Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma

1
Clinical UpdatesNovel Agents for the Treatment
of Metastatic Melanoma

• David F. McDermott, MD
• Clinical Director, Biologic Therapy ProgramBeth
  Israel Deaconess Medical CenterAssistant
  Professor
• Harvard Medical SchoolBoston, MA

2
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

3
Metastatic Melanoma Natural History

• Metastatic melanoma is a bad disease.
• Median age 45-50
• Median Survival 6-10 months
• 5-year survival lt 5
• Few if any effective therapies

4
Proposed New AJCC Staging System Stage IV
Melanoma
M Status Site Serum LDH
5
Staging Factors Importance

• Clinical trial results appear to be influenced as
  much by patient selection as by treatment approach

6
Metastatic Melanoma 2008

• Approved Therapies (USA) Date
• DTIC 1970s
• High Dose Interleukin-2 1998
• Many patients will receive both agents

7
Single Agent DTIC Activity

• Response Rate 19
• Median Response Duration 4 mos
• Median Survival 6-9 mos
• 6-year survival lt 2

DTIC has never been compared to observation or
best supportive care
Hill et al Cancer 531299 1984 (n580)
8
Cytotoxic ChemotherapyStatus

• 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

9
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.
10
Translating Scientific Advances into Improved
Therapy Current Opportunities

• Immunotherapy
• Targeted therapy
• B-Raf inhibition (sorafenib/chemotherapy)
• Antiangiogenic therapy (STA-4783)
• Novel targets

11
Molecular Alterations in Melanoma
15
60-70
N-RAS GTP
RAS GDP
C-RAF
25-50
PTEN
x
12
Rationale for Sorafenib in Melanoma

• B-Raf mutations (mostly V600E) occur in gt60 of
  melanomas1
• Sorafenibmultikinase 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 gt8 months
• Phase III randomized trials with single agent
  DTIC
• Indicate RRs (CR PR) between 7 and 115,6
• Show median PFS of 1.6 months5

1. Hingorani SR et al. Cancer Res.
2003635198-5202 2. Karasarides M et al.
Oncogene. 2004 236292-6298 3. Eisen T et al.
Br J Cancer. 200695581-586 4. Adapted from
Flaherty KT. Presented at TAT March 16-18, 2006
Amsterdam, The Netherlands 5. Bedikian AY et
al. J Clin Oncol. 2006244378-4745 6. Chapman
PB et al. J Clin Oncol. 1999172745-2751.
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Key Chemotherapy Trials in Melanoma
Trial/Author Drug/Regimen N RR () Median Survival (months) Median PFS (months) Comments/Conclusions
Intergroup 3695 (Atkins MB et al. ASCO 2003)1 CVD 201 11.9 9.1 No survival difference
Intergroup 3695 (Atkins MB et al. ASCO 2003)1 CVD/IFN/IL-2 204 16.6 8.4 No survival difference
Chapman PB et al. (J Clin Oncol 1999)2 Dartmouth Regimen 119 18.5 7.7 No difference in survival DTIC remains reference std
Chapman PB et al. (J Clin Oncol 1999)2 DTIC 121 10.2 6.3 No difference in survival DTIC remains reference std
Middleton et al. (J Clin Oncol 2000)3 DTIC 149 12.1 6.4 TemodarDTIC
Middleton et al. (J Clin Oncol 2000)3 Temodar 156 13.5 7.7 TemodarDTIC
Bedikian AY et al. (J Clin Oncol 2006)4 DTIC 385 7.5 7.8 1.6 Combination improves outcomes
Bedikian AY et al. (J Clin Oncol 2006)4 DTIC oblimersen 386 13.5 9 2.6 Combination improves outcomes

• Assessable for response (N108 for Dartmouth and
  N118 for DTIC).
• All patients evaluated on an intent-to-treat
  basis.
• Adapted from Atkins MB et al. Presented at ASCO
  Annual Meeting May 31- June 3, 2003 Chicago,
  IL.
• Chapman PB et al. J Clin Oncol.
  1999172745-2751.
• Middleton MR et al. J Clin Oncol.
  200018158-166.
• Bedikian AY et al. J Clin Oncol.
  2006244738-4745.

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Taxane Activity in Melanoma
Author/group Evaluable ORR
Paclitaxel
Wiernik PH1 12 33
Legha SS2 25 12
Einzig AI3 28 14
DeCOG (Zimpfer-Rechner C)4 2nd line 18 0
average 17
Docetaxel
Aamdal S5 30 17
Bedikian AY6 40 13
Einzig AI7 35 6
average 11
Carboplatin paclitaxel
Hodi FS8 1st line 15 20
DeCOG (Zimpfer-Rechner C)4 2nd line 16 0
1. Wiernik PH et al. J Clin Oncol.
198751232-1239. 2. Legha SS et al. Cancer.
199065 2478-2481. 3. Einzig AI et al. Invest
New Drug. 1991959-64. 4. Zimpfer-Rechner C et
al. Melanoma Res. 200313531-536. 5. Aamdal S
et al. Eur J Cancer. 199430A1061-1064. 6.
Bedikian AY et al. J Clin Oncol.
1995132895-2896. 7. Einzig AI et al. Med
Oncol. 199613111-117. 8. Hodi FS et al. Am J
Clin Oncol (CCT). 200225283-286.
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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?
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Sorafenib in Melanoma PRISMPhase III Paclitaxel
Carboplatin Sorafenib
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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Sorafenib in Melanoma PRISM Phase III Trial
Patient Demographics
Sorafenib Carboplatin/Paclitaxel N135 N () Placebo Carboplatin/Paclitaxel N135 N ()
Gender
Male 84 (62) 87 (64)
Female 51 (38) 48 (36)
Age, years
Median 57 56
Range 2289 2682
Age Group
lt65 years 97 (72) 92 (68)
6574 years 29 (22) 39 (29)
75 years 9 (7) 4 (3)
Race
White 113 (84) 110 (82)
Missing 21 (16) 24 (18)
ECOG
0 76 (56) 70 (52)
1 59 (44) 65 (48)
Data on file. Bayer HealthCare.
18
Sorafenib in Melanoma PRISM Phase III Trial
Disease Characteristics
Sorafenib Carboplatin/Paclitaxel N135 N () Placebo Carboplatin/PaclitaxelN135 N ()
AJCC Stage
III unresectable 4 (3) 1 (1)
IV M1a 12 (9) 10 (7)
IV M1b 27 (20) 31 (23)
IV M1c 92 (68) 93 (69)
LDH
Normal/Low 75 (56) 68 (51)
High 58 (43) 66 (49)
Median time since diagnosis of metastatic disease (months) 8.2 11.3
Evidence of PD at study entry 133 (99) 135 (100)
AJCCAmerican Joint Committee on Cancer. Data on
file. Bayer HealthCare.
19
Sorafenib in Melanoma PRISM Phase III PFS by
Independent Review
Sorafenib Placebo
No. of PFS events 97 (72) 100 (74)
Median PFS (days/wks) 112/17.4 125/17.9
99 Cl (days) (83-162) (79-160)
PFS rate at Day 180 32 29
Hazard ratio (Sorafenib/placebo) 0.906 P0.492 0.906 P0.492
99 Cl (.627-1.310) (.627-1.310)
1.00
0.75
Proportion of Patients Progression-Free
0.50
0.25
0
0
100
200
300
400
500
Days From Randomization
CIconfidence interval.
Agarwala SS, et al. Proc Am Soc Clin Oncol.
200725474s. Abstract 8510.
20
Sorafenib in Melanoma PRISM Phase IIIGrade 3 or
Higher AEs (?5 Incidence in Either Treatment
Arm)
Sorafenib Carboplatin/Paclitaxel N 134 Placebo Carboplatin/PaclitaxelN 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.
21
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

RANDOMIZATION
(N98)
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.
22
Sorafenib in Melanoma Randomized Phase II
Sorafenib DTIC Patient Demographics
Sorafenib DTIC N51 Placebo DTIC N50
Gender
Male 38 (75) 33 (66)
Female 13 (25) 17 (34)
Age
Median 55 60
Range 31-82 18-88
Age Group
lt65 36 (71) 33 (66)
65-74 11 (22) 8 (16)
75 4 (8) 9 (18)
Race
White 51 (100) 47 (94)
Data on file. Bayer HealthCare.
23
Sorafenib in Melanoma Randomized Phase II
Sorafenib DTIC Disease Characteristics
Sorafenib DTIC N51 Placebo DTIC N50
ECOG
0 31 (61) 31 (62)
1 20 (39) 19 (38)
AJCC Stage
III unresectable 2 (4) 1 (2)
IV M1a 3 (6) 7 (14)
IV M1b 18 (35) 17 (34)
IV M1c 28 (55) 25 (50)
LDH
Normal/Low 34 (67) 31 (62)
High 12 (24) 17 (34)
Time since diagnosis of metastatic disease
Median (months) 4.1 6.8
Adjuvant Therapy 14 (27) 13 (26)
Data on file. Bayer HealthCare.
24
Sorafenib in Melanoma Randomized Phase II
Sorafenib DTIC PFS (Independent Assessment)
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
95 CI (0.268-0.552) (0.062-0.294)
Hazard ratio (Sorafenib/placebo) 0.665 P0.070 0.665 P0.070
95 CI (0.427-1.037) (0.427-1.037)
Proportion of Patients Progression-Free
Sorafenib DTIC Placebo DTIC
Censored Treatment for SorafenibCensored
Treatment for Placebo
Days From Randomization
Data on file. Bayer HealthCare.
25
Sorafenib in Melanoma Randomized Phase II
Sorafenib DTIC Response Rates
Best Response(RECIST) Sorafenib DTICN () Placebo DTIC N ()
Independent Review
Partial response 12 (24) 6 (12)
Stable disease 24 (47) 22 (44)
Progressive disease 15 (29) 21 (42)
71Clinical benefit
56Clinical benefit
Data on file. Bayer HealthCare.
26
Sorafenib in Melanoma Randomized Phase II
Sorafenib DTIC Grade 3 or Higher AEs (?5
Incidence in Either Treatment Arm)
Adverse Event Sorafenib DTIC (n51) Placebo DTIC (n50)
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
Platelets Grade 4 Placebo (2) vs Sorafenib
(18).Neutrophils Grade 4 Placebo (6) vs
Sorafenib (20). Data on file. Bayer HealthCare.
27
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.
28
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/paclitax
  el 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

29
Translating Scientific Advances into Improved
Therapy Current Opportunities

• Immunotherapy
• Targeted therapy
• B-Raf inhibition (Sorafenib/chemotherapy)
• Apoptosis induction (STA-4783)
• Novel targets

30
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 (P0.035)
• Evidence of survival advantage
• Well-tolerated, with favorable safety profile
• Entering pivotal, confirmatory Phase III in
  metastatic melanoma

31
STA-4783 MOA
32
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)
33
Apoptosis-Inducing AgentsIncreasing Oxidative
Stress States
STA-4783 Hsp70 inducer Phase II trial in
metastatic melanoma paclitaxel STA-4783 vs.
paclitaxel alone
Paclitaxel STA-4783 Paclitaxel
Dose 80 mg/m2 213 mg/m2 80 mg/m2
Number of Patients 53 28
ORR 15 4
ORR P .153 P .153
Median PFS 3.7 months 1.9 months
Median PFS HR 0.583 P .035 HR 0.583 P .035
Median OS 12 months 7.8 months
Median OS HR 0.856 P .5707 HR 0.856 P .5707
Phase III trial in chemotherapy-naïve patients
initiated anticipated enrollment 600.
ODay S, et al. Proc Am Soc Clin Oncol.
200725479s. Abstract 8528.
34
Kaplan-Meier PlotProgression-free Survival (ITT)
ODay S, et al. Proc Am Soc Clin Oncol.
200725479s. Abstract 8528.
35
New Potential Targets

• Stat 3
• NFkb
• Notch 1
• BCL2
• AKT- TOR
• VEGF
• MITF
• GSK3
• iNos

• PI3K
• IL-8
• MUC18
• CREB-ATF1
• Folded WT p53
• ABCB5
• NEDD9

Chekov When many treatment targets are
proposed, you know the disease is incurable.
36
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