Malignant melanoma: Paradigm shift in management of advanced disease

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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)

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Two Paradigms for Advancing the Therapy of
Metastatic Melanoma
Immunotherapy
Targeted Therapy
Target tumor
Target host
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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

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High dose IL-2 and Ipilimumab The major benefit
is in durable tumor regressions
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Peptide vaccine DC vaccine Genetic vaccine
IL-2 IFN IL-15 IL-21
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Metastatic Melanoma Response to Ipilimumab
Before Ipilimumab 04/22/11
After Ipilimumab 08/05/11
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Quantifying the absolute benefit of ipilimumab
OS at different time points Ipi arms Control arms OS Difference
Hodi-ODay, 2010 Ipigp100 gp100
Median OS 10.0 mo 6.4 mo HR 0.68 Plt 0.001


Ipi gp100
Median OS 10.1 mo 6.4 mo HR 0.66 P 0.003


Wolchok, 2011 IpiDTIC DTIC
Median OS 11.2 mo 9.1 mo HR 0.72 P 0.0009



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Quantifying the absolute benefit of ipilimumab
OS at different time points Ipi arms Control arms OS Difference
Hodi-ODay, 2010 Ipigp100 gp100
Median OS 10.0 mo 6.4 mo HR 0.68 Plt 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 IpiDTIC 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
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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

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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

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Two Paradigms for Advancing the Therapy of
Metastatic Melanoma
Immunotherapy
Targeted Therapy
Target tumor
Target host
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Driver Oncogenic Mutations Define Clinically
Relevant Melanoma Molecular Subsets
Curtin et al. NEJM 2005 Curtin et al. JCO 2006
Van Raamsdonk et al., NEJM 2010
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Inhibition of MAPK signaling in biopsies of
BRAFV600 melanoma from patients treated with
vemurafenib (PLX4032)
GF
Baseline

RTK
Ras GTP
pERK
Y-P
Y-P
cyclin D
Ki67
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Tumor Response to Vemurafenib
Baseline, 3-15-2011
C4 D1, 6-8-2011
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Waterfall plot of melanoma tumor responses with
vemurafenib BRIM2 study (132 patients)
Disease stage
BRIM2
60
M1a M1b M1c
40
20
0
Percent change from baseline in diameter of
target lesion
-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
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Overall survival (12/30/10 cutoff)
Overall survival ()
Chapman et al. NEJM 2011
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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 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
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cuSCC/KAs with vemurafenib
Median
0
5
10
15
20
25
35
30
40
Time on vemurafenib (weeks)

• cuSCCs
• Incidence 26
• Median time 8 weeks (236)
• 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
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cuSCC/KAs with vemurafenib
cuSCC/KA pictures and HE (Grant Macarthur and
Roger Lo)
Left chest KRASG12D
Chin HRASQ61L
Left scalp HRASQ61L
Torso No RAS mutation
IHC staining for pERK (Roger Lo)
Normal Skin
Normal Skin
cuSCC/KA
cuSCC/KA
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CuSCC/KA in Patients Treated with Vemurafenib
Initial series Validation set Total
Gender Female 3 2 5
Gender Male 8 10 18
Age Mean   60 66 60
Age Range 44-83 46-84 44-84
Number of Reported cuSCC/KA Events Mean 2 4 3
Number of Reported cuSCC/KA Events Range 1-6 1-10 1-10
Time to First cuSCC/KA (weeks) Mean 9 11 10
Time to First cuSCC/KA (weeks) 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 21/35 (60)
NRAS G12D 1/21 0/14 21/35 (60)
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
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Differential effects of BRAF inhibition in
BRAFV600 mutant melanoma and BRAF wild type cells
BRAFV600 mutant melanoma
BRAF wild type cells
BRAFV600
CRAF
MEK1/2
P
ERK
P
MAPK signaling
Modeled from Hatzivassiliou et al. Nature 2010,
Heidorn et al. Cell 2010, Poulikakos et al.
Nature 2010
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Paradoxical MAPK activation in HRAS mutant
cuSCC/KAs
BRAFV600 mutant melanoma
BRAF wild type cells
HRASQ61
PLX4032
BRAFV600
CRAF
BRAF
CRAF
MEK1/2
MEK1/2
P
P
ERK
ERK
P
P
MAPK signaling
MAPK signaling
Paradoxical MAPK activation with RAF inhibitors
Fei Su, Amaya Viros, Carla Milagre, Antoni
Ribas, Richard Marais. NEJM Jan 19, 2012
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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
16
14
0
4
6
8
10
12
2
Time (months)
Approx timing of CT assessments
Median duration of response 6.7 months (95 CI
5.6, 9.8 range 1.312.7)
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Response and relapse with vemurafenib
10/02/08 (Pre)
11/26/08 (2 mo)
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Mechanisms of Resistance to Vemurafenib
PI3Ki or AKTi
MEKi
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GSK BRAFiMEKi phase 1 A new paradigm in
combination targeted therapy drug development
Maximum reduction from baseline measurement
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A new paradigm in the combination of oncology
therapies
X antitumor activity
Drug A
X toxicities
Y antitumor activity
Drug B
Y toxicities
XY antitumor activity
Drug AB
XY toxicities
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Treating resistance to BRAFi
BRAFi
Progression of melanoma
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Two Paradigms for Advancing the Therapy of
Metastatic Melanoma
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Can Vemurafenib Improve Immunotherapy?
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Combining immunotherapy and targeted therapy for
melanoma?
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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

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Acknowledgements
Ribas lab
Roger S. Lo, M.D., Ph.D. Ramin Nazarian,
Ph.D. Hubing Shi, Ph.D.
Lidia Robert, M.D.
Earl Aramis Mohammad Atefi, Ph.D.
Nicholas Otte Deborah 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.
Clinical trials team