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Updates in Community Oncology 2011:A Focus on Melanoma
This program is supported by educational grants fromBristol-Myers Squibb, Genentech BioOncology, and Merck.
Updates in Community Oncology 2011: Melanoma
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Updates in Community Oncology 2011: Melanoma
Faculty
Keith T. Flaherty, MDDirector of Developmental TherapeuticsMassachusetts General Hospital Cancer CenterBoston, Massachusetts
John M. Kirkwood, MDProfessor, Medicine, Dermatology, and Translational ScienceDirector, Melanoma and Skin Cancer ProgramUniversity of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania
Jedd D. Wolchok, MD, PhDDirector, Immunotherapy Clinical Trials Department of Medicine Associate Attending Physician Department of Medicine, Melanoma/Sacroma Services Memorial Sloan-Kettering Cancer Center New York, New York
Updates in Community Oncology 2011: Melanoma
Disclosures
Keith T. Flaherty, MD, has disclosed that he has received consulting fees from GlaxoSmithKline and Roche-Genentech BioOncology.
John M. Kirkwood, MD, has disclosed that he has received consulting fees from GlaxoSmithKline, Merck, and Roche-Genentech BioOncology.
Jedd D. Wolchok, MD, PhD, has disclosed that he has received consulting fees from Bristol-Myers Squibb.
Adjuvant Therapy for Melanoma
Updates in Community Oncology 2011: Melanoma
E1684, E1690, and E1694: Durable Impact on RFS and OS All trials of IFNα with durable benefit in terms of RFS and
OS used IV induction at 20 MU/m2 (Cmax > 10,000 µ/mL)
Cooperative Group/PI
Eligibility nN Treatment Agent/Dosage/Duration
Impact on
RFS OS
ECOG 1684[1] T4, N1 287 IFNα2b 20 MU/m2/day IV x 1 mo 10 MU/m2 SC TIW x 11 mos
+ +
at 6.9-12.6 yrs
ECOG 1690[2] T4, N1 642 IFNα2b 20 MU/m2/day IV x 1 mo 10 MU/m2 SC TIW x 11 mos vs 3 MU/D SC
TIW x 2 yrs
+ -
at 4.3-6.6 yrs
ECOG 1694[3] T4, N1 880 IFNα2b 20 MU/m2/day IV x 1 mo 10 MU/m2 SC TIW x 11 mos vs
GMK vaccine x 96 wks
+ +
at 1.3-2.1 yrs
1. Kirkwood JM, et al. J Clin Oncol. 1996;14:7-17. 2. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 3. Kirkwood JM, et al. J Clin Oncol. 2001;19:1430-1436.
Updates in Community Oncology 2011: Melanoma
3 Meta-analyses of All Trials of IFN-alfa Confirm RFS, OS ImpactMeta-analysis
RCT, n
RFS OS Comment
Ives[1] 18 + -/+ Did not include E1694
↑benefit with ↑IFN dose
Wheatley[2] 13 +OR: 0.87;
95% CI: 0.81-0.93; P = .00006
+OR: 0.9;
95% CI: 0.84-0.97; P = .008
OS translates into absolute benefit of 3% (CI: 1% to 5%) at 5 yrs
Mocellin[3] 14 +HR: 0.82
95% CI: 0.77-0.87; P < .001
+HR: 0.89;
95% CI: 0.83-0.96; P = .002
18% risk reduction in DFS 11% risk reduction in OS
1. Ives NJ, et al. J Clin Oncol. 2007;25:5426-5434. 2. Wheatley K, et al. ASCO 2007. Abstract 8526. 3. Mocellin S, et al. J Natl Cancer Inst. 2010;102:493-501.
Updates in Community Oncology 2011: Melanoma
STRATIFICATION
Pathologic Lymph Node StatusKnownUnknown
Lymph Node Staging ProcedureSentinel lymph node procedure; elective lymph node dissection; no lymphadenectomy
Breslow Depth1.5-3.0 mm3.1-4.0 mm > 4 mm
Ulceration of Primary LesionYesNo
Disease StageLymph node positiveLymph node negative
Arm B:
4-wk high-dose IFN alfa-2b
20 MU/m2/day QD IV for 5 consecutive days out of 7 (M-F) every wk x 4 wks
Hypothesis: 1-month induction IV IFN is necessary and sufficient to achieve durable adjuvant benefit in intermediate-risk melanoma patients
E1697: 4 Wks of High-Dose IFN alfa-2b in Stage T3-T4 or N1 Melanoma
Arm A:
Observation
R
A
N
D
O
M
I
Z
E
Agarwala SS, et al. ASCO 2011. Abstract 8505.
Updates in Community Oncology 2011: Melanoma
Median RFS
HDI (n = 425)
6.8 yrs, 95% CI: 5.1-9.0
Observation (n = 413)
7.3 yrs, 95% CI: 5.3-9.8
Efficacy analysis
P value from stratified log-rank test = .962
No significant difference
Futility analysis
HR: 1.01, 95% CI: 0.71-1.43
Conditional power: 3%
E1697: 3rd Interim Analysis—RFS (N = 838)
Pro
bab
ilit
y
1.00.90.80.70.60.50.40.30.20.1
00 111 2 3 4 5 6 7 8 9 10
Yrs
TreatmentObservationHDI
Total413425
Failed111123
Censored302302
Median7.36.8
Agarwala SS, et al. ASCO 2011. Abstract 8505.
Updates in Community Oncology 2011: Melanoma
E1697: Current Assessment
No benefit from 1 mo of IFN in stage IIB/IIIA disease
Patients with IIB/IIIA melanoma require 1 year of standard therapy (E1684, E1690, E1694)
Analysis of mortality and role of salvage therapy indicate that
– Crossover has confounded both adjuvant and advanced disease therapy
– IFN from observation in E1690[1]
– Anti-CTLA4 abstract: tremelimumab phase III trial[2]
– BRAF inhibitor trials?
Potential predictive biomarkers of immunotherapy?
– Autoimmunity[3]
– Cytokine profile pretreatment[4]
1. Kirkwood JM, et al. J Clin Oncol. 2000;18:2444-2458. 2. Ribas A, et al. ASCO 2008. Abstract LBA9011. 3. Gogas H, et al. N Engl J Med. 2006;354:708-718. 4. Yurkovetsky ZR, et al. Clin Cancer Res. 2007;13:2422-2428.
Updates in Community Oncology 2011: Melanoma
Patients with autoimmunity (n = 52)
Patients with autoimmunity (n = 52)
Patients without autoimmunity (n = 148)Patients without autoimmunity (n = 148)
Time to Progression OS
Multivariate Analysis of High-Risk Melanoma Patients Receiving HDI
Positive Autoimmunity Status RFS OS
HR (95% CI) P Value HR (95% CI) P Value
At 3 mos 0.15 (0.06-0.37) < .001 0.07 (0.02-0.28) < .001
At 12 mos 0.08 (0.03-0.22) < .001 0.02 (<0.01-0.15) < .001
1.0
0.5
0
Pro
bab
ilit
y
Mos0 20 40 60 80 100
1.0
0.5
0
Pro
bab
ilit
y
Mos0 20 40 60 80 100
Gogas H, et al. N Engl J Med. 2006;354:709-718.
Updates in Community Oncology 2011: Melanoma
Stratified by:
Microscopic (N1) vs palpable (N2)
1 vs 2-4 vs 5+ nodes
Breslow
Ulceration
Gender and site
Observation
Peg-IFN alfa-2b
Induction (8 wks) 6 µg/kg/wk
Maintenance (5 years or distant metastasis) 3 µg/kg/wk
Dose reduction to 3, 2, 1 to maintain performance status
Primary Endpoints:
Relapse-free survival
Distant metastasis-free survival
Patients (N = 1256): Resected TxN1-2M0 melanoma, within 7 wks of lymphadenectomy
Randomization
Eggermont AM, et al. Lancet. 2008;372:117-126.
EORTC 18991: Peg-IFN alfa-2b vs Observation
Updates in Community Oncology 2011: Melanoma
EORTC 18991 (2011 Update): Outcome at 7.6 Yrs of Follow-up RFS benefit with pegIFN alfa-2b still significant at 7.6 yrs,
but eroded 2007 2009
No change in DMFS or OS
Outcome (ITT)
2007 2011
HR (95% CI) P Value HR (95% CI) P Value
RFS 0.82 (0.71-0.96) .01 0.87 (0.76-1.00) .05
DMFS 0.88 (0.75-1.03) .11 0.93 (0.81-1.07) .33
OS 0.98 (0.82-1.16) .78 0.96 (0.82-1.11) .57
Eggermont AM, et al. ASCO 2011. Abstract 8506b.
Updates in Community Oncology 2011: Melanoma
EORTC 18991 (2011 Update): RFS by Subgroup RFS 2011
HR (99% CI) P Value
Stage III N1 0.82 (0.61-1.10) .08*
Stage III N2 0.89 (0.71-1.13) .21
Ulcerated 0.81 (0.58-1.14) .11*
Not ulcerated 1.05 (0.79-1.41) .64
*Statistically significant vs observation in 2007, but not in 2011
Eggermont AM, et al. ASCO 2011. Abstract 8506b.
Updates in Community Oncology 2011: Melanoma
EORTC 18991 (2011 Update): Stage III N1, Ulcerated Disease Stage III N1 and ulcerated primary tumors showed
significant benefit for multiple endpoints, including OS
– Median OS pegIFN vs observation: > 9.0 vs 3.7 yrs
EORTC 18081 plans comparison of pegIFN x 2 yrs vs observation in ulcerated primary tumors > 1 mm
Outcome in Patients WithStage III N1, Ulcerated Primary
HR (99% CI) P Value
RFS 0.72 (0.46-1.13) .06
DMFS 0.65 (0.41-1.04) .02
OS 0.59 (0.35-0.97) .006
Eggermont AM, et al. ASCO 2011. Abstract 8506b.
Updates in Community Oncology 2011: Melanoma
Adverse Event Summary and Treatment Compliance
Treatment compliance Median induction duration: 8 wks Median maintenance duration: 14.9 mos 31% of patients discontinued treatment due to AEs; 23% remain on
treatment in Yrs 4-5
Grade 3/4 Adverse Event, % PegIFN(n = 627)
Observation(n = 629)
Any 47 16
Events occurring in > 5% of patients (grade 3/4)
Fatigue 14/1 1/0
Liver toxicity 10/< 1 1/< 1
Depression 6/< 1 < 1/< 1
Eggermont AM, et al. ASCO 2011. Abstract 8506b.
Updates in Community Oncology 2011: Melanoma
Summary: Adjuvant Modalities Evaluated to DateIFN alfa-2b, 2a; PegIFN alfa-2b HDI has only confirmed, significant, durable OS and
RFS benefit (ITT) at > 10 yrs (E1684/90/94)
IL-2 Never tested, too toxic
Cellular Vaccines Ganglioside VaccineProtein MAGE A3
Canvaxin detrimental in phase III trialsGMK inactive: neither of benefit, nor detriment
Pending
GM-CSF, Peptide Vaccine Neither GM-CSF nor peptide vaccination achieved objectives of significant improvement in OS or DFSSuggests effects of GM-CSF on DFS and OS are largest among stage IV subjects
Anti-CTLA4 Blocking mAbs PendingEORTC 18071US Intergroup E1609
Molecularly Targeted BRAFi Pending
Molecularly Targeted Therapies for Metastatic Melanoma
Updates in Community Oncology 2011: Melanoma
Oncogenes in Melanoma
Year Target Prevalence, % Drug
1984 NRAS 20
2002 BRAF 50 Sorafenib, PD0325901, selumetinib,
GSK1120212, RAF-265, XL281,
vemurafenib, GSK2118436
2005 c-kit 1 Imatinib, dasatinib, nilotinib
2008 GNAQ/GNA11 1*
*80% to 90% of uveal.
Updates in Community Oncology 2011: Melanoma
Curtin J, et al. J Clin Oncol. 2006;24:4340-4346.
Distribution of Genetic Alterations in BRAF, NRAS, and KIT by Primary Site
100
50
0Non-CSD
Per
cen
t A
ber
ran
t
CSD Acral Mucosal
KITKIT and NRASKIT and BRAFNRASBRAF
Updates in Community Oncology 2011: Melanoma
BRAF Mutation Location (by Amino Acid Position and Substitution)
% of All BRAF Mutations
V600E 97.3
V600K 1.0
K601E 0.4
G469A 0.4
D594G 0.3
V600R 0.3
L597V 0.2
Flaherty KT, et al. Cancer. 2010;116:4902-4913.
Relative Frequency of BRAF Mutations Submitted to COSMIC Database
Updates in Community Oncology 2011: Melanoma
BRAF Mutation Testing
BRAF mutations are present throughout melanoma disease progression
– If metastasis biopsy not available, most recent melanoma surgery sample adequate (eg, lymph node)
BRAF mutation testing is commercially available
– FDA-approved method used in vemurafenib clinical trials
– cobas 4800 BRAF V600 Mutation Test
Updates in Community Oncology 2011: Melanoma
**************Individual Patients Treated With Vemurafenib
60
40
20
0
-20
-40
-60
-80
-100
M1aM1bM1c
Disease stage
Per
cen
t C
han
ge
Fro
m B
asel
ine
in
Dia
met
er o
f T
arg
et L
esio
n
*7 confirmed CRs.*7 confirmed CRs.
Ribas A, et al. ASCO 2011. Abstract 8509.
Change in Tumor Size with Vemurafenib in 132 V600EBRAF-Mutant Patients
Updates in Community Oncology 2011: Melanoma
Phase III BRIM-3 Study Design
V600EBRAF mutation
Stratification Stage ECOG PS (0 vs 1) LDH level (↑ vs nl) Geographic region
Screening
960 mg PO BID(n = 337)
1000 mg/m2 IV q3w (n = 338)
Dacarbazine
Vemurafenib
Randomization(N = 675)
Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.
Updates in Community Oncology 2011: Melanoma
100
90
80
70
60
50
40
30
20
10
0
OS
(%
)
Patients in follow-up, n
Dacarbazine
Vemurafenib
0 1 2 3 4 5 6 7 8 9 10 11 12
Vemurafenib (n = 336)Est 6-mo survival: 84%
Mos
336
336
283
320
192
266
137
210
98
162
64
111
39
80
20
35
1
6
1
1
Dacarbazine (n = 336)Est 6-mo survival: 64%
9
14
HR: 0.37 (95% CI: 0.26-0.55; log-rank P < .0001)
Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.
Vemurafenib vs Dacarbazine in BRAF V600E–Positive Melanoma: OS
Updates in Community Oncology 2011: Melanoma
Change in Tumor Size in 26 V600EBRAF Mutant Melanoma Patients (GSK2118436)
Kefford R, et al. Society for Melanoma Research Congress 2010.
Maxim
um
%
Red
ucti
on
Fro
m
Baselin
e
CR
PDPR
SD
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
-100
Isolated kinase IC50 (nM): B-RAF
B-RAF
V600E
WT
0.6
12
C-RAF WT 5
Updates in Community Oncology 2011: Melanoma
302010
0-10
-20
-30-40-50-60-70-80-90-100
40
Max
imu
m %
C
han
ge
Fro
m B
asel
ine
Patients
403020100
-10-20
-30-40-50-60-70-80-90
-100
*
*V600K.
Long G, et al. ESMO 2010. Abstract 5016.
Response to GSK2118436 in Patients WithV600EBRAF-Positive Brain Lesions (N = 10)
Updates in Community Oncology 2011: Melanoma
Vemurafenib Adverse Event[1] Patients With Toxicity, %
Rash 68
Arthralgia 48
Photosensitivity 42
Fatigue 32
Cutaneous squamous cell carcinoma (keratoacanthoma)
23/7
GSK2118436 Adverse Event[2] Patients With Toxicity, %
Pyrexia 43
Rash 30
Headache 26
1. Flaherty KT, et al. N Engl J Med. 2010;363:809-819. 2. Kefford R, et al. Society for Melanoma Research Congress 2010. Abstract 100.
Most Common Toxicities With Vemurafenib and GSK2118436
Updates in Community Oncology 2011: Melanoma
Lacouture ME, et al. ASCO 2010. Abstract 8592.
Timing of Keratoacanthoma/SCC
Wks on PLX4032
0 12 24 36 48 60 72
Updates in Community Oncology 2011: Melanoma
Subjects
Max
imu
m %
R
edu
ctio
n F
rom
Bas
eli
ne
CR PDPR SD
Preliminary RR is 41% (95% CI: 23% to 61%)
-80
-60
-40
-20
0
20
-100
-80
-60
-40
-20
0
20
-100
40
60
80
100
40
60
80100
Falchook G, et al. ESMO 2010. Abstract 4950.
Tumor Response With MEK Inhibitor (GSK1120212) in BRAF-Mutant Melanoma N = 29; 2 CRs and 10 PRs
~ 90% M1c; 48% history of brain metastases
No previous treatment with a BRAF inhibitor
Updates in Community Oncology 2011: Melanoma
Events 2 mg QD , %
Grade 1/2 Grade 3 Grade 4
Rash 74 4 0
Diarrhea 53 1 0
Fatigue 39 4 0
Nausea 37 0 0
Peripheral edema 32 0 0
Vomiting 25 1 0
Decreased appetite 21 3 0
Most Common AEs (≥ 20%) for GSK1120212 (N = 68)
Falchook G, et al. ESMO 2010. Abstract 4950.
Updates in Community Oncology 2011: Melanoma
Guo J, et al. J Clin Oncol. 2011;29:2904-2909.
Phase II Trial of Imatinib in Patients With c-KIT Genetic Aberrations N = 43 patients with metastatic melanoma and c-KIT
aberrations
Treatment: imatinib 400 mg/day continuously unless intolerant toxicities or disease progression occurred
– 15 patients with progression escalated to 800 mg/day
Endpoints: PFS, 6-month PFS, ORR, OS, 1-year OS
Updates in Community Oncology 2011: Melanoma
Patients (N = 43)
Median age, yrs (range) 57 (27-76)
Sex, male/female 20/23
Primary site, n, acral/mucosal/CSD/NSD/UP 21/11/5/4/2
Previous regimen, n, 0/1/2/≥3 5/18/17/3
Stage, n, M1a/M1b/M1c 10/2/31
KIT status, n, exon 11/13/other 16/6/14
Phase II Trial of Imatinib in Patients With c-KIT Aberrations: Patient Characteristics
Guo J, et al. J Clin Oncol. 2011;29:2904-2909.
Updates in Community Oncology 2011: Melanoma
M1b
M1cM1a
Phase II Trial of Imatinib in Patients With c-KIT Aberrations: Change in Tumor Size
120
100
80
60
40
30
0
-20
-40
-60
-80
Guo J, et al. ASCO 2010. Abstract 8527.
Ch
ang
e in
tu
mo
r si
ze, %
Updates in Community Oncology 2011: Melanoma
c-KIT Status, n PR SD PR+SD
c-KIT amplification 1/3 0/3 1/3
c-KIT mutation
Exon 11 6/17 5/17 11/17
Exon 13 3/9 1/9 4/9
Exon 17 0/5 2/5 2/5
Exon 18 0/6 3/6 3/6
Multiple gene aberrations* 3/5 2/5 4/5
*5 patients harbored multiple c-KIT aberrations, one each as follows:K642E (exon 13) + amplification; I653T (exon 13) + T1940C (exon 13); F848L(exon 18) + T2576C (exon 18); L576P (exon 11) + amplification; P577H (exon13) + N486D (exon 9).
68.6%
Phase II Trial of Imatinib: Correlation of Response and c-KIT Aberrations
Guo J, et al. J Clin Oncol. 2011;29:2904-2909.
Updates in Community Oncology 2011: Melanoma
Conclusions
BRAF inhibitors associated with high response rate and improved survival
– Duration of response highly variable
MEK inhibition is active in BRAF-mutant melanoma
c-KIT mutations present in 10% of mucosal and acral melanomas
– c-KIT inhibitors active in a subset of melanoma patients
Advances in Immunotherapy for Metastatic Melanoma
Updates in Community Oncology 2011: Melanoma
High-Dose IL-2 Therapy
RR: 16% (43/270)
Durable responses
– Median: 8.9 mos
– CR: not reached
Atkins MB, et al. J Clin Oncol. 1999;17:2105-2116.
0 10 20 30 40 50 60 70 80 90 130
0.8
0.6
0.4
0.2
0.0
1.0
100 110 120
Pro
bab
ility
of
Co
nti
nu
ing
Res
po
nse
Duration of Response (Mos)
0
CR (n = 17)PR (n = 26)CR + PR (n = 43)
Updates in Community Oncology 2011: Melanoma
IL-2 ± gp100 Peptide Vaccine in Patients With Advanced Melanoma Based on previous phase II studies demonstrating efficacy
– NCI phase II study: OR in 13/31 (42%)[1]
– CWG phase II trials: OR in 20/121 (16%)[2]
Multicenter phase III trial of IL-2 ± gp100, accruing 185 patients from 21 centers over 7 yrs[3]
1. Rosenberg SA, et al. Nat Med. 1998;4:321-327. 2. Sosman JA, et al. J Clin Oncol. 2008;26:2292-2298. 3. Schwartzentruber DJ, et al. N Engl J Med. 2011;364:2119-2127.
Endpoint IL-2 IL-2 + gp100 P Value
Primary ORR, % 6 16 .03
SecondaryMedian PFS, mos 1.6 2.2 .008
Median OS, mos 11.1 17.8 .06
Updates in Community Oncology 2011: Melanoma
Ipilimumab, CTLA-4 Blocking mAb, Augments T-Cell Activation
T-Cell Remains Active
T-Cell Inactivation
T-Cell Activation
Ipilimumab
APC
CTLA-4
T cell
APC
T cellresting
T cell
APC
B7
CD28TCR
HLA
CTLA-4
CTLA-4
Korman AJ, et al. Adv Immunol. 2006;90:297-339 .
Updates in Community Oncology 2011: Melanoma
Ipilimumab Pattern of Response
Responses after appearance and subsequent disappearance of new lesions
3 mg/kg ipilimumab
q3w x 4
Pretreatment
Wk 36: Still Regressing
Wk 12: Progression
Wk 20: Regression
New lesions
July 2006
Wolchok JD, et al. ASCO 2008. Abstract 3020.
Updates in Community Oncology 2011: Melanoma
Ipilimumab Therapy: 4 Patterns of Response 2 conventional
– Response in baseline lesions
– “Stable disease” with slow, steady decline in total tumor volume
2 novel
– Response after initial increase in total tumor volume
– Response in index plus new lesions at or after the appearance of new lesions
Updates in Community Oncology 2011: Melanoma
Patient Education Tips
Educate patients that a response to ipilimumab is different from a response to chemotherapy
Symptoms that could indicate disease progression may indicate a positive response to ipilimumab
Assure patients that these response patterns are normal
Updates in Community Oncology 2011: Melanoma
MDX010-20 Study Schema
Hodi FS, et al. N Engl J Med. 2010;363:711-723.
Screening
Ipilimumab + gp100(n = 403)
Ipilimumab alone(n = 137)
gp100 alone(n = 136)
Ipilimumab + gp100
Ipilimumab alone
gp100 alone
≥ 1 Reinduction(eligible patients)
Induction
Previously treated,
HLA-A*0201+ patients with
advanced melanoma
(N = 676)
R
A
N
D
O
M
I
Z
E
Follow- up
PD
PD
PD
3:1:1
Induction: Ipilimumab at 3 mg/kg, with or without gp100, q3w for 4 treatments.Reinduction: Patients with SD for 3 months’ duration from Wk 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PD.
Updates in Community Oncology 2011: Melanoma
Ipilimumab + gp100 (A)Ipilimumab alone (B)gp100 alone (C)
Comparison HR P Value Arm A vs C 0.68 < .001 Arm B vs C 0.66 .003 Arm A vs B 1.04 .76
MDX010-20: Kaplan-Meier Analysis of OS
Hodi FS, et al. N Engl J Med. 2010;363:711-723.
OS Ipilimumab + gp100 Ipilimumab Alone gp100 Alone
1 yr, % 44 46 25
2 yr, % 22 24 14
Median, mos 10.0 10.1 6.4
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pro
po
rtio
n A
live
Yrs0 1 2 3 4
Updates in Community Oncology 2011: Melanoma
irAEs, % Ipilimumab + gp100
(n = 380)
Ipilimumab + Pbo(n = 131)
gp100 + Pbo(n = 132)
Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Any 9.7 0.5 12.2 2.3 3.0 0
Dermatologic 2.1 0.3 1.5 0 0 0
GI 5.3 0.5 7.6 0 0.8 0
Endocrine 1.1 0 2.3 1.5 0 0
Hepatic 1.1 0 0 0 2.3 0
Death due to irAE
1.3 1.5 0
Most Common Immune-Related Adverse Events* (Grades 3, 4, and 5)
*Across entire study duration.
Hodi FS, et al. N Engl J Med. 2010;363:711-723. O’Day S, et al. ASCO 2010. Abstract 4.
Updates in Community Oncology 2011: Melanoma
Baseline Tumor Assessment
First Scheduled Tumor Assessment
Screening
Ipilimumab 10 mg/kgq12w
Ipilimumab 10 mg/kgq3w x 4
Induction Maintenance*
*In absence of progression or dose-limiting toxicity.
PreviouslyuntreatedmetastaticMelanoma
(N = 502)Placebo q3w x 4 Placebo q12w
R = blindedrandomization
(1:1)
Study 024: Design
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
RDacarbazine 850 mg/m2
q3w x 8
Dacarbazine 850 mg/m2
q3w x 8
Wk 12 Wk 24Wk 1
Updates in Community Oncology 2011: Melanoma
5942
*3-yr survival was a post hoc analysis.
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
Study 024: Overall Survival
Estimated Survival Rate, % Ipilimumab + Dacarbazine(n = 250)
Placebo + Dacarbazine (n = 252)
Yr 1 47.3 36.3
Yr 2 28.5 17.9
Yr 3* 20.8 12.2
CensoredCensored
100908070605040302010
0
Pa
tie
nts
Su
rviv
ing
(%
)
Ipilimumab + dacarbazine
Placebo + dacarbazine
0 482 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
Months
Ipilimumab + dacarbazinePlacebo + dacarbazine
Patients at Risk, n250252
00
230229
199190
181160
157136
131116
11489
10478
9172
8564
7956
7447
6844
6142
5637
5634
5231
4126
3119
1711
107
45
23
Updates in Community Oncology 2011: Melanoma
Study 024: Tumor Response
*HR: 0.76; 95% CI: 0.63-0.93; P = .006
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
Endpoint Ipilimumab + Dacarbazine
(n = 250)
Placebo + Dacarbazine
(n = 252)
Disease progression events, n
203 223*
DCR, n (%) 83 (33.2) 76 (30.2)
BORR (CR + PR), n (%) 38 (15.2) 26 (10.3)
CR 4 (1.6) 2 (0.8)
PR 34 (13.6) 24 (9.5)
SD 45 (18.0) 50 (19.8)
PD 111 (44.4) 131 (52.0)
Duration of response, mos 19.3 8.1
Updates in Community Oncology 2011: Melanoma
Study 024: Duration of Response
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
CensoredCensored
100
90
80
70
60
50
40
30
20
10
0
Ipilimumab + dacarbazine
Placebo + dacarbazine
Pat
ien
ts W
ith
CR
or
PR
(%
)
Duration of Response (Mos)
0 282 4 6 8 10 12 14 16 18 20 22 24 26
Patients at Risk, nIpilimumab + dacarbazinePlacebo + dacarbazine
3826
3825
3320
3014
2712
2310
229
208
177
86
11
11
10
00
42
Updates in Community Oncology 2011: Melanoma
Study 024: Safety Overview
*1 death due to gastrointestinal hemorrhage in placebo + dacarbazine group.
Robert C, et al. N Engl J Med. 2011;364:2517-2526. Wolchok J, et al. ASCO 2011. Abstract LBA5.
Adverse Events, % Ipilimumab + Dacarbazine
(n = 247)
Placebo + Dacarbazine
(n = 251)
Total Events
Grade 3/4 Events
Total Events
Grade 3/4 Events
All events 98.8 56.3 94.0 27.5
Drug-related events 89.5 50.6 76.5 11.6
Treatment-related deaths
0 -- 0.4* --
Updates in Community Oncology 2011: Melanoma
Study 024: Select Adverse Events*
*Select adverse events are shown, regardless of attribution.
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
Adverse Event, % Ipilimumab + Dacarbazine
(n = 247)
Placebo + Dacarbazine
(n = 251)
Total Events Grade 3/4 Events
Total Events Grade 3/4 Events
Dermatologic
Pruritus 29.6 2.0 8.8 0
Rash 24.7 1.2 6.8 0
GI
Diarrhea 36.4 4.0 24.7 0
Immune-related colitis 4.5 2.0 0 0
GI perforation 0 0 0 0
Updates in Community Oncology 2011: Melanoma
Study 024: Select Adverse Events*
*Select adverse events are shown, regardless of attribution.†1 (0.4%) case of hypophysitis in a patient on maintenance was reported on Day 364.
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
Adverse Event, % Ipilimumab + Dacarbazine
(n = 247)
Placebo + Dacarbazine
(n = 251)
Total Events Grade 3/4 Events
Total Events Grade 3/4 Events
Hepatic
Increased ALT 33.2 21.9 5.6 0.8
Increased AST 29.1 18.2 5.6 1.2
Endocrine
Hypothyroidism 1.6 0 0.4 0
Thyroiditis 0.8 0 0 0
Hyperthyroidism 0.4 0 0.4 0
Hypophysitis† 0 0 0 0
Updates in Community Oncology 2011: Melanoma
Study 024: Efficacy Summary
Ipilimumab 10 mg/kg + dacarbazine prolongs OS vs dacarbazine alone in previously untreated metastatic melanoma (HR: 0.72; P < .001)
Estimated 1-, 2-, and 3-yr survival rates
– 1 yr: 47.3% vs 36.3%
– 2 yrs: 28.5% vs 17.9%
– 3 yrs: 20.8% vs 12.2%
Durable responses
– Median of 19.3 vs 8.1 mos
Robert C, et al. N Engl J Med. 2011;364:2517-2526.
Updates in Community Oncology 2011: Melanoma
Study 024: Safety Summary
Types of ipilimumab AEs consistent with previous studies– Predominantly affect: skin, GI tract, liver, endocrine system
Mechanism (immune) based– Managed with established guidelines
– Generally responsive to dose interruption/discontinuation, corticosteroids, and/or other immunosuppressants
Rates of high-grade events different from those observed in phase II ipilimumab studies– Elevated AST and ALT rates higher
– Diarrhea and colitis rates lower
– No GI perforationsRobert C, et al. N Engl J Med. 2011;364:2517-2526.
Updates in Community Oncology 2011: Melanoma
Patient Education Tips
Patients should immediately report
– Increased bowel movements/onset of diarrhea
– Black, bloody, or clay stools
– Inability to take fluids by mouth due to nausea or vomiting
– Incontinence of stool
– Awakening at night due to stool urgency
– Abdominal pain, cramping, or bloating
Updates in Community Oncology 2011: Melanoma
Summary
IL-2 + gp100 significantly prolonged survival vs IL-2 alone
CTLA-4 blockade with ipilimumab resulted in durable responses and prolonged survival
– Immune-related adverse events occur and may be severe, but are generally medically manageable
– Initial response to ipilimumab is different from response to chemotherapy
Other immune modulating antibodies are in development with anti-PD1 showing activity
Next step: combination regimens with targeted therapies to maximize high, early response rate with durability
Updates in Community Oncology 2011: Melanoma
Targeted:BRAFi MEKiC-KitAkt
Chemotherapy:Dacarbazine
(Temozolomide)& Combinations
Immunological:Interferon alfa-2*
Interleukin 2Anti-CTLA4
Anti-PD1Vaccines
Adjuvant HDIAdjuvant pegIFN
Approved 1976-1998Approved 2011Pending Approval 2011
Evolving Modalities of Systemic Therapy
Go Online for More Educational Activities on Melanoma!
Proceedings of an Independent Expert Panel- experts discuss state-of the-art treatment strategies for melanoma
Interactive Case Challenge
clinicaloptions.com/oncology