Transcript UTD Novel Agents Melanoma

Clinical Updates
Novel Agents for the Treatment of
Metastatic Melanoma
David F. McDermott, MD
Clinical Director, Biologic Therapy Program
Beth Israel Deaconess Medical Center
Assistant Professor
Harvard Medical School
Boston, MA
Melanoma : Epidemiology 2007
Incidence:
50,700/8100 deaths
3% of all cancers
1% of all cancer deaths
12 fold increase since 1935
Lifetime risk: 1 in 75 Americans
1 in 25 Australians
9th most common malignancy,
but 2nd in terms of years of potential life lost
Metastatic Melanoma: Natural History
“Metastatic melanoma is a bad disease.”
• Median age:
• Median Survival:
• 5-year survival:
45-50
6-10 months
< 5%
Few if any effective therapies
Proposed New AJCC Staging
System: Stage IV Melanoma
M Status
Site
Serum LDH
M1a
Distant skin, SC, or nodal
mets
Normal
M1b
Lung metastases
Normal
M1c
All other visceral mets
Or any distant met
Normal
Elevated
Staging Factors: Importance
Clinical trial results appear to be
influenced as much by patient selection
as by treatment approach
Metastatic Melanoma – 2008
Approved Therapies
(USA)
• DTIC
• High Dose Interleukin-2
Date
1970’s
1998
Many patients will receive both agents
Single Agent DTIC Activity*
•
•
•
•
Response Rate
Median Response Duration
Median Survival
6-year survival
19%
4 mos
6-9 mos
< 2%
DTIC has never been compared
to observation or best supportive care
*Hill et al Cancer 53:1299; 1984 (n=580)
Cytotoxic Chemotherapy:
Status
There is currently no evidence that other
single agents, combination chemotherapy or
the addition of tamoxifen or IFN to DTIC is
superior to DTIC alone
Melanoma Therapy
Good News: Many options
Bad News: Many lead nowhere.
Melanoma lagging behind other
cancers in translating basic
research discoveries into new
therapies
Chekov: “When many treatment options are
proposed, you know the disease is incurable.”
Translating Scientific Advances into Improved
Therapy – Current Opportunities
• Immunotherapy
• Targeted therapy
– B-Raf inhibition (sorafenib/chemotherapy)
– Antiangiogenic therapy (STA-4783)
– Novel targets
Molecular Alterations in Melanoma
15%
F
G
F
R
60-70%
GRB2
N-RAS*
GTP
B-Raf*
SOS
PI3K
RAS
GDP
AKT
MEK
MEK
C-RAF
ERK
ERK
25-50%
BCL2
TOR
ELK
ELK
x
PTEN
P16
Cdk4
Cyclin D
Apaf1
Rationale for Sorafenib in Melanoma
• B-Raf mutations (mostly V600E) occur in >60% of melanomas1
• Sorafenib—multikinase inhibitor targeting Raf and RTKs2
– Induces apoptosis in B-Raf wild-type and mutant melanoma cell lines
– Inhibits tumor angiogenesis
• Phase II single agent trial showed minimal activity3
• Phase I/II trial of sorafenib in combination with
carboplatin/paclitaxel4
– Well tolerated with full doses of carboplatin and paclitaxel
– Antitumor activity
• One CR, PR (26%), clinical benefit (85%)
• Median PFS of >8 months
• Phase III randomized trials with single agent DTIC
– Indicate RRs (CR + PR) between 7% and 11%5,6
– Show median PFS of 1.6 months5
1. Hingorani SR et al. Cancer Res. 2003;63:5198-5202; 2. Karasarides M et al. Oncogene. 2004; 23:6292-6298;
3. Eisen T et al. Br J Cancer. 2006;95:581-586; 4. Adapted from: Flaherty KT. Presented at: TAT; March 16-18, 2006 ;
Amsterdam, The Netherlands; 5. Bedikian AY et al. J Clin Oncol. 2006;24:4378-4745;
6. Chapman PB et al. J Clin Oncol. 1999;17:2745-2751.
Key Chemotherapy Trials in Melanoma
Trial/Author
Drug/Regimen
N
RR (%)
Median
Survival
(months)
Median
PFS
(months)
Comments/
Conclusions
• No survival
difference
Intergroup 3695
(Atkins MB et al.
ASCO 2003)1
CVD
201
11.9
9.1
CVD/IFN/IL-2
204
16.6
8.4
Chapman PB et al.
(J Clin Oncol 1999)2
Dartmouth
Regimen
119
18.5*
7.7†
DTIC
121
10.2*
6.3 †
Middleton et al.
(J Clin Oncol 2000)3
DTIC
149
12.1†
6.4†
Temodar
156
13.5†
7.7†
Bedikian AY et al.
(J Clin Oncol 2006)4
DTIC
385
7.5
7.8
1.6
DTIC + oblimersen
386
13.5
9
2.6
• No difference in
survival
• DTIC remains
reference std
• Temodar=DTIC
• Combination
improves
outcomes
*Assessable for response (N=108 for Dartmouth and N=118 for DTIC).
†All patients evaluated on an intent-to-treat basis.
1. Adapted from Atkins MB et al. Presented at: ASCO Annual Meeting; May 31- June 3, 2003; Chicago, IL.
2. Chapman PB et al. J Clin Oncol. 1999;17:2745-2751.
3. Middleton MR et al. J Clin Oncol. 2000;18:158-166.
4. Bedikian AY et al. J Clin Oncol. 2006;24:4738-4745.
Taxane Activity in Melanoma
Author/group
Paclitaxel
Wiernik PH1
Legha SS2
Einzig AI3
DeCOG (Zimpfer-Rechner C)4
# Evaluable
2nd line
Docetaxel
Aamdal S5
Bedikian AY6
Einzig AI7
Carboplatin & paclitaxel
Hodi FS8
DeCOG (Zimpfer-Rechner C)4
1st line
2nd line
ORR
12
25
28
18
33%
12%
14%
0%
average 17%
30
40
35
17%
13%
6%
average 11%
15
16
20%
0%
1. Wiernik PH et al. J Clin Oncol. 1987:5;1232-1239.; 2. Legha SS et al. Cancer. 1990:65; 2478-2481.;
3. Einzig AI et al. Invest New Drug. 1991:9;59-64.; 4. Zimpfer-Rechner C et al. Melanoma Res. 2003:13;531-536.;
5. Aamdal S et al. Eur J Cancer. 1994:30A;1061-1064.; 6. Bedikian AY et al. J Clin Oncol. 1995:13;2895-2896.;
7. Einzig AI et al. Med Oncol. 1996:13:111-117.; 8. Hodi FS et al. Am J Clin Oncol (CCT). 2002:25;283-286.
Sorafenib: Clinical Trials
• Completed
– Industry – Randomized Phase III Taxol/Carbo ±
sorafenib in DTIC/TMZ failures-PRISM Trial
– Industry – Randomized Phase II of DTIC ±
sorafenib-completed
• Ongoing
– TMZ + sorafenib (including pts with CNS mets) –
U Penn + DF/HCC
– E2603 – Phase III of Taxol/Carbo ± sorafenib
Will promising single institution data translate into
benefit for the general melanoma population?
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.
Sorafenib in Melanoma:
PRISM Phase III Trial Patient Demographics
Gender
Male
Female
Age, years
Median
Range
Age Group
<65 years
65–74 years
≥75 years
Race
White
Missing
ECOG
0
1
Sorafenib +
Carboplatin/Paclitaxel
N=135
N (%)
Placebo +
Carboplatin/Paclitaxel
N=135
N (%)
84 (62)
51 (38)
87 (64)
48 (36)
57
22–89
56
26–82
97 (72)
29 (22)
9 (7)
92 (68)
39 (29)
4 (3)
113 (84)
21 (16)
110 (82)
24 (18)
76 (56)
59 (44)
70 (52)
65 (48)
Data on file. Bayer HealthCare.
Sorafenib in Melanoma:
PRISM Phase III Trial Disease Characteristics
Sorafenib +
Carboplatin/Paclitaxel
N=135
N (%)
Placebo +
Carboplatin/Paclitaxel
N=135
N (%)
4 (3)
12 (9)
27 (20)
92 (68)
1 (1)
10 (7)
31 (23)
93 (69)
75 (56)
58 (43)
68 (51)
66 (49)
8.2
11.3
133 (99)
135 (100)
AJCC Stage
III unresectable
IV M1a
IV M1b
IV M1c
LDH
Normal/Low
High
Median time since diagnosis of
metastatic disease (months)
Evidence of PD at study entry
AJCC=American Joint Committee on Cancer.
Data on file. Bayer HealthCare.
Sorafenib in Melanoma:
PRISM Phase III PFS by Independent Review
Proportion of Patients
Progression-Free
1.00
Sorafenib
Placebo
No. of PFS events
97 (72%)
100 (74%)
Median PFS (days/wks)
112/17.4
125/17.9
(83-162)
(79-160)
32%
29%
99% Cl (days)
0.75
PFS rate at Day 180
Hazard ratio
(Sorafenib/placebo)
0.50
0.906 [P=0.492]
99% Cl
(.627-1.310)
0.25
0
0
100
200
300
400
500
Days From Randomization
Sorafenib
Placebo
CI=confidence interval.
Censored Treatment for Sorafenib
Censored Treatment for Placebo
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
Sorafenib in Melanoma: PRISM Phase III
Grade 3 or Higher AEs
(5% Incidence in Either Treatment Arm)
Sorafenib +
Carboplatin/Paclitaxel
N = 134
Placebo +
Carboplatin/Paclitaxel
N = 134
Neutrophils
65 (48%)
61 (45%)
Platelets
37 (28%)
16 (12%)
Leukocytes
29 (22%)
26 (19%)
Hemoglobin
9 (7%)
18 (14%)
Neuropathy-Sensory
27 (20%)
18 (14%)
Fatigue
21 (16%)
13 (10%)
Rash/Desquamation
10 (8%)
0
Hand-Foot Skin Reaction
9 (7%)
0
Febrile Neutropenia
12 (9%)
9 (7%)
Diarrhea
11 (8%)
4 (3%)
Thrombosis/Thrombus/Embolism
5 (4%)
8 (6%)
Data on file. Bayer HealthCare.
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
R
A
N
D
O
M
I
Z
A
T
I
O
N
(N=98)
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.
Sorafenib in Melanoma: Randomized Phase II
Sorafenib + DTIC Patient Demographics
Sorafenib + DTIC
N=51
Placebo + DTIC
N=50
Male
38 (75%)
33 (66%)
Female
13 (25%)
17 (34%)
Median
55
60
Range
31-82
18-88
<65
36 (71%)
33 (66%)
65-74
11 (22%)
8 (16%)
4 (8%)
9 (18%)
51 (100%)
47 (94%)
Gender
Age
Age Group
≥75
Race
White
Data on file. Bayer HealthCare.
Sorafenib in Melanoma: Randomized Phase II
Sorafenib + DTIC Disease Characteristics
Sorafenib + DTIC
N=51
Placebo + DTIC
N=50
0
31 (61%)
31 (62%)
1
20 (39%)
19 (38%)
III unresectable
2 (4%)
1 (2%)
IV M1a
3 (6%)
7 (14%)
IV M1b
18 (35%)
17 (34%)
IV M1c
28 (55%)
25 (50%)
Normal/Low
34 (67%)
31 (62%)
High
12 (24%)
17 (34%)
4.1
6.8
14 (27%)
13 (26%)
ECOG
AJCC Stage
LDH
Time since diagnosis of
metastatic disease
Median (months)
Adjuvant Therapy
Data on file. Bayer HealthCare.
Sorafenib in Melanoma: Randomized Phase II
Sorafenib + DTIC PFS (Independent Assessment)
Proportion of Patients
Progression-Free
1.00
0.75
Sorafenib
Placebo
No. of PFS events
39 (77%)
41 (82%)
Median PFS (days/wks)
148/21.1
82/11.7
95% CI (days)
(112-196)
(43-125)
PFS rate at Day 180
41%
18%
(0.268-0.552)
(0.062-0.294)
95% CI
Hazard ratio
(Sorafenib/placebo)
0.665 [P=0.070]
95% CI
0.50
(0.427-1.037)
Sorafenib + DTIC
Placebo + DTIC
Censored Treatment for Sorafenib
Censored Treatment for Placebo
0.25
0
0
100
200
300
400
500
600
Days From Randomization
Data on file. Bayer HealthCare.
Sorafenib in Melanoma: Randomized Phase II
Sorafenib + DTIC Response Rates
Best Response
(RECIST)
Sorafenib + DTIC
N (%)
Placebo + DTIC
N (%)
Independent Review
Partial response
12 (24)
Stable disease
24 (47)
Progressive disease
15 (29)
71%
Clinical
benefit
6 (12)
22 (44)
56%
Clinical
benefit
21 (42)
Data on file. Bayer HealthCare.
Sorafenib in Melanoma: Randomized Phase II
Sorafenib + DTIC Grade 3 or Higher AEs
(5% Incidence in Either Treatment Arm)
Sorafenib + DTIC
(n=51)
Placebo + DTIC
(n=50)
Platelets*
18 (35%)
9 (18%)
Neutrophils†
17 (33%)
6 (12%)
Leukocytes
7 (14%)
3 (6%)
Hypertension
4 (8%)
0
CNS Hemorrhage
4 (8%)
0
Thrombosis/Thrombus/
Embolus
3 (6%)
0
Adverse Event
*Platelets: Grade 4 – Placebo (2%) vs Sorafenib (18%).
†Neutrophils: Grade 4 – Placebo (6%) vs Sorafenib (20%).
Data on file. Bayer HealthCare.
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.
Sorafenib in Melanoma: Conclusions
• Single agent Sorafenib
–
Limited activity in advanced melanoma
• Sorafenib in combination
–
With carboplatin/paclitaxel
• Did not improve PFS in a second-line patient population that failed DTIC or TMZ
–
With DTIC
• Encouraging results in chemo-naïve patients with advanced melanoma
• Strong efficacy trend toward PFS and PFS rate at 6 months vs placebo and DTIC
–
Generally well tolerated with carboplatin/paclitaxel and DTIC
–
Utility of Sorafenib + carboplatin/paclitaxel in first-line, chemo-naïve, advanced
melanoma patients remains an important question
• A Phase III ECOG trial (E2603) evaluating carboplatin/paclitaxel ± sorafenib in
front-line patients with advanced melanoma in progress
Translating Scientific Advances into Improved
Therapy: Current Opportunities
• Immunotherapy
• Targeted therapy
– B-Raf inhibition (Sorafenib/chemotherapy)
– Apoptosis induction (STA-4783)
– Novel targets
STA-4783 in Melanoma
• Novel small molecule, administered intravenously
• Triggers apoptosis as single agent and sensitizes cancer
cells to agents that induce cell death through mitochondria
pathway
• Demonstrated anti-cancer efficacy in double-blind,
randomized, controlled, 21-center Phase IIb trial in
metastatic melanoma
– Doubled median and 6-month PFS; met primary PFS
endpoint (P=0.035)
– Evidence of survival advantage
• Well-tolerated, with favorable safety profile
• Entering pivotal, confirmatory Phase III in metastatic
melanoma
STA-4783: MOA
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)
Apoptosis-Inducing Agents
Increasing Oxidative Stress States
STA-4783: Hsp70 inducer
Phase II trial in metastatic melanoma: paclitaxel + STA-4783 vs. paclitaxel alone
Dose
Number of Patients
ORR
Median PFS
Median OS
Paclitaxel + STA-4783
Paclitaxel
80 mg/m2 + 213 mg/m2
80 mg/m2
53
28
15%
4%
P = .153
3.7 months
1.9 months
HR 0.583; P = .035
12 months
7.8 months
HR 0.856; P = .5707
Phase III trial in chemotherapy-naïve patients initiated; anticipated enrollment: 600.
O’Day S, et al. Proc Am Soc Clin Oncol. 2007;25:479s. Abstract 8528.
Kaplan-Meier Plot
Progression-free Survival (ITT)
O’Day S, et al. Proc Am Soc Clin Oncol. 2007;25:479s. Abstract 8528.
New Potential Targets
•
•
•
•
•
•
•
•
•
• PI3K
Stat 3
• IL-8
NFkb
• MUC18
Notch 1
• CREB-ATF1
BCL2
• Folded WT p53
AKT- TOR
• ABCB5
VEGF
• NEDD9
MITF
GSK3
iNos
Chekov: “When many treatment targets are
proposed, you know the disease is incurable.”
Approach to Translational Research with
Targeted Therapy
•
•
•
•
•
Identify relevant targets
Identify drugs that hit the target
Select the population that expresses the target
Validate that the target is actually “hit”
Assess the effect of hitting the target on other
proteins and pathways and on tumor regression