in many patients

• Interim PFS ~ 6 months, with many patients still on therapy

• In 3 V600E+ thyroid patients, 1 confirmed PR and 2 SD

A Phase II Study of Imatinib Mesylate

(IM) for Patients with Advanced

Melanoma Harboring Somatic

Alterations of KIT (Abst ID: 9001)

R. D. Carvajal, P. B. Chapman, J. D. Wolchok, L.

Cane, J. B. Teitcher, J. Lutzky, A. C. Pavlick, B. C.

Bastian, C. R. Antonescu, G. K. Schwartz

Study Design

Phase II, open-label, multicenter, 2-stage study of imatinib

in molecularly selected patients based on the presence of a

mutation (exons 9, 11, 13, 17, 18) or amplification of KIT (FISH)

Screening Phase

• KIT sequencing (Bastian)and FISH performed (Antonescu)

• Tumor MUST have either a mutation or amplification to proceed to treatment phase

Treatment Phase

• Eligible pts receive imatinib 400 BID in 6-week cycles

• Restaging imaging studies performed after each cycle

Patients with a response or SD continue daily treatment until

disease progression or unacceptable toxicity

Key Eligibility Criteria

• Inoperable melanoma arising from acral, mucosal, or chronically sun-damaged sites

• Tumor must harbor KIT amplification by FISH or a detectable mutation in KIT by sequencing

• No prior therapy with other KIT tyrosine kinase inhibitors

• Other standard eligibility criteria apply

Response Data (n = 12)

n %

Complete Response 2 17%

Partial Response 2 17%

Stable Disease 6 50%

Progression 2 17%

Overall RECIST RR 4/12 33%

(Updated 5/12/09)

# Melanoma

Subtype

KIT Mutation KIT Amp Best

Response

Cycles Wks

1 Mucosal Exon 11 L576P Yes CR 7 37+

2 Acral Exon 11 L576P Yes CR 4 18+

3 Mucosal Exon 11 L576P No PR 7 40+

4 Acral Exon 13 K642E No PR 3 13+

5 Mucosal Exon 13 K642E No SD 3 18

6 Mucosal Exon 11 L576P No SD 2 12

7 Mucosal None Yes SD 2 11

8 Mucosal None Yes SD 2 11

9 Acral Exon 13 K642E No SD 2 8+

10 Acral Exon 13 K643X Yes SD 2 6+

11 Mucosal Exon 13 V654A No POD 1 6

12 Mucosal Exon 9 N463S

Exon13 N655S

No POD 1 4

KIT Alteration and Response

(Updated 5/18/09)Red – on study; Blue – off study

Conclusions• There is 21% prevalence of a KIT mutation and/or

amplification in this selected cohort.

• We have observed 4 responses in 12 evaluable

patients thus far, allowing expansion to the second

stage of the study (ongoing).

• The 2 CRs were in tumors with both an exon 11

L576P mutation and amplification of KIT.

• It is feasible to identify appropriate patients

prospectively for treatment with imatinib.

• Only molecularly appropriate patients with melanoma

should be treated with imatinib.

Clinical relevance of miRNA expression in metastatic melanoma

Abstract #9006Eva Hernando, Ph.D.

Interdisciplinary Melanoma Program

microRNAs: small, non-coding RNAs

with a critical role in cancer

• miRNA genes are frequently located at fragile sites and chromosomal regions

frequently altered in human cancer (e.g. amplifications, deletions,

translocations)

• miRNA patterns are able to sub-classify tumor types (Calin and Croce,2006)

• miRNAs can act as tumor suppressors (e.g. let-7) or oncogenes (e.g. miR-17-92)

• Some miRNAs are known to contribute to metastasis (e.g. miR-10b, miR-335).

ADVANTAGES TO THEIR ANALYSIS

Tissue/cell-type specificity

Stable in formalin-fixed paraffin-embedded tissues.

Can be tested by standardized methods (qRT-PCR)

Represent closely the functional level of the gene.

The 18 miRNA signature clusters melanoma

patients

based on post-recurrence survival

A 6-miRNA subset separates melanoma patients based onpost-recurrence survival

p=0.001

Low Risk

High Risk

n=29

n=30

0 500 1000 1500 2000

Survival (days)

0.0

0.2

0.4

0.6

0.8

1.0

Surv

ival

Pro

bab

ility

miRNA predictor:

miR-150 miR-455-3p miR-145 miR-497 miR-155miR-342-3p

The 6 miRNA signature retains its predictive

value in an optimized multivariate model

Conclusions

A miRNA signature associates with post-recurrence

survival of a cohort of 61 melanoma patients

miRNAs add to the power of clinicopathological

parameters (Stage, site of metastasis) in predicting post-

recurrence survival.

miRNA profiles discriminate between Stages IIIB and IIIC.

A model that integrates a miRNA predictor and Stage

accurately predicts post-recurrence survival.

Certain miRNAs might hold prognostic information at the

time of diagnosis.

A Phase III Multi-institutional Randomized Study of

Immunization with gp100:209-217(210M) Peptide

Followed by High Dose IL-2 vs High Dose IL-2 Alone

in Patients With Metastatic Melanoma CRA #9011

Doug Schwartzentruber, MD, FACS

Medical Director, Goshen Center for Cancer Care

Clinical Associate Professor of Surgery Indiana

UniversityAuthors: D. Schwartzentruber, D. Lawson, J. Richards, R. Conry, D. Miller,

J. Treisman, F. Gailani, L. Riley, D. Vena, P. Hwu

Support: NCI, Chiron, Novartis, Goshen Health System, Goshen Hospital

and Health Care Foundation, Luke Brennen Research Fund

BackgroundTreatment of Patients with Metastatic Melanoma

• gp100 209-217 (210M) in Montanide ISA 51 + HD IL-2

(720K) every 3 weeks, RR 42% (13/31).1

• gp100 209-217 (210M) in Montanide ISA 51 every 3 weeks

+ HD IL-2 (600K) on a variable schedule.2

Trial 1 (IL-2 C1 and C2 only) RR 23.8% (n=42)

Trial 2 (IL-2 C3 and C4 only) RR 12.5% (n=40)

Trial 3 (IL-2 C1 through C4) RR 12.8% (n=39)

• Retrospective results Surgery Branch: HD IL-2 alone

(n=305) RR 12.8%; gp100 + HD IL-2 (n=49) RR 25.0%.3

1. Rosenberg S.A., et. al., Nature Medicine 4: 321-327, 1998.

2. Sosman J.A., et. al., J Clin Oncol 26: 2292-2298, 2008.

3. Smith F.O., et. Al., Clin Cancer Res 14:5610-5618, 2008.

Objectives of Study

• Primary

Compare RR of HD IL-2 with and without

gp100 vaccine.

• Secondary

Evaluate toxicity.

Compare disease and progression free survival.

Immunologic monitoring (PBL and serum)

QOL measurements (before and after 2 cycles of

treatment)

Study Design

• Prospective, randomized (1:1), multi-institutional.

• Stratified for cutaneous / SQ disease only vs. all other.

• Arm A: HD IL-2 (720K) IV q 8hrs, max 12 doses,

repeated every 3 weeks.

• Arm B: gp100 209-217 (210M) in Montanide ISA 51 SQ

and HD IL-2 as in Arm A, starting day after vaccine.

• Response assessment (WHO criteria) after 2 cycles of

treatment.

• Re-treatment with 2 cycles when disease stable.

• IL-2 obtained commercially.

• gp100 and Montanide provided by CTEP, NCI (IND

holder).

Central Response Assessment

ResponseIL-2

N (%)

IL-2 + gp100

N (%)

P Value

CR + PR 6 (6.5) 16 (18.6) 0.013

SD + PD 87 (93.5) 70 (81.4)

Overall Survival

Median Survival months (95% CI)

IL-2 Alone: 12.8 (8.7-16.3)

IL-2+gp100: 17.6 (11.8-26.3)

p value: 0.084

Median Survival months (95% CI)

IL-2 Alone: 12.8 (8.7-16.3)

IL-2+gp100: 17.6 (11.8-26.3)

p value: 0.084

Median Survival months (95% CI)

IL-2 Alone: 12.8 (8.7-16.3)

IL-2+gp100: 17.6 (11.8-26.3)

Summary and Conclusions

• Investigator assessed Response Rate in the vaccine arm is

significantly higher: 22.1% vs. 9.7% (p=0.022).

• Patients with lung metastases (M1b) accounted for the

majority of the response difference (p=0.002).

• Central review: Response Rate in the vaccine arm is

significantly higher: 18.6% vs. 6.5% (p=0.013).

• Progression Free Survival is significantly higher in the

vaccine arm: 2.9 vs. 1.6 months (p=0.01).

• Trend for greater Overall Survival in the vaccine arm: 17.6

vs. 12.8 months (p=0.084). Median follow up for surviving

patients is 28.7 months.

A Randomized, Double-blind, Phase 3 Trial of STA-

4783 (elesclomol) in Combination with Paclitaxel

versus Paclitaxel Alone for Treatment of Patients

with Stage IV Metastatic Melanoma (SYMMETRY)

Review of Preliminary Data abstract # LBA 9012

A. Hauschild, A.M. Eggermont, E. Jacobson, S. O’Day. University of Kiel, Kiel, Germany; Erasmus University Medical Center, Rotterdam, The Netherlands; Synta Pharmaceuticals,

Lexington, MA; The Angeles Clinic and Research Institute, Santa Monica, CA

On behalf of the SYMMETRY Trial Investigators

Elesclomol: Mechanism of Action

• Elesclomol is an investigational drug candidate that induces oxidative

stress (reactive oxygen species, ROS)1

• Oxidative stress induction represents a potential novel way of

selectively targeting and killing cancer cells

• Cancer cells produce higher levels of reactive oxygen species (ROS)

than normal cells, making them potentially more susceptible to further

oxidative stress and ROS mediated apoptosis2

• Elevation of ROS may facilitate the ability of taxanes to induce

apoptosis through the intrinsic mitochondrial pathway3

• Preclinical in vivo studies demonstrated synergistic efficacy of

paclitaxel and elesclomol in a variety of solid tumor models, including

melanoma1. Kirshner et al. (2008) Molecular Cancer Therapy 7:2319-2327

2. Kong et al. (2000) Medical Hypothesis 55:29-35; Pelicano et al. (2004)

Drug Resistance Updates 7:97-110

3. Ramanathan et al. (2005) Cancer Research 65:8455-8460

SYMMETRY Study design

• 160 centers in 15 countries

• Tumor Assessment: at baseline and every 8 weeks from time of

randomization (RECIST)

• No patient cross-over

Study

Population

• Stage IV

metastatic

melanoma

• Chemo-naïve

• LDH ≤ 2x ULN

• ECOG PS 0-2

• Absence of

CNS mets

paclitaxel 80mg/m2

+

elesclomol 213 mg/m2

(N=315)

Randomization

1:1

(N=630)

Stratification Factors

• LDH status

• M1 subclass

• Prior permitted

(non-chemo) therapy*paclitaxel 80mg/m2

(N=315)

Primary

endpoint:

Progression-

free survival

qw for 3 weeks; 1 week off

* Kinase inhibitor, immunotherapy, biologic therapy, vaccine, or investigational non-chemo

Study Steering Committee: Steven O’Day, Axel Hauschild, Alexander Eggermont

PFS Analysis Methodology

• The protocol assumption was that treatment with ELPAC

would extend PFS by two months (3 vs. 5)

– 2-sided alpha 0.05, power 90%

– required number of PFS events = 164

• There were a total of 219 PFS events at the time of the

February 23rd, 2009 DMC meeting which exceeded the

required number of events by 34%

• Follow-up for disease progression stopped at time of study

stop; patients were censored at last valid tumor

assessment prior to stopping the treatment phase of the

study on February 26th, 2009

Progression-Free Survival - ITT Population

ELPAC PAC

Events/Number at risk 170/309 192/312

Median (months)

95% CI

3.4

(2.6 - 3.6)

1.9

(1.9 - 2.9)

6 Month PFS Rate 23% 17%

HR (ELPAC vs. PAC)

95% CI

0.84

(0.68 – 1.04)

p-value (Stratified Log-

Rank)

0.1107

PAC 312 200 87 42 20 8 2 2 1 0 0

ELPAC 309 187 107 53 21 10 6 3 2 2 0

Subjects at Risk

Overall Survival: Not Yet Mature

Currently Favors PAC ArmITT Population (N=651)

Data Cut % censored HR

(CI)

p-value

Feb 200980% 1.62*

(1.14 - 2.31)

0.0068

April 200972% 1.31

(0.98 - 1.76)

0.0719

* There were 80 OS events in the ELPAC arm vs. 53 OS events in the

PAC arm, i.e. the HR favored the control, not the treatment arm

Pts enrolled as of Sep 1, 2008 (N=300)

Data Cut % censored HR

(CI)

p-value

Feb 2009 63% 1.28

(0.88 - 1.87)

0.1930

April 2009 54% 1.22

(0.87 - 1.71)

0.2552

Conclusions

• Despite a trend in improvement of PFS, elesclomol in combination with

paclitaxel (ELPAC) failed to demonstrate a statistically significant

improvement when compared with paclitaxel alone in chemo-naive

patients with metastatic melanoma

• There was a statistically significant increase in PFS with ELPAC in the

subgroup of patients with normal LDH (68% of the ITT, pre-specified

exploratory analysis)

• An imbalance in deaths favoring the paclitaxel arm was observed,

leading to early study termination

• No organ-specific toxicities have been identified that explain the

observed imbalance in deaths at this time; safety data is continuing to

be evaluated

• At this point OS data is not mature; mature data will be presented at a

future scientific meeting

Phase II Study of Aflibercept (VEGF Trap) in

Recurrent Inoperable Stage III or Stage IV

Melanoma of Cutaneous or Ocular origin

abstract #9028

Ahmad A. Tarhini, Scott Christensen, Kim Margolin, Paul Frankel, Christopher Ruel, Stergios Moschos, Hussein Tawbi, Janice Shipe-

Spotloe, John M. Kirkwood

Support: NCI, Sanofi-aventis, Regeneron, UPCI CTRC

University of Pittsburgh, Pittsburgh, PA

City of Hope National Medical Center, Duarte CA

USC/Norris Comprehensive Cancer Center, Los Angeles

University of California, Davis Cancer Center, Sacramento

Introduction• Aflibercept (VEGF Trap) is a unique fusion protein combining

the Fc portion of human IgG1 with the principal extracellular

ligand-binding domains of human VEGFR1 & VEGFR2

• Acts as a high-affinity soluble decoy VEGF receptor and potent

angiogenesis inhibitor

• Aflibercept has highest binding affinity for VEGF described to date.

Dissociation constant 0.5 pM

Treatment Plan

• Schedule of administration

– Aflibercept 4 mg/kg I.V. every 2 wks for 8 wks

(4 cycles; 1 cycle=14 days)

– Response assessment every 8 wks

• Correlative Studies– Pharmacokinetics

– Anti-VEGF Trap Antibody

Efficacy Summary: Responses (N=41)**

No.

Pts

(%)

Primary

No. Pts (%)

Classification

No. Pts (%)

Cutaneous Ocular Unknown M1a,

N3

M1b M1c

RR* 1

(2)

1

(100)

1

(100)

SD 20 (49) 13

(65)

5

(25)

2

(10)

4

(20)

5

(25)

11

(55)

PD 13

(32)

9

(69)

3

(23)

1

(8)

1

(8)

2

(15)

10

(77)

Not

Eval

5

(12)

Too

Early

2

(5)

Conclusions• Aflibercept has promising clinical activity

in metastatic melanoma of cutaneous or ocular origin in 41 pts

• It is highly likely that we will meet the 4-months PFS milestone of at least 17 instances of 4-month PFS with longer follow up

• Serious adverse events noted with this class of drugs such as hypertension require close follow up and monitoring of patients

Ipilimumab Treatment May Be Associated With A

Long-term Survival Benefit: 18-month* Survival Rate Of

Patients With Advanced Melanoma Treated With

10 mg/kg Ipilimumab In Three Phase II Clinical Trials

*24-month survival data is also presented

Steven J. O’Day,1 Jeffrey Weber,2 Celeste Lebbé,3

Michele Maio,4 Hubert Pehamberger,5

Kaan Harmankaya,5 Jonathan Siegel,6 Axel Hoos,6

Rachel Humphrey,7 and Jedd Wolchok,8

ASCO 2009

Poster Discussion

Abstract 9033

1The Angeles Clinic and Research Institute, Santa Monica, CA USA; 2H. Lee Moffitt Cancer Center and Research Institute, Tampa,

FL USA; 3Saint-Louis Hospital Department of Dermatology, Center of Clinical Investigation, Paris, France; 4Division of Medical

Oncology and Immunotherapy Department of Oncology University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 5Univ. of

Vienna, Department of General Clinical Dermatology, Vienna, Austria; 6Bristol-Myers Squibb Company, Wallingford, CT, USA; 7Bristol-Myers Squibb Company, Princeton, NJ, USA; 8Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Email: SODay@theangelesclinic.org

Overall Survival Rates In

CA184-008, CA184-022, And CA184-007a

Study

12-month

survival rate

% (95% CI)

18-month

survival rate

% (95% CI)

24-month

survival rate

% (95% CI)

CA184-008 (N=155)

(previously treated)47.2 (39.5-55.1) 39.4 (31.7-47.2) 32.8 (25.4-40.5)

CA184-022 (N=217)b, c

10 mg/kg (n=72)

(previously treated)

48.6 (36.8-60.4) 34.5 (23.6-46.2) 29.8 (19.1-41.1)

CA184-007 (N=115)

Ipilimumab + placebo (n=57) 62.4 (49.4-75.1) 50.9 (37.5-64.1) 41.8 (28.3-55.5)

Treatment-naive (n=32) 71.4 (55.2-87.2) 61.0 (43.4-77.7) 56.6 (38.4-74.3)

Previously treated (n=25) 50.8 (31.5-71.1) 38.1 (20.0-57.6) 24.2 (8.0–42.8)

Ipilimumab + budesonide (n=58) 55.9 (42.7-68.8) 47.9 (34.7-61.2) 40.6 (27.1-54.4)

Treatment-naive (n=21) 65.9 (45.0-85.7) 65.9 (45.0-85.7) 56.5 (30.6-81.0)

Previously treated (n=37) 49.9 (33.3-66.6) 37.9 (22.2-54.3) 31.6 (16.5-47.6)

aStatistics are based on randomized patients in studies -007 and -022, and treated patients in study -008. For study -022, the statistics are for patients in

the 10 mg/kg arm only bIn study -022, there were 217 patients randomized and 214 treated patientscFor the 10 mg/kg arm of study -022, there were 72 patients randomized and 71 treated patients

CI = confidence interval

Median Survival Times In Studies CA184-

008, CA184-022, And CA184-007

Study

Median Survival Time

months (95% CI)

CA184-008 (N=155) 10.2 (7.6 - 16.3)

CA184-022 (N=217)a

10 mg/kg (n=72)b 11.4 (6.9 - 16.1)

CA184-007 (N=115)

Ipilimumab + placebo (n=57)

Ipilimumab + budesonide (n=58)

19.3 (12.0 - NR)

17.7 (6.8 - NR)

aIn study -022, there were 217 randomized and 214 treated patients bFor the 10 mg/kg arm of study -022, there were 72 patients randomized and 71 treated patients;

CI = confidence interval; NR = not reached

Conclusions

• With a median follow-up of 10.1 to 16.3 months, and with a

range reaching up to 37.5 months, patients receiving

ipilimumab 10 mg/kg showed durable survival

• Across 3 studies, 12-month OS was >47%, 18-month OS

was >34%, 24-month OS was ≥30% and median survival

was >10 months

• Long-term survivors include patients with PD according to mWHO

criteria

– Reassessment and confirmation of PD is recommended to

prevent premature discontinuation of ipilimumab treatment

• Updated phase II trial survival results with ipilimumab 10 mg/kg in

advanced melanoma encourage continued investigation of this

therapy, and patients continue to be followed to evaluate long-term

survival

Ipilimumab Exerts Disease Control And Survival

Benefits In Advanced Melanoma Patients With

And Without Immune-related Adverse Events

(irAEs)

Jose Lutzky,1 Jedd Wolchok,2 Omid Hamid,3

Celeste Lebbé,4 Hubert Pehamberger,5 Gerald Linette,6

Veerle De Pril,7 Ramy Ibrahim,8 Axel Hoos,8

and Steven O’Day3

E-mail: jlutzky@aptiumoncology.com

1Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL, US; 2Memorial Sloan-Kettering

Cancer Center, New York, NY, US; 3The Angeles Clinic and Research Institute, Los Angeles, CA,

US; 4Saint-Louis Hospital, Paris, France; 5Department of Dermatology, University of Vienna,

Vienna, Austria; 6Washington University School of Medicine, St. Louis, MO, US; 7Bristol-Myers

Squibb, Braine-l’Alleud, Belgium; 8Bristol-Myers Squibb, Wallingford, CT, US

Abstract 9034

Disease control by irAE grade

(ipilimumab 10 mg/kg monotherapy)

Study

Disease control rate (PR+CR+SD)

P-value

irAE Grade

0/1

irAE Grade

≥ 2

DC

No

DC DC

No

DC

CA184-007 4 16 16 21 ≤ 0.09

CA184-008 21 73 21 40 ≤ 0.14

CA184-022 10 31 11 19 ≤ 0.3

DC = Disease Control by mWHO criteria

Kaplan-Meier estimate for median OS

at day 81 – any irAEPooled data from CA184-008 and CA184-022

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n a

live

Any irAE within 12 weeks

Censored

No irAE within 12 weeks

Censored

Months

Group

Median OS

months (95% CI)

Any irAE within 12 weeks

Non irAE within 12 weeks

14.8 (10.0–21.7)

8.21 (5.29–13.7)

Patients at risk

Any irAE

No irAE

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

145 128 118 110 103 97 94 93 86 82 80 77 74 72 68 64 63 60

48 44 40 33 32 30 27 24 23 20 19 18 17 15 14 14 13 13

57 53 43 26 15 8 2 1 0

10 8 3 2 1 1 1 0 0

Conclusions

• Ipilimumab 10 mg/kg induced disease control in

patients with advanced melanoma

• Disease control and survival benefits are

observed among patients regardless of whether

they do or do not develop grade ≥2 irAEs

• Patients that do not experience an irAE by the

end of the induction dosing period (week 12)

may still demonstrate clinical benefit with

ipilimumab

A phase II trial of carboplatin and nab-paclitaxel

(ABI-007) in patients with unresectable stage IV

melanoma, final data from N057E1 abstract # 9055

L. A. Kottschade RN, MSN, CNP2; V.J.Suman, PhD2; T. Amatruda, MD3;; R.R. McWilliams,

MD2; S.R. Dakhil, MD4; D.A. Nikcevich, MD5; R.P. Morton, MD6; T.R. Fitch, MD7; A.J.

Jaslowski, MD8 ; N. Desai, PhD9; V. Trieu, PhD9; D. Knauer, PhD9; S.N Markovic,

MD, PhD2

This study was conducted as a collaborative trial of the North Central Cancer Treatment

Group and Mayo Clinic and was supported in part by Public Health Service Grants

CA-25224, CA-37404, CA-35113.

Mayo Clinic, Rochester, MN

Metro MN Community Clinical Oncology Program, St. Louis Park, MN

Wichita Community Clinical Oncology Program, Wichita, KS

Duluth Community Clinical Oncology Program, Duluth, MN

Iowa Oncology Research Association CCOP, DesMoines, IA

Mayo Clinic Scottsdale, Scottsdale, AZ

St. Vincent Regional Cancer Center CCOP, Green Bay, WI

Abraxis Bioscience LLC, Los Angeles, CA

Methods• Nab-P (100 mg/m2) and Carboplatin (AUC2) were administered on

days 1, 8, and 15 of a 28 day cycle.

• A parallel phase II trial was conducted in pts who were

chemotherapy naïve (CN) or were previously treated (PT), with

unresectable stage IV melanoma.

• Testing:

– CN patients

• CR+PR rate by RECIST of ≤15% vs ≥35% with this combination

• If ≥ 9 responses (CR+PR) were seen among the first 35 evaluable patients

enrolled to this arm we would consider this regimen for further testing in this

patient population.

– PT patients

• CR+PR rate by RECIST of ≤5% vs 20% with this combination

• If ≥ 4 responses (CR+PR) were seen among the first 35 evaluable patients

enrolled to this arm we would consider this regimen for further testing in this

patient population.

Results from the CN group

• Patients were followed for a minimum of 1.7 years or until death.

• Among the first 35 patients enrolled, there were 9 (25.7%; 90%CI:

14.1-40.6%) patients who had a confirmed response (1-CR and 8

PRs).

• Among all 39 patients enrolled, there were 10 (25.6%; 90%CI: 14.6-

39.6%) patients who had a confirmed response (1-CR and 9 PRs).

• The median progression free survival time was 4.3 months and the

median overall survival was 11.1 months.

• At last contact:

– 5 patients are alive without progression of disease

– 3 patients are alive with disease progression

– 31 patients have dies from their disease

Results from the PT group

• All but one patient was followed for a minimum of 9 months or until

death.

• Among the 34 patients enrolled, there were 3 (8.8%; 90% CI: 2.5%-

21.3%) patients who had a confirmed partial response and 11

patients remained on treatment with stable disease for at least 4

cycles.

• There were no complete responses.

• The median progression-free survival time was 4.2 months.

• The median overall survival time was 10.9 months.

• At last contact:

– 1 patient is alive without progression of their disease

– 7 patients are alive with disease progression

– 26 patients have died from their disease

Discussion

• The weekly combination of nab-P and C appears to be

well tolerated and with promising clinical activity as first-

line therapy for MM.

• For patients who are previously treated the weekly

combination of nab-P and C appears to be a viable

option for salvage therapy.

• The impact of adding targeted agents (i.e bevacizumab)

to this regimen is currently being explored by our group

in a Phase II study.

nab-Paclitaxel and Bevacizumab as

First-Line Therapy in Patients with

Unresectable Stage III and IV

Melanoma

abstract # 9061

P.Boasberg1, S Cruickshank2, O.Hamid1, S.O’Day1,

R.Weber3, L. Spitler3

The Angeles Clinic and Research Institute, Los Angeles,

CA1; Scott Cruickshank and Associates, Santa Barbara, CA2;

The Northern California Melanoma Center, St. Mary’s

Medical Center, San Francisco, CA3

Background: nab-Paclitaxel and

Bevacizumab for melanoma

• nab-paclitaxel (albumin bound paclitaxel particles) delivers increased intra-tumoral concentrations of paclitaxel and has superior efficacy in the treatment of metastatic breast cancer (J Clin Oncol 2005;23:7794-7803)

• nab-paclitaxel has demonstrated single agent activity in metastatic melanoma (ASCO 2005;#7558)

• VEGF Increases vascular permeability and inhibits antigen-presenting dendritic cell function

• VEGF is over expressed by melanoma cells, and is targeted by Bevacizumab

• Bevacizumab enhances tumor responses to paclitaxel (NEJM 2007:357:2666-2676)

nab-Paclitaxel and Bevacizumab for

melanoma

Regimen

• nab-paclitaxel 150mg/m2 – Days 1, 8, 15 Bevacizumab 10mg/kg – Days 1 & 15 of a 28-day cycle

• Treated to progression, dose limiting toxicity, or 2 years

Endpoints

• Primary– Progression free survival (PFS) at 4 months

• Secondary– Progression-free survival (PFS)

– Overall Survival (OS)

– Objective Response Rate (RR)

Results

• 4-month progression-free survival 74%

• Median progression-free survival 5.8 months

• Median duration of follow-up 7.83 months

• Survival Status

Dead 9 (20.9%)

Alive 34 (79.1%)

• 6-month survival rate 91%

• 12-month survival rate 68%

• Median duration of survival Not reached yet

Complete response 1 (2.7%)

Partial response 10 (27.0%)

Stable disease (4wks) 18 (48.6%)

Progressive disease 8 (21.6%)

Conclusions

• Preliminary results suggest that:

– Combined therapy with nab-paclitaxel and bevacizumab has promise in terms of progression-free survival and overall survival benefit compared to a meta-analysis of previous Phase II studies (J Clin Oncol 2008; 26:527-534)

– The combination is safe to administer

– The number of patients and short follow-up prevent definitive conclusions to be reached concerning safety and efficacy of the combination

– The study is ongoing with continued patient treatment and follow-up.

My overall conclusions

• These data mark a new era of targeted therapy for melanoma with impressive PLX-4032 and imatinib data

• The gp100 peptide/IL-2 data are intriguing but would require a confirmatory trial unlikely to occur; it might encourage other IL-2 vaccine trials and combinations

• Overall ipilimumab survival data are very promising, bode well for its future development

• Nab-Bev and Nab-carbo are promising regimens that look at least as good as DTIC