Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma Future Directions: Opportunities for Targeting B-RAF and Other Targets in Melanoma Management

1
Clinical Updates Novel Agents for the Treatment
of Metastatic MelanomaFuture Directions
Opportunities for Targeting B-RAF and Other
Targets in Melanoma Management

• Keith T. Flaherty, MD
• Assistant Professor of Medicine
• Abramson Cancer Center of the
• University of Pennsylvania
• Philadelphia, PA

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Novel Cytotoxics
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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

4
Altering the Threshold for Chemotherapy-induced
Apoptosis
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STA-4783 Induces Programmed Cell Death via the
Intrinsic Mitochondrial Apoptotic Pathway
STA-4783 induces ROS which accumulate in the
mitochondria
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
STA-4783
? ROS
Mitochondria
TARGET
Cytochrome c exits the mitochondria through pores
which are created by pro-apoptotic members of the
Bcl2 family and are dependent upon elevated ROS
Cytochrome c release
Caspase 9 activation
APOPTOSIS
Cytochrome c activates caspase 9 which then
activates caspase 3/7 leading to apoptosis
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STA-4783 in Metastatic MelanomaStudy Design

• 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

1/week for 3 weeks 1 week off
Coordinating investigator Steven ODay, MD, The
Angeles Clinic and Research Institute (81
patients were enrolled from December 2004 to
September 2005)
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Kaplan-Meier Plot of Progression-free Survival
6 Month PFS
STA-4783 Paclitaxel 35
Paclitaxel 15
Hazard Ratio .583 P 0.035
The P-value is from a 2-sided log-rank test.
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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

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GM301 Study Design
G3139 7 mg/kg/d x 5 days ? DTIC 1000 mg/m²
Stratification/ Randomization
DTIC 1000 mg/m²

• 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

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Overall Survival (24-Month)Intent-to-treat
Population N771
1.0
GDTIC DTIC
Median (mos) 9.0 7.8
Hazard Ratio 0.87 0.87
Logrank p 0.077 0.077
0.8
0.6
Proportion Surviving
0.4
0.2
0.0
0
20
24
4
8
12
16
Months
11
Overall SurvivalBaseline LDH lt 0.8 x ULN N274
GDTIC DTIC
Median (mos) 12.3 9.9
Hazard Ratio 0.64 0.64
Logrank P 0.0009 0.0009
Proportion Surviving
Months
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AGENDA (GM307) Study Design
Genasense 7 mg/kg/d CIV x 5 days ? DTIC 1000
mg/m²
Stratification/ Randomization
Matching PCBO CIV x 5 days ? DTIC 1000 mg/m²

• 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

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Signal Transduction Angiogenesis Inhibitors
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B-RAF, An Oncogene in 7 of Human Cancers
Mutated in 60-70 of melanoma 90 of mutations
are V600E
Davies et al. Nature 2002 417949-54 Wan PT et
al. Cell. 2004 19116(6)855-67
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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 212(1)46.
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MAP kinase pathway inhibitors in melanoma
NRAS
B-RAF
BAY 43-9006/sorafenib CHR-265 PLX4032
SB-590885
MEK
ERK
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Sorafenib
O
C
F
3
O
C
l
N
O
H
N
N
N
H
H
Kinase assays IC50
C-Raf 2 nM
mVEGFR2, VEGFR3 6-10 nM
wt B-Raf, V599E B-Raf 2040 nM
p38, PDGFrß 2838 nM
FLT-3, c-KIT 4080 nM
EGFR, PKC, MEK, ERK Inactive at 10 mM
Wilhelm S et al. Cancer Res. 2004647099-109
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Sorafenib Spectrum vs. Whole Kinome
Fabian, M.A. et al. Nat Biotechnol, 2005.
23(3)329-36.
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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
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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.
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Line of therapy
Randomized Trials in Metastatic Melanoma
Chemotherapy backbone

• 1ST 2ND
• DTIC/temozolomide randomized
  phase II
• Carboplatin/paclitaxel E2603 phase III OS
  PFS

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Sorafenib in Melanoma Randomized Phase II
Sorafenib DTIC Trial Design

• 1 end point PFS
• 2 end point OS
• 3 end points TTP, tumor response rate, duration
  of response, EQ-5D QoL

• 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-M1c
• ECOG PS
• 0
• 1

Group A DTIC, 1000 mg/m2 IV q3w Sorafenib 400
mg po bid
Group B DTIC, 1000 mg/m2 IV q3w Placebo 2
tablets po bid
Data on file. Bayer HealthCare.
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Phase II Dacarbazine Sorafenib
ORR 24 12
1.00 0.75 0.50 0.25 0.00
Sorafenib DTIC (39 events)
Median 2.7 mo.
Placebo DTIC (42 events)
Median 4.9 mo.
Hazard Ratio 0.67 P 0.068
Progression-Free Survival Probability
0
100
200
300
400
500
600
Days From Randomization
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Sorafenib in Melanoma PRISMPhase III Paclitaxel
Carboplatin Sorafenib
RANDOMIZATION
Carboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2
IV Day 1 Sorafenib 400 mg po bid Days 2-19 Cycles
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

Mandatory dose reduction after cycle 4 to
paclitaxel 175 mg/m2 and carboplatin AUC 5
Carboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2
IV Day 1 Placebo 2 tablets po bid Days
2-19 Cycles repeated every 21 days
Primary endpoint progression-free survival (by
independent assessment) Secondary and tertiary
endpoints time to progression, objective
response rate, duration of response, overall
survival
N270
Agarwala SS, et al. Proc Am Soc Clin Oncol.
200725474s. Abstract 8510.
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Phase III Carboplatin/Paclitaxel Sorafenib
ORR 11 10
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
Probability of Progression-Free Survival
Hazard Ratio 0.91 P 0.492
Agarwala SS, et al. Proc Am Soc Clin Oncol.
200725474s. Abstract 8510.
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Paclitaxel/Carboplatin Sorafenib in Advanced
Melanoma E2603 Phase III Trial
RANDOMIZE
Arm A Carboplatin AUC 6 IV Day 1 Paclitaxel 225
mg/m2 IV Day 1 Placebo 2 tablets po bid Days 2-19
Q3W

• Stratified by
• AJCC Stage
• ECOG PS
• Prior Therapy

Arm B Carboplatin AUC 6 IV Day 1 Paclitaxel
225 mg/m2 IV Day 1 Sorafenib 400 mg po bid
Days 2-19 Q3W
800 patients with metastatic melanoma and no
prior chemotherapy primary endpoint - OS
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?order1.
Accessed September 17, 2007.
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RAF265 Causes Tumor Regression in Xenografts of
V600E B-RAF Human Melanoma
MEXF 276 (B-RafV600E)
2400
0 / 0
Vehicle
2000
1600
Mean Tumor Volume (mm3)(/- SE)
0 / 0
100 mg/kg qd Sorafenib

1200
800
1 / 0
10 mg/kg q2d RAF265
400
8 / 0
30 mg/kg q2d RAF265
8 / 0
100 mg/kg q2d RAF265
0
Courtesy of
Darrin Stuart, Novartis
0
4
8
12
16
20
Days Post Staging
RAF265
Sorafenib
Vehicle
Vehicle
Vehicle
10 mg/kg 30 mg/kg 100 mg/kg
Vehicle 10 mg/kg 30 mg/kg 100 mg/kg
pMEK
-
-
MEK
-
-
Vehicle 10 mg/kg 30 mg/kg 100 mg/kg
Vehicle
10 mg/kg 30 mg/kg 100 mg/kg
BIM
p27Kip
?-actin
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RAF-265-MEL01 Study Design
40-60 B-RAFWT
Phase I
MTD
40-60 B-RAFMUT
Phase II expansion
Serial biopsies once target drug exposure
achieved

• 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

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Selectivity of PLX4032 in vivo
B-RafMUT
N-RasMUT
Lee J et al. 2006 NCI/AACR/EORTC
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PLX4032 Dose Escalation Study
3-6pts
6 patients with V600E melanoma
Maximum tolerated dose
Dose level 4
3-6pts
Serial biopsies
Dose level 3
3-6pts
Target AUC
6 patients with V600E melanoma
Dose level 2
3-6pts
3-6pts
Dose level 1
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AZD6244 Suppresses the Growth of 1205Lu Melanoma
Xenograft (B-RAF mutant)
K Smalley et al, NCI/AACR/EORTC 2006
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Tumor pERK Suppression in Individual Patients
MEK Inhibitor (PD0325901)
Lorusso et al. ASCO 2005, abstract 3011
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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

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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
  IFNa 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 gt 24 weeks (3 on bevacizumab alone)
• Not published

Carson W et al. ASCO 2003, abstract 2873
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Randomized Phase II Trial of Carboplatin/Paclitaxe
l Bevacizumab
Arm A Carboplatin AUC 5 IV q 21d Paclitaxel 175
mg/m2 IV q21d Placebo
R A N D O M I Z E
Stratify AJCC stage ECOG PS
Arm B Carboplatin AUC 5 IV q21d Paclitaxel 175
mg/m2 IV q21d Bevacizumab 15 mg/kg IV q 21d
N 200 patients with previously untreated
metastatic melanoma Primary endpoint
progression-free survival
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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
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Novel Immunologics
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Dendritic Cell/T Cell Activating Therapies in
Clinical Development
PD-L1 (B7-H1)
PD-1
-
B7-1 (CD80)
-
CTLA4
T cell receptor

MHC
B7-2 (CD86)
CD28
Dendritic cell
T cell
39
Dendritic Cell/T Cell Activating Therapies in
Clinical Development
OX40L
OX40
4-1BB (CD137)
4-1BBL


CD70

CD27
T cell receptor

MHC
CD28
B7

CD40
CD40L
Dendritic cell
T cell
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Response Duration with Ipilimumab
Hamid. ASCO. 2007 (abstr 8525).
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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)
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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