Download Key Messages Off label prescribing in oncology is a real

Should genome sequencing of multiple oncogenes
surplant
V600 mutation testing by an FDA approved test ?
Omid Hamid MD
Director, Melanoma Program
Chief, Translational Research & Immunotherapy
The Angeles Clinic and Research Institute
Delivering Rational, Affordable Cancer Care
in the 21st Century
Omid Hamid MD
Director, Melanoma Program
Chief, Translational Research & Immunotherapy
The Angeles Clinic and Research Institute
What is expected from this discussion ?
“ Jane you ……. “
What will happen .
Background
• Benefits of accelerating progress
• ? Fundamental drivers of carcinogenesis
– More effective, less toxic tx
• The cost on treatment competes with
availability of effective therapy
• Few options
Where to begin ?
•
•
•
•
bcr/abl in APL
Ckit in GIST
BRAF in Melanoma
ALK & ROS in NSCLC
• Deep sequencing > 200 oncogenes
• Cost – $5,000 to 6,000
• Actionable genes
BRIM3: OS*
(October 3, 2011, Cutoff†)
1.0
HR=0.62
(95% CI: 0.49-0.77)
0.9
0.8
OS, %
0.7
0.6
0.5
0.4
0.3
DTIC
median OS:
9.6 months
0.2
0.1
Vemurafenib
median OSa:
13.2 months
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20
Time, Months
Number of patients at risk:
338 305 274 242 215 191 169 150 122 101 79 62 46 31 22 15 6 4
DTIC
337 336 335 326 313 299 280 259 245 223 181 147 112 86 54 35 17 10
Vemurafenib
1
3
0
0
*Ad-hoc analysis for European Medicines Agency regulatory filing. †Patients on DTIC who received vemurafenib after the investigator assessment
(by data and safety monitoring board recommendation; n=81) were censored at the date of crossover. aProjected median for ad-hoc analysis.
Data on file. Genentech, Inc.
Main Points
•
•
•
•
BRIM Studies – central BRAF determination
Created a standard for community
No cost to patient/insurance
Led to randomized phase III studies with
– Significant OS and PFS
• Accrued in less than 1 year due to demand
• Drug not available commercially
Rationale for Sorafenib in Melanoma
• Induces apoptosis in B-Raf wild-type and mutant
melanoma cell lines
• Phase I/II trial of Sorafenib in combo with
Carbo/Taxol
– One CR, PR (26%) , clinical benefit (85%)
– Median PFS of > 8 months
Sorafenib in Melanoma: PRISM
Phase III Paclitaxel + Carboplatin ± Sorafenib
Stratified by:
AJCC stage:
 Unresectable stage III
 Stage IV – M1a, M1b
 Stage IV – M1c
ECOG PS:
 0 vs 1
Key Eligibility:
 Progresses on DTIC/TMZ
 No active brain Metastases
 Measurable disease by RECIST
Primary endpoint: progression-free
survival (by independent assessment)
Secondary and tertiary endpoints: time
to progression, objective response rate,
duration of response, overall survival
R
A
N
D
O
M
I
Z
A
T
I
O
N
Carboplatin AUC 6 IV Day 1
Paclitaxel 225 mg/m2 IV Day 1
Sorafenib 400 mg po bid Days 2-19
Cycles repeated every 21 days
Mandatory dose reduction after
cycle 4 to paclitaxel 175 mg/m2 and
carboplatin AUC 5
Carboplatin AUC 6 IV Day 1
Paclitaxel 225 mg/m2 IV Day 1
Placebo 2 tablets po bid Days 2-19
Cycles repeated every 21 days
N=270
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
Phase III Carboplatin/Paclitaxel ± Sorafenib
Probability of Progression-Free Survival
ORR
11%
Sorafenib + C/P (97 events)
Median: 4.0 mo.
1.00
Placebo + C/P (100 events)
10%
Median: 4.1 mo.
0.75
Hazard Ratio = 0.91; P = 0.492
0.50
0.25
0.00
0
14
29
43
57
71
Weeks From Randomization
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
PRISM: Overall Survival
Sorafenib + C/P (91 deaths)
Median: 42 weeks (95% CI: 35, 46)
Placebo + C/P (89 deaths)
Median: 42 weeks (95% CI: 37, 54)
Hazard Ratio = 1.014; p = 0.924
0
14
29
43
57
71
Weeks From Randomization
86
100
Paclitaxel/Carboplatin ± Sorafenib in
Advanced Melanoma
E2603 Phase III Trial
Stratified by:
 AJCC Stage
 ECOG PS
 Prior Therapy
800 patients with metastatic
melanoma and no prior
chemotherapy; primary endpoint - OS
R
A
N
D
O
M
I
Z
E
Arm A
Carboplatin AUC 6 IV Day 1
Paclitaxel 225 mg/m2 IV Day 1
Placebo
2 tablets po bid Days 2-19 Q3W
Arm B
Carboplatin
Paclitaxel
Sorafenib
AUC 6 IV Day 1
225 mg/m2 IV Day 1
400 mg po bid Days 2-19 Q3W
Carboplatin and paclitaxel with or without sorafenib in treating patients
with unresectable stage III or stage IV melanoma.
Available at: www.clinicaltrials.gov/ct/show/NCT0010019?order=1.
Accessed September 17, 2007.
E2603: Efficacy
Carboplatin/paclitaxel
Carboplatin/paclitaxel
& sorafenib
Overall survival
11.3 mo.
11.1 mo.
Progression-free
survival
4.1 mo.
4.9 mo.
Response rate
16%
p > 0.05 for all comparisons
18%
Efficacy and safety of oral MEK162 in patients with locally advanced and
unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS
mutations
Patients with advanced
cutaneous melanoma
BRAFV600 - mutant
n = 41 pts
MEK162 45 mg BID
AJCC stage IIIB-IV
NRAS or BRAF mutation
WHO PS 0-2
No prior MEKi therapy
Prior BRAF inhibitor permitted
Prior therapy permitted
NRAS-mutant
n = 30 pts
MEK162 45 mg BID
Paolo A. Ascierto,* Carola Berking, Sanjiv S. Agarwala, Dirk Schadendorf, Carla van Herpen, Paola Queirolo, Christian U. Blank, Axel
Hauschild, J. Thaddeaus Beck, Angela Zubel, Faiz Niazi, Simon Wandel, Reinhard Dummer
*National Cancer Institute, Naples Italy
*as of 29 Feb 2012.
Best percentage change from baseline and best
overall response (NRAS)
N=28*
45 mg NRAS
Progressive Disease (PD)
Stable Disease (SD)
Partial Response (PR)
Unconfirmed PR
*Patients with missing best % change from baseline and unknown overall response are not included.
Ongoing pts
Is it actionable ?
What is “actionable”?
ERROR:
•
•
•
•
•
•
Actionable = Druggable
not always
Actionable = Beneficial
E2603/PRISM
BEAM (bevacizumab)
Temodar based on MGMT
BRAF for lung/CRC/thyroid
CD117 for ckit
??? MEKi for NRAS mut melanoma
Concerns
• Off label use leading
– Decreased enrollment to clinical trial
mechanism
– Lack of data
– Excess toxicity with Questionable Benefit
• Morbidity
• Mortality
– Cost
– Right drug ?
Key Messages
Delivering Affordable Cancer Care in the 21st Century
Off label prescribing in oncology is a real part of care and substantial
contributor to cost
* Reinforced by the Compendia-based reimbursement mechanism
* Rapidly evolving evidence/information without mechanism to make
sense of it all
* Need a strategy to define appropriate off-label use
October 8, 2012 - October 9, 2012
…escalating healthcare cost is no laughing matter
Source: Bach PB. Limits on Medicare’s Ability to control rising spending on cancer Drugs.
N Engl J Med 2009;360:626-633.
U.S. Health Care Spending
In 2012, the U.S. will spend $2.80 TRILLION on Health Care
CHINA
JAPAN
GERMANY
FRANCE
BRAZIL
UK
GDP in 2011
$7.30 trillion
$5.87 trillion
$3.58 trillion
$2.78 trillion
$2.49 trillion
$2.42 trillion
Rank of Economy
#2
#3
#4
#5
#6
#7
Cost of Healthcare and Cancer Care
Healthcare costs accounted for
18% of GDP in 2010
Total cost of cancer in 2006:
$284.4 billion (in 2011$)
Direct medical cost: $123.9 billion
Indirect (morbidity + mortality) cost $160.5
billion
Total medical costs of cancer accounts for
5% of all health care expenditures
10% of the Medicare expenditures
1% of all payor’s patients
Source: (1) Cancer Trends Progress Report – 2009/2010 Update,
National Cancer Institute, http://progressreport.cancer.gov.
US Spending vs. Other Countries
* Purchasing power parity.
** Estimated Spending According to Wealth.
Source: Organization for Economic Co-operation and Development (OECD)
Rising costs and Stagnant wages
“Medicaid and other health-care expenses are predicted to grow to as much as 40%
of the state budget by 2015. That will force the state to cut higher education funding
because there are few other options. ... It certainly seems to be on a collision course.”
John Arnold, Director of the Arizona Office of Strategic Planning and Budgeting
“Medicare and Medicaid will rise from 4.5% of the economy today to 20% of
the economy by 2050. This is the central long-term fiscal challenge facing the
United States, period.”
Peter Orszag, while director of the Congressional Budget Office
Over the last 30 years:
• Health insurance
premiums increased by
300% after inflation.
• Corporate profits increased
200% after taxes.
• Net worker income in
private industries declined
by 4%.
Source: Emanuel and Fuchs. Who Really Pays for Health Care? JAMA. 2008
Responsibility to Practice Effective and Efficient Health Care
American College of Physicians Ethics Manual, Sixth Edition
“Physicians have a responsibility to practice effective and efficient health care and
to use health care resources responsibly.
Parsimonious care that utilizes the most efficient means to effectively diagnose a
condition and treat a patient respects the need to use resources wisely…”
Conduct thoughtful pragmatic trials with
comparators whenever possible
Collect the data about what is happening in
real practice –
…….and learn from it