Brendan D Curti MD Director Melanoma Program Director Biotherapy Program Providence Cancer Center Earle A Chiles Research Institute Disclaimers Earle A Chiles Research Institute accepted grants of ID: 340562
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Slide1
New Targets and New Treatments in Melanoma
Brendan D. Curti, MD
Director, Melanoma Program
Director Biotherapy Program
Providence Cancer Center
Earle A. Chiles Research InstituteSlide2
Disclaimers
Earle A. Chiles Research Institute accepted grants of
from BMS,
Medarex
, and Roche to cover costs of clinical trials.
I am neither employed nor do I have equity in any company or entity whose products/drugs will be discussed
today.
Research Support: NIH, Prostate Cancer Foundation, Safeway Foundation,
Kuni
Foundation, Prometheus Pharmaceuticals
Speakers Bureau: Genentech,
Prometheus
Advisory Board: BMS, PrometheusSlide3
Melanoma Statistics
More than
70,000
people in the United States will get melanoma
2011
.
About
8,800 patients die
per year
from melanoma.
During the 1970s, the rate of new cases of melanoma each year increased at about 6% per year. Since the 1980s, the rate of increase has slowed to a little less than 3% per year.
Melanoma is more often found in whites who are about 10X more likely to develop melanoma than African Americans.
Men are slightly more likely than women to have melanoma.
Melanoma rates are highest in older people, but occur
in
all ages. In fact, melanoma is one of the most common cancers in people under age 30. Slide4
Balch, C. M. et al. J
Clin
Oncol
; 27:6199-6206 2009
Survival
curves from the
AJCC
Melanoma Staging
DatabaseSlide5
Balch, C. M. et al. J
Clin
Oncol
; 27:6199-6206 2009
Survival of
7,635 patients with metastatic melanomas
(
stage IV)
by
(A) the site of metastatic disease and (B) serum
(
LDH) levelsSlide6
TREATING METASTATIC MELANOMA
The Long Dark Tunnel
No documented improvement in survival over the past 30 years
No new FDA-approved drugs for melanoma from 1992 until 2011.
Until this year, first
-line therapy of questionable
value
over supportive care, no established second-line therapy at all, no proven value of combination regimens
Treatment of choice is a clinical trial
Vern Sondak ASCO 2010Slide7
TREATING METASTATIC MELANOMA
Not Just Bad, Consistently Bad
Korn et al.
J Clin Oncol
2008;26:527-534
DECADE TRIAL PERFORMED
1
st
LINE VS PRETREATED
PROGRESSION-FREE SURVIVAL ON COOPERATIVE GROUP PHASE II TRIALS BY DECADE AND PRETREATMENT ALLOWEDSlide8
MHC-I/II TCR
4-1BBL
B7-DC/PD-L2
OX40
B7-2(CD86)
OX40L
4-1BB
PD-1
Antigen
Presenting Cell
T Cell
CTLA-4
-
+
B7-H1/PD-L1
+
TNFR family
TNF family
B7 family
CD28
family
Adapted from:
Melero
et al.
Nature Rev Cancer
. 2007;7:95.
Targets of novel
immunotherapySlide9
CTLA-4: The Brake on T-Cell Activation
CTLA-4 B7
Vaccine?
CD28 B7
T-cell receptor: antigen/MHC
IL-2Slide10
Original Article
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
F.
Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., Robert W. Weber, M.D., Jeffrey A. Sosman, M.D., John B.
Haanen
, M.D., Rene Gonzalez, M.D., Caroline Robert, M.D., Ph.D., Dirk Schadendorf, M.D., Jessica C. Hassel, M.D., Wallace
Akerley
, M.D.,
Alfons
J.M. van den
Eertwegh
, M.D., Ph.D., Jose Lutzky, M.D., Paul Lorigan, M.D., Julia M.
Vaubel
, M.D., Gerald P.
Linette
, M.D., Ph.D., David Hogg, M.D., Christian H.
Ottensmeier
, M.D., Ph.D., Celeste
Lebbé
, M.D., Christian
Peschel
, M.D., Ian Quirt, M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D., Jeffrey S. Weber, M.D., Ph.D., Jason
Tian
, Ph.D., Michael J. Yellin, M.D., Geoffrey M. Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D., and
Walter J. Urba, M.D., Ph.D.
N
Engl
J Med
Volume 363(8):711-723
August 19, 2010Slide11
MDX-020: Study Design
R
A
N
D
O
M
I
Z
E
Pre-treated
Metastatic
Melanoma
(N=676)
(N=137)
(N=136)
(N=403)
gp100
+ placebo
Ipilimumab
+ placebo
Ipilimumab
+ gp100Slide12
Kaplan-Meier Analysis of Survival
Ipi + gp100 (A)
Ipi alone (B)
gp100 alone (C)
1
2
3
4
Years
Survival Rate
Ipi + gp100
N=403
Ipi + pbo
N=137
gp100 + pbo N=136
1 year
44%
46%
25%
2 year
22%
24%
14%Slide13
Ipilimumab Improves Best Objective Response Rate (BORR)
Arm A
Ipi + gp100
N=403
Arm B
Ipi + pbo
N=137
Arm C
gp100 + pbo
N=136
BORR, %
5.7
10.9
1.5
P-value: A vs C
0.0433
P-value: B vs C
0.0012
DCR
‡
, %
20.1
28.5
11.0
P-value: A vs C
0.0179
P-value: B vs C
0.0002
‡: Disease control rate: percentage of patients with CR, PR, or SD Slide14
Ipilimumab
and DTIC
versus DTIC (+ placebo)Slide15Slide16
CTLA-4 Immunotherapy: Toxicity = Immune Response-related Adverse Event (IRAE)
Most common IRAEs
Rash
Diarrhea (colitis)
Endocrinopathies
Hepatitis
IRAEs are almost always reversible and manageable with steroids
Toxicity does not always equal response, but there does appear to be an association
Weber, 2007.Slide17
Dermatologic IRAEs
Image courtesy of Jeffrey S. Weber, MD, PhD.Slide18
Robinson et al, 2004;
Phan
et al, 2003.
Ipilimumab
-Induced
Colitis and
IritisSlide19
6/30/04 Baseline
(4.5 mm)
12/3/04 Headache/fatigue after 5 doses
(
10.8 mm)
Ipilimumab-Related Pituitary Swelling and Dysfunction
Blansfield
et al, 2005.Slide20
Beck et al, 2006.
IRAE Management
Patient education for early recognition of IRAEs
Aggressive work-up and management for moderate/severe events
Non-specific complaints may reflect endocrine (e.g.:, pituitary) toxicity
Established therapies (e.g.:, corticosteroids) are effective
Dexamethasone
: 4 mg IV q6hrs x 7 days followed by 17 days taper. If ineffective then
infliximab
5 mg IV x 1.
Algorithms established for work-up, treatment, and reporting of
IRAEs
Patient wallet card and/or medical ID braceletSlide21
Conclusions- Ipilimumab
Ipilimumab represents a new class of T-cell
potentiators
and a breakthrough for the field of immunotherapy
Further development of ipilimumab is ongoing
Treatment of a variety of cancer types
Alternative combination regimens
Refinements in dose and schedule
Approved by the FDA on March 25, 2011
Price for 4 doses = ~$120,000Slide22
Targeted TherapySlide23
Hocker
, et al. 2008 The Society for Investigative DermatologySlide24
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%
*Indicates most common amino substitution, but % represents all amino acid changes reported at that position
Relative frequency of BRAF mutationsSlide25
Distribution of BRAF/NRAS/c-kit mutations
by primary site
Curtin J et al. JCO 2006; 24: 4340 Slide26Slide27
Representative Findings of the Effect of PLX4032
in Patients
with Melanoma That Carried the V600E
BRAF Mutation
Flaherty KT et al. N
Engl
J Med 2010;363:809-819Slide28
Antitumor Response in Each of the 32 Patients in the Extension Cohort
Flaherty KT et al. N
Engl
J Med 2010;363:809-819Slide29Slide30Slide31
BRAF and
Vemurafenib
:
Conclusions
Approximately 50% of melanomas contain an activating mutation in BRAF:
glutamic
acid for
valine
at amino acid 600 (the V600E mutation).
Side effects included rash,
arthralgia
, fatigue, and
keratoacanthoma
.
Treatment of patients with V600E BRAF mutated metastatic melanoma with PLX4032 resulted in complete or partial
tumor
regression in the majority of patients.
Remissions do not appear to be durable.
Approved by the FDA on 8/16/2011
Bargain price: $9800 per month ($117,600 per year)Slide32
Patient 1
76 year old grandmother diagnosed in 2002 years with TXN3M0 (stage 3) melanoma of left neck s/p RLND
2004: Left axillary LN recurrence, 24/28 + on axillary dissection
May 2010: New onset dyspnea. Found to large left pleural effusion, bulky chest and abdominal adenopathy. Biopsy confirms melanoma. ECOG 2 (on a good day)
What would you do? Slide33
PLX4032 vs DTIC (BRIM3)
Patient has had 16
squamous
cell cancers
resected
in 6 monthsSlide34
Patient 251 year old salesman with T2bN1M0 melanoma on back in 2005. S/P WLE, SLN and CLND. One year “Kirkwood” IFN.
Surveillance CT shows new mediastinal and hilar adenopathy, new SQ nodule.
What would you do?Slide35
PLX4032 vs DTIC (BRIM3)
Assigned to DTIC,
PR after
after 6
cycles, then PD, now responding to IL-2Slide36
Patient 364 year old dentist, presents with acute abdominal pain. CT shows liver mets and adrenal tumors. Additional staging shows lung, LN, adrenal mets. LDH 8000. Biopsy confirms melanoma, PS 2 (and sliding rapidly).
What would you do?Slide37
Before
After
Pt 11 – Melanoma
CT PR
PET CRSlide38
Patient 456 year old woman presents with cough. Imaging shows mediastinal lymph nodes. Biopsy shows melanoma.
IL-2: Mixed response. RT to progressing lesion. 6 months later, new SQ, lung and LN disease. SQ nodule harvested for autologous vaccine.
What would you do? Slide39
IpilimumabSlide40
Questions for the future:
How excited should we be with PFS of 6 – 8 months with targeted therapies (despite the high initial response rate)?
How do we sequence “targeted” therapies?
We have entered the age of personalized medicine to characterize targets for melanoma treatment. Do we need to enter the age of personalized mechanisms of resistance? (and include physiologic, immunologic and other mechanisms of resistance)
If BRAF resistance can (in part) be overcome with MEK inhibition, and MEK resistance can be overcome with WNT inhibition (at least in vitro), what will we need for WNT resistance?
A melanoma “wiring diagram” was shown at a recent meeting with 35 nodes (connections). If we assume that there are 2 interactions from each node, and each interaction represents a path of resistance (or a path of recovery if you take the perspective of a melanoma cell), then there are 2
35
(= 3.4
x
1010) potential resistance pathways. How easy will it be to address address these several pathways of resistance in an individual? (and even if my estimate is wrong by 99.999999999%, there are 34 resistance pathways to manage).