should genome sequencing of multiple oncogenes surplant
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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 - PowerPoint PPT PresentationTRANSCRIPT
Should genome sequencing of multiple oncogenes surplant
V600 mutation testing by an FDA approved test ?
Omid Hamid MDDirector, Melanoma Program
Chief, Translational Research & ImmunotherapyThe Angeles Clinic and Research Institute
Delivering Rational, Affordable Cancer Carein the 21st Century
Omid Hamid MDDirector, Melanoma Program
Chief, Translational Research & ImmunotherapyThe 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†)
1.00.90.80.70.60.50.40.30.20.1
00 1 2 3 4 5 6 7 8 9 10 11 12
Time, Months13 14
Number of patients at risk:DTICVemurafenib
338337
305336
274335
242326
215313
191299
122245
101223
62147
46112
1535
617
410
13
00
HR=0.62 (95% CI: 0.49-0.77)
DTICmedian OS: 9.6 months
15 16 17 18 19 20
Vemurafenib median OSa: 13.2 months
169280
150259
79181
3186
2254
*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.
OS,
%
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: PRISMPhase III Paclitaxel + Carboplatin ± Sorafenib
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
N=270
Primary endpoint: progression-free survival (by independent assessment)Secondary and tertiary endpoints: time to progression, objective response rate, duration of response, overall survival
Carboplatin AUC 6 IV Day 1Paclitaxel 225 mg/m2 IV Day 1
Sorafenib 400 mg po bid Days 2-19Cycles repeated every 21 days
Stratified by:AJCC stage:· Unresectable stage III· Stage IV – M1a, M1b· Stage IV – M1cECOG PS:· 0 vs 1Key Eligibility:· Progresses on DTIC/TMZ· No active brain Metastases· Measurable disease by RECIST Carboplatin AUC 6 IV Day 1
Paclitaxel 225 mg/m2 IV Day 1Placebo 2 tablets po bid Days 2-19
Cycles repeated every 21 days
RANDOMIZATION
Mandatory dose reduction after cycle 4 to paclitaxel 175 mg/m2 and
carboplatin AUC 5
Phase III Carboplatin/Paclitaxel ± Sorafenib
Hazard Ratio = 0.91; P = 0.492
Sorafenib + C/P (97 events)Median: 4.0 mo.
Placebo + C/P (100 events)Median: 4.1 mo.
1.00
0.75
0.50
0.25
0.00Pro
babi
lity
of P
rogr
essi
on-F
ree
Sur
viva
l
0 14 29 43 57 71Weeks From Randomization
ORR
11%
10%
Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.
PRISM: Overall Survival
Hazard Ratio = 1.014; p = 0.924
Sorafenib + C/P (91 deaths)Median: 42 weeks (95% CI: 35, 46)
Placebo + C/P (89 deaths)Median: 42 weeks (95% CI: 37, 54)
0 14 29 43 57 71Weeks From Randomization
86 100
Paclitaxel/Carboplatin ± Sorafenib in Advanced Melanoma
E2603 Phase III Trial
Arm ACarboplatin AUC 6 IV Day 1Paclitaxel 225 mg/m2 IV Day 1Placebo 2 tablets po bid Days 2-19 Q3WStratified by:
· AJCC Stage· ECOG PS· Prior Therapy Arm B
Carboplatin AUC 6 IV Day 1Paclitaxel 225 mg/m2 IV Day 1Sorafenib 400 mg po bid Days 2-19 Q3W
RANDOMIZE
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.
800 patients with metastatic melanoma and no prior chemotherapy; primary endpoint - OS
E2603: EfficacyCarboplatin/paclitaxel Carboplatin/paclitaxel & sorafenib
Overall survival 11.3 mo. 11.1 mo.
Progression-free 4.1 mo. 4.9 mo. survival
Response rate 16% 18%
p > 0.05 for all comparisons
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
AJCC stage IIIB-IVNRAS or BRAF mutation
WHO PS 0-2No prior MEKi therapyPrior BRAF inhibitor
permittedPrior therapy permitted
BRAFV600 - mutantn = 41 pts
MEK162 45 mg BID
NRAS-mutantn = 30 pts
MEK162 45 mg BID
*as of 29 Feb 2012.
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
Best percentage change from baseline and best overall response (NRAS)
*Patients with missing best % change from baseline and unknown overall response are not included.
N=28*Progressive Disease (PD)Stable Disease (SD)Partial Response (PR)Unconfirmed PR
45 mg NRAS
Ongoing pts
Is it actionable ? What is “actionable”?
ERROR: Actionable = Druggablenot 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 ?
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
Key Messages
October 8, 2012 - October 9, 2012
Delivering Affordable Cancer Care in the 21st Century
…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.
In 2012, the U.S. will spend $2.80 TRILLION on Health Care
GDP in 2011 Rank of EconomyCHINA $7.30 trillion #2JAPAN $5.87 trillion #3GERMANY $3.58 trillion #4FRANCE $2.78 trillion #5BRAZIL $2.49 trillion #6UK $2.42 trillion
#7
U.S. Health Care Spending
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 billionIndirect (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.
Cost of Healthcare and Cancer Care
* Purchasing power parity.** Estimated Spending According to Wealth.Source: Organization for Economic Co-operation and Development (OECD)
US Spending vs. Other Countries
“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
Rising costs and Stagnant wages
“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
“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 acondition and treat a patient respects the need to use resources wisely…”
Responsibility to Practice Effective and Efficient Health Care
American College of Physicians Ethics Manual, Sixth Edition
Conduct thoughtful pragmatic trials with comparators whenever possible
Collect the data about what is happening in real practice –
…….and learn from it