Oncology Highlights from ASCO 2009 Melanoma August 1, 2009 Santa - - PowerPoint PPT Presentation

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

• f 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 Centre 2Vanderbilt University 6Hoffmann-La Roche Inc 3MD Anderson Cancer Center 7Plexxikon Inc 4University 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

PLX4032 optimized formulation achieves preclinical target exposure for tumor regression

Initial Formulation Optimized Formulation

1000 2000 3000

AUC 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

AUC 0-24 hr (uM*hr)

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

• 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,
• r 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 #9006

Eva 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 on post-recurrence survival

p=0.001

Low Risk High Risk

n=29 n=30

500 1000 1500 2000

Survival (days)

0.0 0.2 0.4 0.6 0.8 1.0

Survival Probability miRNA predictor:

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

Authors: 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

Background

Treatment 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

Response IL-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

• xidative 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 melanoma

1. 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 ELPAC 309 187 107 53 21 10 6 3 2 2 Subjects at Risk

Overall Survival: Not Yet Mature Currently Favors PAC Arm

ITT Population (N=651) Data Cut % censored HR (CI) p-value Feb 2009 80% 1.62* (1.14 - 2.31) 0.0068 April 2009 72% 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
• bserved 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

• cular 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

• f 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 patients cFor 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 irAE

Pooled data from CA184-008 and CA184-022

1.0 0.8 0.6 0.4 0.2 0.0 Proportion alive

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

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 10 8 3 2 1 1 1

Conclusions

• Ipilimumab 10 mg/kg induced disease control in

patients with advanced melanoma

• Disease control and survival benefits are
• bserved 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

• ption 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

• ccur; 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