Transcript The Changing Landscape of Melanoma Therapy with new Drug

Malignant melanoma:
Paradigm shift in management
of advanced disease
Antoni Ribas, M.D., Ph.D.
Professor of Medicine
Professor of Surgery
Professor of Molecular and Medical Pharmacology
Director, Tumor Immunology Program, Jonsson
Comprehensive Cancer Center (JCCC)
University of California Los Angeles (UCLA)
Two Paradigms for Advancing the Therapy of
Metastatic Melanoma
Immunotherapy
Target host
Targeted
Therapy
Target
tumor
Immunotherapy, a reality for patient
benefit in melanoma
• Immunotherapy is the only treatment that can
reproducibly result in cures in (few) patients with
metastatic melanoma
• FDA-approved immunotherapies for melanoma:
– Adjuvant treatment:
• High dose interferon alpha 2b
• Pegylated interferon alpha 2b
– Metastatic melanoma:
• High dose IL-2
• Ipilimumab
High dose IL-2 and Ipilimumab: The major
benefit is in durable tumor regressions
Impact on the
tail of the curve!
Peptide vaccine
DC vaccine
Genetic vaccine
IL-2
IFN
IL-15
IL-21
CTLA4
PD1
CD40
CD137
OX40
T cell cloning
TCR or CAR
genetic engineering
Metastatic Melanoma Response to Ipilimumab
Before Ipilimumab
04/22/11
After Ipilimumab
08/05/11
Quantifying the absolute benefit of ipilimumab
OS at different time
points
Ipi arms
Control arms
Hodi-O’Day, 2010
Ipi+gp100
gp100
10.0 mo
6.4 mo
Ipi
gp100
Median OS
10.1 mo
6.4 mo
Wolchok, 2011
Ipi+DTIC
DTIC
Median OS
11.2 mo
9.1 mo
Median OS
OS Difference
HR= 0.68;
P< 0.001
HR= 0.66;
P= 0.003
HR= 0.72;
P= 0.0009
Quantifying the absolute benefit of ipilimumab
OS at different time
points
Ipi arms
Control arms
Hodi-O’Day, 2010
Ipi+gp100
gp100
10.0 mo
6.4 mo
HR= 0.68;
P< 0.001
1 yr
43.6%
25.3%
18.3%
2 yr
21.6%
13.7%
7.9%
Ipi
gp100
10.1 mo
6.4 mo
HR= 0.66;
P= 0.003
1 yr
45.6%
25.3%
20.3%
2 yr
23.5%
13.7%
9.8%
Wolchok, 2011
Ipi+DTIC
DTIC
Median OS
11.2 mo
9.1 mo
HR= 0.72;
P= 0.0009
1 yr
47.3%
36.3%
11%
2 yr
28.5%
17.9%
10.6%
3 yr
20.8%
12.2%
8.6%
Median OS
Median OS
OS Difference
Summary on Ipilimumab
• Positive impact in overall survival in two randomized
clinical trials using different schedules and combinations:
– FDA approval as single agent at 3 mg/kg x 4 doses
• The major benefit is evident in a small population of
patients (10-15%, most probably cured)
• Clinically-significant inflammatory and immune toxicities
in approximately 15-20% of patients
• Responses usually take time (1-4 months) to declare,
and may go through a period of uncertainty about
response or progression
What should we expect next from advances in
melanoma immunotherapy?
• Ipilimumab in the adjuvant setting
• Combinations with ipilimumab
• Other immune modulating antibodies:
– Anti-PD1
– Anti-CD137 (4-1BB)
– Anti-OX40
• Other immunotherapies for melanoma:
– MAGE-A3 ASCI vaccine
– IL-21
– Oncovex
• Wider use of ACT therapy approaches:
– TIL therapy
– TCR engineering
– CAR engineering
Two Paradigms for Advancing the Therapy of
Metastatic Melanoma
Immunotherapy
Target host
Targeted
Therapy
Target
tumor
Driver Oncogenic Mutations Define Clinically Relevant
Melanoma Molecular Subsets
Arising from Skin
Without Chronic
Sun Damage
50% BRAF
20% NRAS
0% KIT
Arising from Skin
With Chronic
Sun Damage
10% BRAF
10% NRAS
2% KIT
Arising from
Mucosal
Surfaces
5% BRAF
15% NRAS
20% KIT
Arising from
Acral
Surfaces
15% BRAF
15% NRAS
15% KIT
Uveal Melanoma
25% GNAQ 55% GNA11
Curtin et al. NEJM 2005; Curtin et al. JCO 2006; Van Raamsdonk et al., NEJM 2010
Inhibition of MAPK signaling in biopsies of BRAFV600 melanoma
from patients treated with vemurafenib (PLX4032)
GF
Baseline
RTK
Y-P
Y-P
BRAFV600
Ras
GTP
MEK
pERK
PLX4032
P
ERK
P
cyclin D
Cyclin D
Cell cycle
(Ki67)
Ki67
Day 15
Tumor Response to Vemurafenib
Baseline, 3-15-2011
C4 D1, 6-8-2011
Waterfall plot of melanoma tumor responses
with vemurafenib: BRIM2 study (132 patients)
Percent change from baseline
in diameter of target lesion
60
Disease stage
BRIM2
M1a
M1b
M1c
40
20
0
-20
-40
-60
-80
-100
Individual patients treated with vemurafenib
*******
Ribas, Kim, Schuchter, Gonzalez, Pavlick, Weber, McArthur, Hutson, Flaherty, Moschos,
Lawrence, Hersey, Kefford, Chmielowski, Puzanov, Li, Nolop, Lee, Joe, Sosman. ASCO
2011, Abstract #8509
Overall survival (12/30/10 cutoff)
100
Overall survival (%)
90
Vemurafenib (N=336)
80
70
60
Dacarbazine (N=336)
50
40
30
Hazard ratio 0.37
(95% CI; 0.26 - 0.55)
20
Log-rank P<0.0001
10
0
0
1
2
3
4
5
192
266
137
210
98
162
64
111
No. of patients in follow up
Dacarbazine
Vemurafenib
336
336
283
320
Chapman et al. NEJM 2011
6
7
Months
39
80
20
35
8
9
10
9
14
1
6
1
1
11
12
= 63% decrease in the risk of being
dead compared to chemotherapy
BRIM2: Toxicities with vemurafenib
Includes AEs reported in ≥20 patients
All grades
n (%)
Grade 3
n (%)
Grade 4
n (%)
Overall
130 (99)
79 (60)
5 (4)†
Arthralgia
78 (59)
8 (6)
–
Rash
69 (52)
9 (7)
–
Photosensitivity reaction
69 (52)
4 (3)
–
Fatigue
56 (42)
2 (2)
–
Alopecia
48 (36 )
–
–
Pruritus
38 (29)
3 (2)
–
Skin papilloma
38 (29)
–
–
cuSCC / KA‡
34 (26)
34 (26)
–
Nausea
30 (23)
2 (2)
–
Elevated liver enzymes
23 (17)
8 (6) §
4 (3)¶
†One
patient with 2 grade 4 AEs
of cuSCC/KA were generally managed with simple excision and did not generally require dose modification
§Managed with dose reduction; one removed from study
¶Led to discontinuation of therapy
‡Cases
Ribas et al. ASCO 2011
cuSCC/KAs with vemurafenib
Median
0
5
10
15
20
25
30
35
40
Time on vemurafenib (weeks)
• cuSCCs:
– Incidence: 26%
– Median time 8 weeks (2–36)
– Median number of cuSCC/KAs per patient 1 (range 1
to 7)
– Each dot represents weeks to development of first
cuSCC/KA lesion
Ribas et al. ASCO 2011
cuSCC/KAs with vemurafenib
cuSCC/KA pictures and H&E (Grant Macarthur and Roger Lo)
Torso
Left chest
No RAS mutation KRASG12D
Chin
HRASQ61L
Left scalp
HRASQ61L
IHC staining for pERK (Roger Lo)
Normal Skin
cuSCC/KA
Normal Skin
cuSCC/KA
CuSCC/KA in Patients Treated with Vemurafenib
Initial series
Validation set
Total
Female
3
2
5
Male
8
10
18
Mean
60
66
60
Range
44-83
46-84
44-84
Number of Reported
cuSCC/KA Events
Mean
2
4
3
Range
1-6
1-10
1-10
Time to First cuSCC/KA
(weeks)
Mean
9
11
10
Range
5-16
3-22
3-22
HRAS
G12D, G13D, G13V,
Q61K, Q61L, Q61R
12/21
4/14
KRAS
G12C, G12D
1/21*
4/14
NRAS
G12D
1/21*
0/14
TP53
P278S, R196X
2/18
NA
Gender
Age
21/35 (60%)
2/18 (11%)
*Co-incident with HRAS mutations in the same lesion
Most prevalent = HRASQ61L
Su, Viros, Alegre, …Ribas*, Marais*. RAS Mutations in Cutaneous Squamous Cell Carcinomas
with BRAF Inhibitors. NEJM Jan 19, 2012
Differential effects of BRAF inhibition in BRAFV600
mutant melanoma and BRAF wild type cells
BRAFV600 mutant melanoma
BRAF wild type cells
PLX4032
CRAF
BRAFV600
CRAF
MEK1/2
P
BRAFV600
ERK
MAPK signaling
CRAF
MEK1/2
P
P
RAS
BRAF
ERK
P
MAPK signaling
CRAF
MEK1/2
P
PLX4032
RAS
BRAF
MEK1/2
P
ERK
P
MAPK signaling
ERK
P
MAPK signaling
Modeled from Hatzivassiliou et al. Nature 2010, Heidorn et al. Cell 2010, Poulikakos et al. Nature 2010
Paradoxical MAPK activation in HRAS mutant
cuSCC/KAs
BRAFV600 mutant melanoma
BRAF wild type cells
PLX4032
CRAF
BRAFV600
CRAF
MEK1/2
P
BRAFV600
ERK
MAPK signaling
CRAF
MEK1/2
P
P
RAS
BRAF
ERK
BRAF
MEK1/2
P
ERK
P
MAPK signaling
CRAF
MEK1/2
P
P
HRASQ61 PLX4032
MAPK signaling
ERK
P
MAPK signaling
Paradoxical MAPK activation with RAF inhibitors
Fei Su, Amaya Viros, Carla Milagre, … Antoni Ribas*, Richard Marais*. NEJM Jan 19, 2012
Acquired Resistance to vemurafenib:
Time to response and progression
BRIM2 study
Ribas et al.
ASCO 2011
Time on study
Time to response
Progressive disease
Continued response
0
2
Approx timing
of CT
assessments
4
6
8
Time (months)
10
12
14
Median duration of response = 6.7 months (95% CI: 5.6, 9.8; range 1.3–12.7)
16
Response and relapse with vemurafenib
10/02/08 (Pre)
11/26/08 (2+ mo)
02/20/09 (4+ mo)
Pt #43, UCLA
melanoma
stroma
Mechanisms of Resistance to Vemurafenib
PDGFRb or IGF1R
Nazarian et al.
Nature 2010
NRASQ61
Nazarian et al.
Nature 2010
Villanueva et al.
Cancer Cell 2010
BRAF inh
CRAF
COT
PI3Ki or AKTi
BRAFV600E
Johannessen et al.
Nature 2010
MEK
MEK-dependent
progression
PI3K
P
MEKi
Poulikakos et al.
Nature 2011
Wagle et al.
JCO 2011
ERK
P
Survival
AKT
MEK-independent
progression
Maximum % reduction from baseline measurement
GSK BRAFi+MEKi phase 1: A new paradigm in
combination targeted therapy drug development
GSK436 75 mg BID/GSK212 1 mg QD
GSK436 150 mg BID/GSK212 1 mg QD
GSK436 150 mg BID/GSK212 1.5 mg QD
GSK436 150 mg BID/GSK212 2 mg QD
83% of responses ongoing (1-12 mo f/y)
1% incidence of cuSCC
ASCO 2011, abstract #8503: Infante, J. R., G. S. Falchook, D. P. Lawrence, J. S. Weber, R.
F. Kefford, J. C. Bendell, R. Kurzrock, G. Shapiro, R. R. Kudchadkar, G. V. Long, H. A.
Burris, K. B. Kim, A. Clements, S. Peng, B. Yi, A. J. Allred, D. Ouellet, K. Patel, P. F.
Lebowitz, and K. T. Flaherty.
A new paradigm in the combination of
oncology therapies
X antitumor activity
Drug A
X antitumor activity
BRAFi
X toxicities
X toxicities
Y antitumor activity
Y antitumor activity
Drug B
MEKi
Y toxicities
X+Y antitumor activity
Drug A+B
X+Y toxicities
Y toxicities
BRAFi
+MEKi
↑↑↑↑ antitumor activity
↓↓↓↓ toxicities
Treating resistance to BRAFi
BRAFi
Local Tx + BRAFi
Occasional prolonged
responses
(Kim et al. ASCO 2011)
BRAFi
MEKi
No activity
(Kim et al. SMR 2011)
BRAFi
BRAFi
ORR 19%
(Flaherty et al. SMR 2011)
MEKi
BRAFi
MEKi
ORR 50-74%, increased PFS?
(Infante et al. ASCO 2011)
Progression of melanoma
Two Paradigms for Advancing the Therapy of
Metastatic Melanoma
Immunotherapy
Target host
Targeted
Therapy
Target
tumor
Can Vemurafenib Improve Immunotherapy?
Combining immunotherapy and targeted therapy for melanoma?
Targeted therapy
Combination
0
1
Years
2
3
Percent alive
Percent alive
Percent alive
Immunotherapy
0
1
2
Years
3
?
0
1
2
Years
3
Conclusions
• Single agent immunotherapies (ipilimumab) give
low but durable response rates
• Single agent targeted therapies (vemurafenib,
BRAF inhibitors) give high but non-durable
responses
• The science supports combination therapies to
advance the treatment of patients with
metastatic melanoma
Acknowledgements
Ribas lab
Roger S. Lo, M.D., Ph.D.
Ramin Nazarian, Ph.D.
Hubing Shi, Ph.D.
James S. Economou, M.D., Ph.D.
Bartosz Chmielowski, M.D., Ph.D.
John A. Glaspy, M.D., M.P.H.
Lidia Robert, M.D.
Nicholas Otte
Earl Aramis
Mohammad Atefi, Ph.D. Deborah Wong, M.D.
Clinical
trials
team
Vanderbilt: Jeff Sosman, M.D.
Peter Mac: Grant McArthur, M.D., Ph.D.
MGH: Keith Flaherty, M.D.
MSKCC: Paul Chapman, M.D., Neil Rosen, M.D.,
David Solit, M.D.
ICR, London: Richard Marais, Ph.D.
Roche: Fei Su, Ph.D.
Plexxikon: Gideon Bollag, Ph.D.