Transcript Novel Agents for the Treatment of Malignant Melanoma

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, MD
Assistant Professor of Medicine
Abramson Cancer Center of the
University of Pennsylvania
Philadelphia, 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 induces ROS
which accumulate in the
mitochondria
STA-4783
S
S
O
N
H3C
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
O
N
N
H
H
N
CH3
↑ ROS
Mitochondria
TARGET
Cytochrome c
release
APOPTOSIS
Caspase 9
activation
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 activates
caspase 9 which then
activates caspase 3/7
leading to apoptosis
STA-4783 in Metastatic Melanoma
Study 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
Study Population
 Stage IV
 0-1 prior
Chemo for
Metastatic
disease
 ECOG 0-2
 No brain mets
Randomization
2:1
Paclitaxel: 80 mg/m2
+
STA-4783 213 mg/m2
(N=53)
Primary
Endpoint
Progression-free
Survival
(N=81)
Paclitaxel: 80 mg/m2
(N=28)
Coordinating investigator: Steven O’Day, MD, The Angeles Clinic and Research Institute
(81 patients were enrolled from December 2004 to September 2005)
Kaplan-Meier Plot of Progression-free Survival
6 Month PFS
Hazard Ratio= .583
P= 0.035*
* The P-value is from a 2-sided log-rank test.
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
O
Base
O
-O O
P
S O
O
S O
P
-O O
• Other MOAs possible
-O O
P
S O
Base
O
Base
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
Overall Survival (24-Month)
Intent-to-treat Population; N=771
Proportion Surviving
1.0
Median (mos)
Hazard Ratio
Logrank p
0.8
0.6
G+DTIC DTIC
9.0
7.8
0.87
0.077
0.4
0.2
0.0
0
4
8
12
Months
16
20
24
Overall Survival
Baseline LDH < 0.8 x ULN; N=274
1.0
Median (mos)
Hazard Ratio
Logrank P
0.8
Proportion Surviving
G+DTIC
DTIC
12.3
9.9
0.64
0.0009
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
Months
16
18
20
22
24
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
Signal Transduction & Angiogenesis
Inhibitors
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; 417:949-54 & Wan PT et al. Cell. 2004 19;116(6):855-67
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.
MAP kinase pathway
inhibitors in melanoma
B-RAF
MEK
ERK
NRAS
BAY 43-9006/sorafenib
CHR-265
PLX4032
SB-590885
PD0325901
ARRY-142886
O
CF3
Sorafenib
Cl
O
O
N
H
N
N
H
Kinase assays
N
H
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
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.
Randomized Trials in Metastatic Melanoma
Line of therapy
Chemotherapy
backbone
1ST
DTIC/temozolomide
randomized
phase II
Carboplatin/paclitaxel
E2603
OS
2ND
phase III
PFS
Sorafenib in Melanoma: Randomized Phase II
Sorafenib + DTIC Trial Design
• 1° end point: PFS
• 2° end point: OS
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
Randomization
(N=98)
• 3° end points: TTP, tumor response rate, duration of response, EQ-5D QoL
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.
Progression-Free Survival Probability
Phase II Dacarbazine ± Sorafenib
ORR
1.00
0.75
Sorafenib + DTIC (39 events)
Median: 2.7 mo.
24%
Placebo + DTIC (42 events)
Median: 4.9 mo.
12%
Hazard Ratio = 0.67; P = 0.068
0.50
0.25
0.00
0
100
200
300
400
Days From Randomization
500
600
Sorafenib in Melanoma: PRISM
Phase III Paclitaxel + Carboplatin ± Sorafenib
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
Primary endpoint: progression-free
survival (by independent assessment)
Secondary and tertiary endpoints: time
to progression, objective response rate,
duration of response, overall survival
R
A
N
D
O
M
I
Z
A
T
I
O
N
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
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
N=270
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
Phase III Carboplatin/Paclitaxel ± Sorafenib
Probability of Progression-Free Survival
ORR
Sorafenib + C/P (97 events)
Median: 4.0 mo.
1.00
Placebo + C/P (100 events)
Median: 4.1 mo.
0.75
11%
10%
Hazard Ratio = 0.91; P = 0.492
0.50
0.25
0.00
0
14
29
43
57
71
Weeks From Randomization
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
Paclitaxel/Carboplatin ± Sorafenib in
Advanced Melanoma
E2603 Phase III Trial
Stratified by:
 AJCC Stage
 ECOG PS
 Prior Therapy
800 patients with metastatic
melanoma and no prior
chemotherapy; primary endpoint - OS
R
A
N
D
O
M
I
Z
E
Arm A
Carboplatin AUC 6 IV Day 1
Paclitaxel 225 mg/m2 IV Day 1
Placebo
2 tablets po bid Days 2-19 Q3W
Arm B
Carboplatin
Paclitaxel
Sorafenib
AUC 6 IV Day 1
225 mg/m2 IV Day 1
400 mg po bid Days 2-19 Q3W
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.
Mean Tumor Volume
(mm3)(+/- SE)
RAF265 Causes Tumor Regression in Xenografts of V600E
B-RAF Human Melanoma
Tumor Regressions
(N=8/group)
PR / CR
0/0
MEXF 276 (B-RafV600E)
2400
Vehicle
2000
1600
100 mg/kg qd
Sorafenib
0/0
10 mg/kg q2d RAF265
30 mg/kg q2d RAF265
100 mg/kg q2d RAF265
1/0
8/0
8/0
1200
800
400
0
Courtesy of
Darrin Stuart, Novartis
0
4
8
12
16
20
Days Post Staging
RAF265
Vehicle
Vehicle
10 mg/kg
30 mg/kg
Sorafenib
100 mg/kg
-
Vehicle 10 mg/kg
30 mg/kg
Vehicle
10 mg/kg
30 mg/kg
Vehicle
10 mg/kg 30 mg/kg
100 mg/kg
pMEK
MEK
100 mg/kg
BIM
p27Kip
-actin
100 mg/kg
RAF-265-MEL01 Study Design
40-60 B-RAFWT
Phase I
MTD
40-60 B-RAFMUT
Serial biopsies once target
drug exposure achieved
Phase II
expansion
•
Dose escalate to MTD without
regard to B-RAF status using
Bayesian methodology
• Expand at MTD and stratify based on
B-RAF mutation status
•
Assess Safety, PK, PD
• Assess PFS, ORR
Selectivity of PLX4032 in vivo
N-RasMUT
B-RafMUT
Lee J et al. 2006 NCI/AACR/EORTC
PLX4032 Dose Escalation Study
3-6pts
Maximum tolerated dose
3-6pts
Dose
level 4
Serial biopsies
3-6pts
Dose
level 3
3-6pts
Dose
level 2
Dose
level 1
6 patients with
V600E+ melanoma
3-6pts
Target AUC
6 patients with
V600E+ melanoma
AZD6244 Suppresses the Growth of 1205Lu
Melanoma Xenograft (B-RAF mutant)
K Smalley et al, NCI/AACR/EORTC 2006
Tumor pERK Suppression in Individual Patients
MEK Inhibitor (PD0325901)
Lorusso et al. ASCO 2005, abstract 3011
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
Arm A
Stratify:
AJCC stage
ECOG PS
R
A
N
D
O
M
I
Z
E
Carboplatin AUC 5 IV q 21d
Paclitaxel 175 mg/m2 IV q21d
Placebo
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
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
PD-L1
(B7-H1)
B7-1
(CD80)
PD-1
-
CTLA4
T cell
MHC
B7-2
(CD86)
Dendritic cell
+
receptor
CD28
T cell
Dendritic Cell/T Cell Activating Therapies in
Clinical Development
OX40L
4-1BBL
CD70
OX40
4-1BB
(CD137)
+
+
CD27
T cell
MHC
B7
+
CD40
Dendritic cell
+
receptor
CD28
CD40L
T cell
+
Response Duration with Ipilimumab
Number of Patients
46 responding patients out of 356 patients
enrolled in 6 clinical trials
Duration of OR (months)
*Indicates patient with ongoing response, N=25.
Hamid. ASCO. 2007 (abstr 8525).
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