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Malignant melanoma: Paradigm shift in management
of advanced disease
Antoni Ribas, M.D., Ph.D.Professor of MedicineProfessor of Surgery
Professor of Molecular and Medical PharmacologyDirector, Tumor Immunology Program, Jonsson
Comprehensive Cancer Center (JCCC)University of California Los Angeles (UCLA)
Two Paradigms for Advancing the Therapy of Metastatic Melanoma
Target host
Target tumor
Immunotherapy TargetedTherapy
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!
IL-2IFNIL-15IL-21
Peptide vaccineDC vaccineGenetic vaccine
OX40
CD137
CD40
PD1CTLA4
T cell cloningTCR or CAR
genetic engineering
Metastatic Melanoma Response to Ipilimumab
Before Ipilimumab04/22/11
After Ipilimumab08/05/11
Quantifying the absolute benefit of ipilimumabOS at different time points
Ipi arms Control arms OS Difference
Hodi-O’Day, 2010 Ipi+gp100 gp100
Median OS 10.0 mo 6.4 mo HR= 0.68;
P< 0.001
Ipi gp100
Median OS 10.1 mo 6.4 mo HR= 0.66;
P= 0.003
Wolchok, 2011 Ipi+DTIC DTIC
Median OS 11.2 mo 9.1 mo HR= 0.72;
P= 0.0009
Quantifying the absolute benefit of ipilimumabOS at different time points
Ipi arms Control arms OS Difference
Hodi-O’Day, 2010 Ipi+gp100 gp100
Median OS 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
Median OS 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%
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
Target host
Target tumor
Immunotherapy TargetedTherapy
Driver Oncogenic Mutations Define Clinically Relevant Melanoma Molecular Subsets
Arising from SkinWithout Chronic
Sun Damage
Arising from SkinWith Chronic Sun Damage
Arising from MucosalSurfaces
Arising fromAcral
Surfaces
Uveal Melanoma
Curtin et al. NEJM 2005; Curtin et al. JCO 2006; Van Raamsdonk et al., NEJM 2010
50% BRAF20% NRAS
0% KIT
10% BRAF10% NRAS
2% KIT
5% BRAF15% NRAS
20% KIT
15% BRAF15% NRAS
15% KIT
25% GNAQ 55% GNA11
Ras GTP
Inhibition of MAPK signaling in biopsies of BRAFV600 melanoma from patients treated with vemurafenib (PLX4032)
Baseline
pERK
cyclin D
Ki67
Day 15
Cyclin D
BRAFV600
MEK
ERK
P
P
Cell cycle(Ki67)
PLX4032
RTK
Y-PY-P
GF
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)
Individual patients treated with vemurafenib
60
40
20
0
-20
-40
-60
-80
-100
M1aM1bM1c
Disease stage
Per
cen
t ch
ang
e fr
om
bas
elin
e i
n d
iam
eter
of
targ
et
lesi
on
**************
Ribas, Kim, Schuchter, Gonzalez, Pavlick, Weber, McArthur, Hutson, Flaherty, Moschos, Lawrence, Hersey, Kefford, Chmielowski, Puzanov, Li, Nolop, Lee, Joe, Sosman. ASCO 2011, Abstract #8509
BRIM2
100
90
80
70
60
50
40
30
20
10
0
Ove
rall
surv
ival
(%
)
0 1 2 3 4 5 6 7 8 9 10 11 12
No. of patients in follow up
Dacarbazine
Vemurafenib
Months
336
336
283
320
192
266
137
210
98
162
64
111
39
80
20
35
1
6
1
1
9
14
Hazard ratio 0.37 (95% CI; 0.26 - 0.55)Log-rank P<0.0001
Overall survival (12/30/10 cutoff)
Vemurafenib (N=336)
Dacarbazine (N=336)
Chapman et al. NEJM 2011= 63% decrease in the risk of being dead compared to chemotherapy
BRIM2: Toxicities with vemurafenib
All grades n (%)
Grade 3n (%)
Grade 4n (%)
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)¶
Includes AEs reported in ≥20 patients
†One patient with 2 grade 4 AEs‡Cases 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
Ribas et al. ASCO 2011
cuSCC/KAs with vemurafenib
• 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
0 5 10 15 20 25 3530 40
Time on vemurafenib (weeks)
Median
Ribas et al. ASCO 2011
cuSCC/KAs with vemurafenib
Left chestKRASG12D
ChinHRASQ61L
Left scalpHRASQ61L
TorsoNo RAS mutation
Normal Skin Normal SkincuSCC/KA cuSCC/KA
IHC staining for pERK (Roger Lo)
cuSCC/KA pictures and H&E (Grant Macarthur and Roger Lo)
CuSCC/KA in Patients Treated with Vemurafenib
Initial series Validation set Total
Gender Female 3 2 5
Male 8 10 18
Age 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
21/35 (60%)KRAS G12C, G12D 1/21* 4/14
NRAS G12D 1/21* 0/14
TP53 P278S, R196X 2/18 NA 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
CRAF
MEK1/2
ERK
P
P
BRAFV600
BRAFV600 mutant melanoma BRAF wild type cells
Modeled from Hatzivassiliou et al. Nature 2010, Heidorn et al. Cell 2010, Poulikakos et al. Nature 2010
MAPK signaling
CRAF
MEK1/2
ERK
P
P
BRAFV600
PLX4032
MAPK signaling
CRAF
MEK1/2
ERK
P
P
BRAF
MAPK signaling
RAS
CRAF
MEK1/2
ERK
P
P
BRAF
PLX4032
MAPK signaling
RAS
Paradoxical MAPK activation in HRAS mutant cuSCC/KAs
CRAF
MEK1/2
ERK
P
P
BRAFV600
BRAFV600 mutant melanoma BRAF wild type cells
MAPK signaling
CRAF
MEK1/2
ERK
P
P
BRAFV600
PLX4032
MAPK signaling
CRAF
MEK1/2
ERK
P
P
BRAF
MAPK signaling
RAS
CRAF
MEK1/2
ERK
P
P
BRAF
PLX4032
MAPK signaling
HRASQ61
Fei Su, Amaya Viros, Carla Milagre, … Antoni Ribas*, Richard Marais*. NEJM Jan 19, 2012
Paradoxical MAPK activation with RAF inhibitors
Acquired Resistance to vemurafenib: Time to response and progression
16140
Approx timing of CT assessments
Approx timing of CT assessments
Continued response
Progressive diseaseProgressive disease
Time to responseTime to response
Time (months)4 6 8 10 122
Time on studyTime on study
Median duration of response = 6.7 months (95% CI: 5.6, 9.8; range 1.3–12.7)
BRIM2 studyRibas et al. ASCO 2011
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
Survival
BRAFV600E
MEK
ERK
P
P
BRAF inh
PDGFRb or IGF1R
PI3K
AKT
Nazarian et al. Nature 2010Villanueva et al. Cancer Cell 2010
Nazarian et al. Nature 2010Villanueva et al. Cancer Cell 2010
MEK-independentprogression
Nazarian et al. Nature 2010Nazarian et al. Nature 2010
NRASQ61
COT
Johannessen et al. Nature 2010Johannessen et al. Nature 2010
CRAF
Wagle et al. JCO 2011Wagle et al. JCO 2011MEK-dependent
progression
Poulikakos et al.Nature 2011
MEKi
PI3Ki or AKTi
GSK436 150 mg BID/GSK212 1.5 mg QD
GSK436 150 mg BID/GSK212 1 mg QD
GSK436 75 mg BID/GSK212 1 mg QD
GSK436 150 mg BID/GSK212 2 mg QD
GSK BRAFi+MEKi phase 1: A new paradigm in combination targeted therapy drug development
Max
imum
% r
educ
tion
from
bas
elin
e m
easu
rem
ent
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
Drug AX antitumor activity
X toxicities
Drug BY antitumor activity
Y toxicities
Drug A+BX+Y antitumor activity
X+Y toxicities
BRAFiX antitumor activity
X toxicities
MEKiY antitumor activity
Y toxicities
BRAFi+MEKi
↑↑↑↑ antitumor activity
↓↓↓↓ toxicities
Treating resistance to BRAFi
BRAFi MEKi No activity(Kim et al. SMR 2011)
BRAFi Local Tx + BRAFiOccasional prolonged responses(Kim et al. ASCO 2011)
BRAFi BRAFi ORR 19%(Flaherty et al. SMR 2011)MEKi
BRAFiORR 50-74%, increased PFS?(Infante et al. ASCO 2011)MEKi
Progression of melanoma
Two Paradigms for Advancing the Therapy of Metastatic Melanoma
Target host
Target tumor
Immunotherapy TargetedTherapy
Can Vemurafenib Improve Immunotherapy?
Years
Immunotherapy Targeted therapy
Per
cent
aliv
e
Per
cent
aliv
e
1 2 30 1 2 30Years
Combining immunotherapy and targeted therapy for melanoma?
Combination
Per
cent
aliv
e
1 2 30Years
?
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
Clinical trialsteam
Acknowledgements
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.
Ribas lab
Earl AramisMohammad Atefi, Ph.D.
Nicholas OtteDeborah Wong, M.D.
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.
Lidia Robert, M.D.
