Transcript Treatment of choice is a clinical trial

New Targets and New
Treatments in Melanoma
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
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, Prometheus
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.
Survival curves from the AJCC Melanoma Staging
Database
Balch, C. M. et al. J Clin Oncol; 27:6199-6206 2009
Copyright © American Society of Clinical Oncology
Survival of 7,635 patients with metastatic melanomas
(stage IV) by (A) the site of metastatic disease and (B)
serum (LDH) levels
Balch, C. M. et al. J Clin Oncol; 27:6199-6206 2009
Copyright © American Society of Clinical Oncology
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 2010
TREATING METASTATIC MELANOMA
Not Just Bad, Consistently Bad
PROGRESSION-FREE SURVIVAL ON COOPERATIVE GROUP
PHASE II TRIALS BY DECADE AND PRETREATMENT ALLOWED
DECADE TRIAL PERFORMED
1st LINE VS PRETREATED
Korn et al. J Clin Oncol 2008;26:527-534
Antigen
Presenting Cell
T Cell
B7-DC/PD-L2
B7-H1/PD-L1
PD-1
CTLA-4
B7-2(CD86)
+
-
MHC-I/II
TCR
OX40L
OX40
4-1BBL
4-1BB
+
Targets of novel immunotherapy
TNFR family
TNF family
Adapted from: Melero et al. Nature Rev Cancer. 2007;7:95.
B7 family
CD28 family
CTLA-4: The Brake on T-Cell Activation
T-cell receptor: antigen/MHC
CD28 B7
CTLA-4 B7
Vaccine?
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, 2010
MDX-020: Study Design
Pre-treated
Metastatic
Melanoma
(N=676)
R
A
N
D
O
M
I
Z
E
Ipilimumab + gp100
(N=403)
Ipilimumab + placebo
(N=137)
gp100 + placebo
(N=136)
Kaplan-Meier Analysis of Survival
Ipi + gp100
Ipi alone
gp100 alone
1
2
Years
3
(A)
(B)
(C)
4
Ipi + gp100
N=403
Ipi + pbo
N=137
gp100 + pbo
N=136
1 year
44%
46%
25%
2 year
22%
24%
14%
Survival Rate
Ipilimumab Improves Best Objective
Response Rate (BORR)
BORR, %
Arm A
Ipi + gp100
N=403
Arm B
Ipi + pbo
N=137
Arm C
gp100 + pbo
N=136
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
P-value: A vs C
0.0179
P-value: B vs C
0.0002
11.0
‡: Disease control rate: percentage of patients with CR, PR, or SD
Ipilimumab and DTIC
versus DTIC (+ placebo)
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.
Dermatologic IRAEs
Image courtesy of Jeffrey S. Weber, MD, PhD.
Ipilimumab-Induced
Colitis
and
Robinson et al, 2004; Phan et al, 2003.
Iritis
Ipilimumab-Related Pituitary
Swelling and Dysfunction
6/30/04 Baseline
(4.5 mm)
Blansfield et al, 2005.
12/3/04 Headache/fatigue after 5 doses
(10.8 mm)
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 bracelet
Beck et al, 2006.
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 = ~$120,000
Targeted Therapy
Hocker, et al. 2008 The Society for Investigative Dermatology
Relative frequency of BRAF mutations
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
Distribution of BRAF/NRAS/c-kit
mutations by primary site
Curtin J et al. JCO 2006; 24: 4340
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;363:809-819
Antitumor Response in Each of the 32 Patients in the Extension Cohort
Flaherty KT et al. N Engl J Med 2010;363:809-819
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)
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?
PLX4032 vs DTIC (BRIM3)
Patient has had 16 squamous cell cancers resected in 6 months
Patient 2
• 51 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?
PLX4032 vs DTIC (BRIM3)
Assigned to DTIC, PR after after 6 cycles, then PD, now responding to IL-2
Patient 3
• 64 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?
Before
Pt 11 – Melanoma
CT PR
PET CR
After
Patient 4
• 56 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?
Ipilimumab
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 235 (= 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).