Teràpies diana: fer un bon ús dels biomarcadors i del seu

valor predictiu

Joan Albanell

Hospital del Mar, PSM

Universitat Pompeu Fabra

A virtuous circle?

Challenges

1. Only a fraction of targeted drugs have a biomarker

2. When a biomarker is available, not all tests/labs provide reliable results

3. Reimbursement and accreditation strategies of biomarkers

unclear/ongoing

Nov 2005

Erlotinib

(pancreas)

Dec 2005

Sorafenib

(RCC)

Jan 2006

Sunitinib

(GIST)

Jan 2006

Sunitinib

(RCC)

Jun 2006

Cetuximab

(SCCHN)

Sep 2006

Panitunumab

(colon)

Oct 2006

Bevacizumab

(NSCLC & Colon)

Nov 2006

Trastuzumab

(adjuvant BC)

Apr 2007

Lapatinib

(BC)

May 2007

Temsirolimus

(RCC)

2005 2006 2010

Oct 2009

Pazopanib

(RCC)

July 2009

Bevacizumab

(RCC)

March2009

Everolimus

(RCC)

Nov 2010

Trastuzumab

(gastric cancer)

Targeted therapies approved by the US Food and Drug

Administration for the treatment of solid tumours since 2005-2010

November 2007

Sorafenib

(HCC)

February 2008

Bevacizumab

(Breast)

May 2009

Bevacizumab

(Gliobastoma)

2007 2008 2009

June 2005

Gefitinib

(NSCLC)

Molecularly Targeted Anti-Cancer Agents that Need a Target/Biomarker for

Prescription and Are EMA Approved

Drug

Trastuzumab

Lapatinib

Pertuzumab

T-DM1

Cetuximab

Panitumumab

Gefitinib

Erlotinib

Crizotinib

Vemurafenib

Imatinib

Biomarker

HER2 ampl/overexpr

HER2 ampl/overexpr

HER2 ampl/overexpr

HER2 ampl/overexpr

K-Ras, N-Ras wt

K-Ras, N-Ras wt

EGFR mutation

EGFR mutation

Alk translocation

B-Raf mutation

C-kit positive

Tumor type (% with target)

Breast (early and advanced), Gastric (15-20%)

Advanced breast (15-20%)

Advanced breast (15-20%)

Advanced breast (15-20%)

Advanced colorectal (40%), head and neck

Advanced colorectal (40%)

Advanced lung cancer (NSCLC) (10%)

Advanced lung cancer (NSCLC) (10%)

Advanced lung cancer (NSCLC) (2-4%)

Advanced Melanoma (50%)

Advanced GIST (95%)

Challenge 1. Only a subset of targeted drugs have a

validated biomarker

Targeting Treatment to a Specific Variant in the Melanoma Gene

McDermott U et al. N Engl J Med 2011;364:340-350.

NRAS

KRAS

EXON 2 EXON 3 EXON 4 EXON 1

12 13 61 117 146

EXON 2 EXON 3 EXON 4 EXON 1

12 13 61 117 146

40% 4% 6%

3% 4% 1%

59

59

12 13 61 117 146 59

12 13 61 117 146 59

RAS mutations in colorectal cancer detected in

daily clinical practice

RAS detection Platform – Hospital del Mar

SAMPLES RECIEVED 392

Not evaluable 1

Analyzed 358

Mutated 157

KRAS 12-13 114

KRAS A59 1

KRAS Q61 7

KRAS EXON 4 10

NRAS 12-13 15

NRAS Q61 10

Not Mutated 201

114; 32%

1; 0%

7; 2%

10; 3%

15; 4%

10; 3%

201; 56%

KRAS 12-13

KRAS 59

KRAS 61

KRAS EXON 4 NRAS 12-13

NRAS 61

NO MUTADAS

HER2+++

Courtesy JM. Corominas (quality control SEAP)

Challenge 2. A good therapy starts with a good diagnosis

HER2 FALSE NEGATIVE

HER2+++

Courtesy JM. Corominas (quality control SEAP)

Challenge 2. A good therapy starts with a good diagnosis

- Identification of labs that do not provide

adequate results

- Acreditation process ongoing (SEAP)

Challenge 2. A good therapy starts with a good diagnosis

EGFR results from the EMQN quality control - 2011

Courtesy of Bea Bellosillo (Hospital del Mar)

Challenge 2. A good therapy starts with a good diagnosis

PR PD

CE

A

(ng/m

L)

Liv

er

targ

et le

sio

n

(mm

)

CEA Liver target lesion

PR PD

Cetuximab based therapy Panitumumab therapy

Time (weeks)

EGFR S492R (% of detected alleles)

KRAS Q61H (% of detected alleles)

Muta

tio

ns

(% o

f de

tecte

d a

llele

s) EGFR gene amplification

1

2

Gene

co

py n

um

be

r

(ratio E

GF

R/C

EP

7)

25%

44%

0% 0% 0%

Time (weeks)

On (un)natural selection (Bellosillo…Montagut, in preparation)

Treatment Recommendation Shifted in a

Third of the Patients After Oncotype DX Testing

11.2% HT alone to CHT

20.6% CT to HT alone

Global

Therapy

Subset

Therapy

Personalized

Therapy

Challenge 3. Reimbursement and accreditation strategies

of biomarkers unclear/ongoing

Plataforma de biomarcadores SEOM SEAP

Selección de centros

Gestión de recursos (Industria)

Comisiones: evaluación de centros, técnica, ética