clinical updates novel agents for the treatment of metastatic melanoma david f. mcdermott, md...
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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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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