Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma

Future Directions: Opportunities for Targeting B-RAF and Other Targets in

Melanoma Management

Keith T. Flaherty, MDAssistant Professor of MedicineAbramson Cancer Center of the

University of PennsylvaniaPhiladelphia, PA

Novel Cytotoxics

Albumin-bound paclitaxel

• Established superiority to conventional paclitaxel in metastatic breast cancer

• Phase II trial in metastatic melanoma

• 35 patients with chemotherapy-naïve metastatic melanoma received ABI-007 100 mg/m2 IV weekly for 3 out of 4 weeks

• Objective response rate 26%

• Median PFS 4 months

• Phase III trial being conducted compared to dacarbazine

Altering the Threshold for Chemotherapy-induced Apoptosis

STA-4783 Induces Programmed Cell Death via

the Intrinsic Mitochondrial Apoptotic Pathway

STA-4783

TARGET

↑ ROSMitochondria

Cytochrome c release

APOPTOSISCaspase 9activation

STA-4783 induces ROS which accumulate in the mitochondria

Cytochrome c activates caspase 9 which then activates caspase 3/7 leading to apoptosis

ROS elevation leads to the oxidation of cardiolipin, a mitochondrial phospholipid which holds cytochrome c in the mitochondria. Oxidation of cardiolipin leads to the release of cytochrome c

Cytochrome c exits the mitochondria through pores which are created by pro-apoptotic members of the Bcl2 family and are dependent upon elevated ROS

STA-4783 in Metastatic MelanomaStudy Design

Coordinating investigator: Steven O’Day, MD, The Angeles Clinic and Research Institute

(81 patients were enrolled from December 2004 to September 2005)

• Double-blind, randomized, controlled; 21 centers in United States

• Treatment: 3 weekly treatments per each 4-week cycle, until PD

• Assessment: at baseline and every other cycle thereafter (RECIST)

• Cross-over for paclitaxel-alone arm after PD

Paclitaxel: 80 mg/m2

+STA-4783 213 mg/m2

(N=53)

Study Population

Stage IV 0-1 prior

Chemo for Metastatic disease

ECOG 0-2 No brain mets

Paclitaxel: 80 mg/m2

(N=28)

Randomization2:1

(N=81)

Primary Endpoint

Progression-freeSurvival

1/week for 3 weeks; 1 week off

Kaplan-Meier Plot of Progression-free Survival

Hazard Ratio= .583

P= 0.035*

* The P-value is from a 2-sided log-rank test.

6 Month PFS

STA-4783 + Paclitaxel

35%

Paclitaxel 15%

Genasense Drug Substance (Oblimersen Sodium, G3139)

• 18-base DNA oligonucleotide

• TCTCCCAGCGTGCGCCAT

• Phosphorothioate backbone

• Selectively targets Bcl-2 RNA

• Decreases Bcl-2 protein

• Other MOAs possible

O BaseO

BaseO

BaseO

OP

S O

-O

OP

-O O

S

OP

S O

-O

GM301 Study Design

• Primary endpoint: overall survival

• Secondary endpoints: response rate, progression free survival

• Sample size: N = 771

• Cycles every 21 days (maximum of 8): no cross-over

• Radiologic assessment every 2 cycles

• Minimum follow-up: 2 years

DTIC 1000 mg/m²

G3139 7 mg/kg/d x 5 days DTIC 1000 mg/m²

Stratification/

Randomization

1.0

0.4

0.2

0.0

0 20 24

0.8

0.6

4 8 12 16

Months

Pro

po

rtio

n S

urv

ivin

g

G+DTIC DTIC

Median (mos) 9.0 7.8

Hazard Ratio 0.87

Logrank p 0.077

Overall Survival (24-Month)Intent-to-treat Population; N=771

0 2 6 10 14 18 20 244 8 12 16 22

1.0

0.4

0.2

0.0

0.8

0.6

Months

Pro

port

ion

Su

rviv

ing

G+DTIC DTIC

Median (mos) 12.3 9.9

Hazard Ratio 0.64

Logrank P 0.0009

Overall SurvivalBaseline LDH < 0.8 x ULN; N=274

AGENDA (GM307) Study Design

• Co-Primary Endpoints: PFS/Overall survival

• Secondary endpoints: overall response rate, durable response rate, duration of response

• Sample size: N = 300

• Cycles every 21 days (maximum of 8): no cross-over

• Radiologic assessment every 42 days

• Minimum follow-up: 2 years

Genasense 7 mg/kg/d CIV x 5 days DTIC 1000 mg/m²

Stratification/

RandomizationMatching PCBO CIV x 5 days DTIC 1000 mg/m²

Signal Transduction & Angiogenesis Inhibitors

Mutated in 60-70% of melanoma 90% of mutations are V600E

Davies et al. Nature 2002; 417:949-54 & Wan PT et al. Cell. 2004 19;116(6):855-67

B-RAF, An Oncogene in 7% of Human Cancers

Response Rates & B-RAF Mutation Status

combination chemotherapy response rate

Wild type B-RAF 33%

Mutant B-RAF 11%

Chang et al. J Transl Med. 2004 Dec 21;2(1):46.

NRASB-RAF

MEK

ERK

MAP kinase pathway inhibitors in melanoma

PD0325901 ARRY-142886

BAY 43-9006/sorafenib

CHR-265

PLX4032

SB-590885

Sorafenib

Kinase assays IC50

C-Raf 2 nM

mVEGFR2, VEGFR3 6-10 nM

wt B-Raf, V599E B-Raf 20–40 nM

p38, PDGFrβ 28–38 nM

FLT-3, c-KIT 40–80 nM

EGFR, PKC, MEK, ERK Inactive at 10 mM

Wilhelm S et al. Cancer Res. 2004;64:7099-109

NH

NH

OO

N

NH

OCF3

Cl

Sorafenib Spectrum vs. Whole Kinome

Fabian, M.A. et al. Nat Biotechnol, 2005. 23(3):329-36.

Single-agent Sorafenib in Melanoma

• 39 patients with metastatic melanoma

– 1 responder

– 7 patients with stable disease at 12 weeks

• 22 patients with metastatic melanoma

– 1 partial response

– 12 with stable disease

Median progression-free survival: 3 months

Sorafenib with Chemotherapy

Single arm phase II trials

N ORR PFS

Dacarbazine 30 17% 3.6 mo.

Temozolomide 76 24% 6.0 mo.

Carboplatin & paclitaxel 105 26% 8.8 mo.

1ST 2ND

DTIC/temozolomide randomized phase II

Carboplatin/paclitaxel E2603 phase III OS PFS

Line of therapyChemotherapy

backbone

Randomized Trials in Metastatic Melanoma

Eligibility criteria• No prior chemotherapy,

one prior immunotherapy allowed

• Measurable disease by RECIST

• No active brain metastases, screening brain MRI required

Stratified: AJCC stage• Unresectable stage III• Stage IV-M1a, M1b• Stage IV-M1cECOG PS• 0• 1

Group A: DTIC, 1000 mg/m2 IV q3wSorafenib 400 mg po bid

Group B: DTIC, 1000 mg/m2 IV q3wPlacebo 2 tablets po bid

Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Trial Design

Ran

do

miz

atio

n

(N=

98)

• 1° end point: PFS

• 2° end point: OS

• 3° end points: TTP, tumor response rate, duration of response, EQ-5D QoL

Data on file. Bayer HealthCare.

Phase II Dacarbazine ± Sorafenib

1.00

0.75

0.50

0.25

0.000 100 200 300 400 500

Days From Randomization

Pro

gres

sion

-Fre

e S

urvi

val P

roba

bilit

y

600

Hazard Ratio = 0.67; P = 0.068

Sorafenib + DTIC (39 events)Median: 2.7 mo.

Placebo + DTIC (42 events) Median: 4.9 mo.

ORR

24%

12%

Sorafenib in Melanoma: PRISMPhase III Paclitaxel + Carboplatin ± Sorafenib

Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.

N=270

Primary endpoint: progression-free survival (by independent assessment)

Secondary and tertiary endpoints: time to progression, objective response rate, duration of response, overall survival

Carboplatin AUC 6 IV Day 1Paclitaxel 225 mg/m2 IV Day 1

Sorafenib 400 mg po bid Days 2-19Cycles repeated every 21 days

Stratified by:

AJCC stage: Unresectable stage III Stage IV – M1a, M1b Stage IV – M1c

ECOG PS: 0 vs 1

Key Eligibility: Progresses on DTIC/TMZ No active brain Metastases Measurable disease by RECIST Carboplatin AUC 6 IV Day 1

Paclitaxel 225 mg/m2 IV Day 1Placebo 2 tablets po bid Days 2-19

Cycles repeated every 21 days

RRAANNDDOOMMIIZZAATTIIOONN

Mandatory dose reduction after cycle 4 to paclitaxel 175 mg/m2 and

carboplatin AUC 5

Phase III Carboplatin/Paclitaxel ± Sorafenib

Hazard Ratio = 0.91; P = 0.492

Sorafenib + C/P (97 events)

Median: 4.0 mo.

Placebo + C/P (100 events)

Median: 4.1 mo.

1.00

0.75

0.50

0.25

0.00

Pro

babi

lity

of P

rogr

essi

on-F

ree

Sur

viva

l

0 14 29 43 57 71

Weeks From Randomization

ORR

11%

10%

Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.

Paclitaxel/Carboplatin ± Sorafenib in Advanced Melanoma E2603 Phase III Trial

Arm ACarboplatin AUC 6 IV Day 1Paclitaxel 225 mg/m2 IV Day 1Placebo 2 tablets po bid Days 2-19 Q3WStratified by:

AJCC Stage ECOG PS Prior Therapy

Arm BCarboplatin AUC 6 IV Day 1Paclitaxel 225 mg/m2 IV Day 1Sorafenib 400 mg po bid Days 2-19 Q3W

RRAANNDDOOMMIIZZEE

Carboplatin and paclitaxel with or without sorafenib in treating patients with unresectable stage III or stage IV melanoma.

Available at: www.clinicaltrials.gov/ct/show/NCT0010019?order=1. Accessed September 17, 2007.

800 patients with metastatic melanoma and no prior chemotherapy; primary endpoint - OS

BIM

p27Kip

-actin

pMEK

MEK

RAF265 Sorafenib

Vehicle

10 mg/kg q2d RAF26530 mg/kg q2d RAF265 100 mg/kg q2d RAF265

Mea

n T

um

or

Vo

lum

e (m

m3)(

+/-

SE

)

0

400

800

1200

1600

2000

2400

0 4 8 12 16 20

Days Post Staging

MEXF 276 (B-RafV600E)

RAF265 Causes Tumor Regression in Xenografts of V600E B-RAF Human Melanoma

Tumor Regressions (N=8/group)

PR / CR

1 / 08 / 08 / 0

100 mg/kg qd Sorafenib

0 / 0

0 / 0

Courtesy of Darrin Stuart, Novartis

-

Vehicle

-

Vehicle

-

Vehicle 10 mg/kg 30 mg/kg 100 mg/kg

Vehicle 10 mg/kg 30 mg/kg 100 mg/kg

-

Vehicle 10 mg/kg 30 mg/kg 100 mg/kg

Vehicle 10 mg/kg 30 mg/kg 100 mg/kg

RAF-265-MEL01 Study Design

40-60 B-RAFWT

40-60 B-RAFMUT

• Dose escalate to MTD without regard to B-RAF status using Bayesian methodology

• Assess Safety, PK, PD

• Expand at MTD and stratify based on B-RAF mutation status

• Assess PFS, ORR

Phase I

MTD

Serial biopsies once target drug exposure achieved

Phase II expansion

Selectivity of PLX4032 in vivo

N-RasMUT B-RafMUT

Lee J et al. 2006 NCI/AACR/EORTC

PLX4032 Dose Escalation Study

Dose level 1

Dose level 2

Dose level 3

Dose level 4

Maximum tolerated dose

3-6pts

3-6pts

3-6pts

3-6pts

3-6pts

Target AUC 6 patients with V600E+ melanoma

Serial biopsies

6 patients with V600E+ melanoma

AZD6244 Suppresses the Growth of 1205Lu Melanoma Xenograft (B-RAF mutant)

K Smalley et al, NCI/AACR/EORTC 2006

Lorusso et al. ASCO 2005, abstract 3011

Tumor pERK Suppression in Individual Patients MEK Inhibitor (PD0325901)

Phase II Trials with MEK Inhibitors

• ARRY-142886/AZ6244 (AstraZeneca)

– Randomized phase II: ARRY-142886 vs. temozolomide

– N = 182

– Archival, paraffin-embedded tissue collection

– Sample size allows allows exploration of effect in patients with a B-RAF or N-RAS mutation

• PD0325901 (Pfizer)

– Single-arm phase II

Single-agent Bevacizumab or Bevacizumab/IFN in Melanoma

• Randomized phase II trial:

– bevacizumab 15 mg/kg IV every 2 weeks vs.

– bevacizumab 15 mg/kg IV every 2 weeks + 1 MIU IFNα SQ QD

• 17 patients accrued as of preliminary analysis

– 44% with lymph node/skin metastases (M1a)

• 1 CR, 1 PR both on combination arm, both with M1a disease

• 4 SD > 24 weeks (3 on bevacizumab alone)

• Not published

Carson W et al. ASCO 2003, abstract 2873

Randomized Phase II Trial of Carboplatin/Paclitaxel ± Bevacizumab

RRAANNDDOOM M IIZZEE

Arm A

Carboplatin AUC 5 IV q 21dPaclitaxel 175 mg/m2 IV q21d Placebo

Arm B

Carboplatin AUC 5 IV q21dPaclitaxel 175 mg/m2 IV q21dBevacizumab 15 mg/kg IV q 21d

Stratify:

AJCC stage

ECOG PS

N = 200 patients with previously untreated metastatic melanoma

Primary endpoint = progression-free survival

Current Phase I or II Melanoma Trials with Angiogenesis Inhibitors

• AG-013736 (VEGFR & PDGFR)

– Single arm phase II

• CHR-258 (VEGFR & FGFR)

– Phase I in melanoma

• Sunitinib

– Phase I with temozolomide in melanoma

• Sorafenib/bevacizumab

• Sorafenib/temsirolimus

• Bevacizumab/temsirolimus

NCI/CTEP sponsored phase II

Novel Immunologics

Dendritic Cell/T Cell Activating Therapies in Clinical Development

Dendritic cell T cell

+T cell

receptorMHC

CD28

B7-1 (CD80)

CTLA4

B7-2 (CD86)

-

PD-L1 (B7-H1)

PD-1

-

Dendritic Cell/T Cell Activating Therapies in Clinical Development

Dendritic cell T cell

OX40L OX40

4-1BBL 4-1BB (CD137)

CD40LCD40

+

+

CD70 CD27

+

+T cell

receptorMHC

CD28B7

+

Hamid. ASCO. 2007 (abstr 8525).

46 responding patients out of 356 patientsenrolled in 6 clinical trials

*Indicates patient with ongoing response, N=25.

Duration of OR (months)

Nu

mb

er o

f P

atie

nts

Response Duration with Ipilimumab

Phase I Trial of CP-870,893• 29 patients with advanced solid tumors; 15 with melanoma

evaluated by RECIST

– 4 Partial Responses

– 7 Stable Disease

• All partial responses were in patients with melanoma

– Regression of lesions in liver, skin, lymph nodes, lung, muscle

– All PRs at 0.2 mg/kg or 0.3 mg/kg

• One melanoma patient (0.2 mg/kg) had a near CR for 18 months, then isolated LN recurrence, underwent surgery, now CR for 18 additional months

UPIN 1017 (melanoma)

Future Directions in Melanoma

• Diverse mechanisms currently being explored in melanoma

– Novel cytotoxics, signal transduction inhibitors, anti-angiogenic & novel immunotherapies

• Critical for new therapies to establish which subpopulation derives the greatest benefit