Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma David F. McDermott, MD Clinical Director, Biologic Therapy Program Beth Israel Deaconess.

Clinical UpdatesClinical Updates

Novel Agents for the Treatment of Novel Agents for the Treatment of Metastatic MelanomaMetastatic Melanoma

David F. McDermott, MD

Clinical Director, Biologic Therapy ProgramBeth Israel Deaconess Medical Center

Assistant Professor

Harvard Medical SchoolBoston, MA

Melanoma : Epidemiology 2007Melanoma : 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: Natural History

“Metastatic melanoma is a bad disease.”

• Median age: 45-50

• Median Survival: 6-10 months

• 5-year survival: < 5%

Few if any effective therapies

Proposed New AJCC Staging Proposed New AJCC Staging System: Stage IV MelanomaSystem: Stage IV Melanoma

M1a Distant skin, SC, or nodal mets

Normal

M1b Lung metastases

Normal

M1c All other visceral mets Or any distant met

Normal Elevated

M Status Site Serum LDH

Staging Factors: ImportanceStaging Factors: Importance

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

as by treatment approach

Metastatic Melanoma Metastatic Melanoma – – 20082008

Approved Therapies (USA) Date

• DTIC 1970’s

• High Dose Interleukin-2 1998

Many patients will receive both agents

Single Agent DTIC Activity*Single Agent DTIC Activity*

• Response Rate 19%

• Median Response Duration 4 mos

• Median Survival 6-9 mos

• 6-year survival < 2%

*Hill et al Cancer 53:1299; 1984 (n=580)

DTIC has never been compared to observation or best supportive care

Cytotoxic Chemotherapy:Cytotoxic Chemotherapy:StatusStatus

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 TherapyMelanoma 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

GRB2

RASGDP

N-RAS*GTP

PTEN

PI3K

AKT

TOR

P16 Cdk4

Cyclin D

FGFR

B-Raf*

MEK

ERK

ELK

MEK

ELK

ERKBCL2

Apaf1

60-70%15%

SOS

25-50%

x

C-RAF

Molecular Alterations in MelanomaMolecular Alterations in Melanoma

Rationale for Sorafenib in MelanomaRationale 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 MelanomaKey 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

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† • No difference in survival

• DTIC remains reference std

DTIC 121 10.2* 6.3 †

Middleton et al. (J Clin Oncol 2000)3

DTIC 149 12.1† 6.4† • Temodar=DTIC

Temodar 156 13.5† 7.7†

Bedikian AY et al. (J Clin Oncol 2006)4

DTIC 385 7.5 7.8 1.6 • Combination improves outcomesDTIC + oblimersen 386 13.5 9 2.6

*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 MelanomaTaxane Activity in MelanomaAuthor/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. 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 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: 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

Sorafenib in Melanoma: Sorafenib in Melanoma: PRISM Phase III Trial Patient DemographicsPRISM Phase III Trial Patient Demographics

Data on file. Bayer HealthCare.

Sorafenib + Carboplatin/Paclitaxel

N=135N (%)

Placebo + Carboplatin/Paclitaxel

N=135N (%)

GenderMale 84 (62) 87 (64)Female 51 (38) 48 (36)

Age, years

Median 57 56Range 22–89 26–82

Age Group

<65 years 97 (72) 92 (68)65–74 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)

Sorafenib in Melanoma: Sorafenib in Melanoma: PRISM Phase III Trial Disease CharacteristicsPRISM Phase III Trial Disease Characteristics

AJCC=American Joint Committee on Cancer.Data on file. Bayer HealthCare.

Sorafenib + Carboplatin/Paclitaxel

N=135 N (%)

Placebo + Carboplatin/Paclitaxel

N=135 N (%)

AJCC StageIII 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)

Sorafenib in Melanoma: Sorafenib in Melanoma: PRISM Phase III PFS by Independent ReviewPRISM 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 [P=0.492]

99% Cl (.627-1.310)

0

0.25

0.50

0.75

1.00

0 100 200 300 400 500

Pro

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P

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-Fre

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Days From RandomizationSorafenib Censored Treatment for Sorafenib

CI=confidence interval.

Placebo Censored Treatment for Placebo

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

Sorafenib in Melanoma: PRISM Phase IIISorafenib in Melanoma: PRISM Phase III

Grade 3 or Higher AEs Grade 3 or Higher AEs ((5% Incidence in Either Treatment Arm)5% Incidence in Either Treatment Arm)

Data on file. Bayer HealthCare.

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%)

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

(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.

RRAANNDDOOMMIIZZAATTIIOONN

Sorafenib + DTICN=51

Placebo + DTICN=50

Gender

Male 38 (75%) 33 (66%)

Female 13 (25%) 17 (34%)

Age

Median 55 60

Range 31-82 18-88

Age Group

<65 36 (71%) 33 (66%)

65-74 11 (22%) 8 (16%)

≥75 4 (8%) 9 (18%)

Race

White 51 (100%) 47 (94%)

Sorafenib in Melanoma: Randomized Phase II Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Patient DemographicsSorafenib + DTIC Patient Demographics

Data on file. Bayer HealthCare.

Sorafenib + DTICN=51

Placebo + DTICN=50

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%)

Sorafenib in Melanoma: Randomized Phase II Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Disease CharacteristicsSorafenib + DTIC Disease Characteristics

Data on file. Bayer HealthCare.

Sorafenib in Melanoma: Randomized Phase II Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC PFS Sorafenib + DTIC PFS (Independent Assessment)(Independent Assessment)

Pro

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P

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-Fre

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Days From Randomization

Sorafenib + DTIC Placebo + DTIC

Censored Treatment for SorafenibCensored Treatment for Placebo

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 [P=0.070]

95% CI (0.427-1.037)

1.00

0.75

0.50

0.25

0

0 100 200 300 400 500 600

Data on file. Bayer HealthCare.

Sorafenib in Melanoma: Randomized Phase II Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Response RatesSorafenib + 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)

71%Clinical benefit

56%Clinical benefit

Data on file. Bayer HealthCare.

Sorafenib in Melanoma: Randomized Phase II Sorafenib in Melanoma: Randomized Phase II

Sorafenib + DTIC Grade 3 or Higher AEs Sorafenib + DTIC Grade 3 or Higher AEs ((5% Incidence in Either Treatment Arm) 5% Incidence in Either Treatment Arm)

Adverse EventSorafenib + 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

*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

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

Sorafenib in Melanoma: ConclusionsSorafenib 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 Translating Scientific Advances into Improved Therapy: Current OpportunitiesTherapy: Current Opportunities

• Immunotherapy

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

STA-4783 in MelanomaSTA-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: MOASTA-4783: MOA

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

Apoptosis-Inducing AgentsIncreasing Oxidative Stress States

Paclitaxel + STA-4783 Paclitaxel

Dose 80 mg/m2 + 213 mg/m2 80 mg/m2

Number of Patients 53 28

ORR15% 4%

P = .153

Median PFS3.7 months 1.9 months

HR 0.583; P = .035

Median OS12 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.

STA-4783: Hsp70 inducerPhase II trial in metastatic melanoma: paclitaxel + STA-4783 vs. paclitaxel alone

Kaplan-Meier PlotProgression-free Survival (ITT)

O’Day S, et al. Proc Am Soc Clin Oncol. 2007;25:479s. Abstract 8528.

New Potential TargetsNew Potential Targets

• Stat 3

• NFb

• Notch 1

• BCL2

• AKT- TOR

• VEGF

• MITF

• GSK3

• iNosChekov: “When many treatment targets are proposed, you know the disease is incurable.”

• PI3K

• IL-8

• MUC18

• CREB-ATF1

• Folded WT p53

• ABCB5

• NEDD9

Approach to Translational Research with Approach to Translational Research with Targeted TherapyTargeted 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