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

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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 Presentation

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Page 1: Should genome sequencing of multiple oncogenes surplant

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

Page 2: Should genome sequencing of multiple oncogenes surplant

Delivering Rational, Affordable Cancer Carein the 21st Century

Omid Hamid MDDirector, Melanoma Program

Chief, Translational Research & ImmunotherapyThe Angeles Clinic and Research Institute

Page 3: Should genome sequencing of multiple oncogenes surplant

What is expected from this discussion ?

“ Jane you ……. “

Page 4: Should genome sequencing of multiple oncogenes surplant

What will happen .

Page 5: Should genome sequencing of multiple oncogenes surplant

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

Page 6: Should genome sequencing of multiple oncogenes surplant

Where to begin ?

• bcr/abl in APL• Ckit in GIST• BRAF in Melanoma• ALK & ROS in NSCLC

Page 7: Should genome sequencing of multiple oncogenes surplant

• Deep sequencing > 200 oncogenes

• Cost – $5,000 to 6,000

• Actionable genes

Page 8: Should genome sequencing of multiple oncogenes surplant

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,

%

Page 9: Should genome sequencing of multiple oncogenes surplant

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

Page 10: Should genome sequencing of multiple oncogenes surplant

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

Page 11: Should genome sequencing of multiple oncogenes surplant

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

Page 12: Should genome sequencing of multiple oncogenes surplant

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.

Page 13: Should genome sequencing of multiple oncogenes surplant

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

Page 14: Should genome sequencing of multiple oncogenes surplant

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

Page 15: Should genome sequencing of multiple oncogenes surplant

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

Page 16: Should genome sequencing of multiple oncogenes surplant
Page 17: Should genome sequencing of multiple oncogenes surplant

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

Page 18: Should genome sequencing of multiple oncogenes surplant

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

Page 19: Should genome sequencing of multiple oncogenes surplant

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

Page 20: Should genome sequencing of multiple oncogenes surplant

Concerns• Off label use leading

– Decreased enrollment to clinical trial mechanism

– Lack of data – Excess toxicity with Questionable

Benefit • Morbidity • Mortality

– Cost– Right drug ?

Page 21: Should genome sequencing of multiple oncogenes surplant

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

Page 22: Should genome sequencing of multiple oncogenes surplant

…escalating healthcare cost is no laughing matter

Page 23: Should genome sequencing of multiple oncogenes surplant

Source: Bach PB. Limits on Medicare’s Ability to control rising spending on cancer Drugs. N Engl J Med 2009;360:626-633.

Page 24: Should genome sequencing of multiple oncogenes surplant

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

Page 25: Should genome sequencing of multiple oncogenes surplant

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

Page 26: Should genome sequencing of multiple oncogenes surplant

* Purchasing power parity.** Estimated Spending According to Wealth.Source: Organization for Economic Co-operation and Development (OECD)

US Spending vs. Other Countries

Page 27: Should genome sequencing of multiple oncogenes surplant

“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

Page 28: Should genome sequencing of multiple oncogenes surplant

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

Page 29: Should genome sequencing of multiple oncogenes surplant

“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

Page 30: Should genome sequencing of multiple oncogenes surplant

Conduct thoughtful pragmatic trials with comparators whenever possible

Collect the data about what is happening in real practice –

…….and learn from it