Dr. Luis M. Zetina Toaché Oncomédica. Multimédica

GENOMICA EN CANCER DE PULMON

Clin

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20

20092013

Updates in Community Oncology 2011: A Focus on Non-Small-Cell Lung Cancer

20142015

“ It is much more important to know what kind of patient has a disease, than to know what kind of disease a patient has”

Caleb Parry. 18th Century physician, Bath.

“We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes”

J.D Watson. Time Magazine 20 March 1989

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

65-yr-old malesmoker,

squamous

KRAS Mt

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

In 2012: Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

39-yr-old female

never-smoker,adenoca

EGFR Mt

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

In 2012: Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy

65-yr-old malesmoker,

squamous

KRAS Mt

ALK fusion

54-yr-old malenever-smoker,

adenoca

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy

39-yr-old female

never-smoker,adenoca

EGFR Mt

65-yr-old malesmoker,

squamous

KRAS Mt

Non-small-cell lung cancer (NSCLC)

Presented By Daniel Costa at 2014 ASCO Annual Meeting

Only a fraction of molecular aberrations are clinically relevant

Presented By David Gerber at 2014 ASCO Annual Meeting

Competition is fierce

Report, Medicines in Development for Cancer, PhRMA, www.phrma.org,

136

136

GENOMICA EN CANCER DE PULMON

OBJETIVOS DE LA CONFERENCIA1. Epidemiologia (CA y Caribe)2. Historia del Dx. y Tx. ( Pesimismo) 3. Blancos terapéuticos (Genómica)4. Resultados de Terapia Blanco

(Optimismo)5. Inmunoterapia.. (El Futuro…)6. Optimismo…..

30 million ptes living with cancer 2015

CA&C: 255,900 CASES

173

134

TER

CER

O IN

CID

ENC

IA

PR

IME

RO

MO

RTA

LID

AD

581 328 390

235 299 349

2182

6943

5333 985 425

148 22 30

TOTAL

case

s of L

ung Cance

r: 9

125

TOTAL

case

s of C

ancer:

101900

(11%)

QT 1era linea NSCLC avanzado llego

“PLATEAU”

Urgente necesidad de Nuevos opciones de

tratamiento

1990s

Schiller JH, et al. N Engl J Med 2002;346:92–8

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25 30Meses

Cisplatino/paclitaxel (R)Cisplatino/gemcitabineCisplatino/docetaxelCarboplatino/paclitaxel (R)

dis

trib

uti

on

fu

nct

ion

SV

ida

1930 1940 1950 1960 1970 1980 1990 2000 2010

Sv ½ 7.9mTR: 19%

Carcinoma PulmonarHistoria . E1594 (n=1155)

. Adapted from Hanahan and Weinberg. Cell. 2000;100:57.

Evadingapoptosis

Self-sufficiency in growth signals

Tissue invasionand metastasis

Limitless replicative potential

Sustainedangiogenesis

Insensitivity to antigrowth signals

Cancercells

Fundamental Hallmarks of Cancer

Updates in Community Oncology 2011: A Focus on Non-Small-Cell Lung Cancer

History of Therapy in Advanced NSCLC: FDA Approval Dates

First lineSecond lineThird lineMaintenanceNot approved

1970 1980 1990 2000

MedianOS (mos)

12+

~ 6~ 2-4

BSC Single-agent platinum Doublets

Bevacizumab + PC

Carboplatin*1989

ErlotinibPemetrexed

2004

Docetaxel1999

PaclitaxelGemcitabine

1998

Vinorelbine1994

Docetaxel2002

Bevacizumab2006

Gefitinib2003

Standard therapies

*Label does not include NSCLC-specific indication Pemetrexed

2008/2009

Histology-directed therapy

~ 8-10

Cisplatin*1978

1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

. Adapted from Hanahan and Weinberg. Cell. 2000;100:57.

Evadingapoptosis

Self-sufficiency in growth signals

Tissue invasionand metastasis

Limitless replicative potential

Sustainedangiogenesis

Insensitivity to antigrowth signals

Cancercells

Fundamental Hallmarks of Cancer

Numerous driver mutations have been identified in NSCLC

Presented By David Gerber at 2014 ASCO Annual Meeting

KRAS mutations are the most common genomic alteration in lung adenocarcinoma

Presented By David Gerber at 2014 ASCO Annual Meeting

Epidermal growth factor receptor (EGFR) pathway

Presented By Daniel Costa at 2014 ASCO Annual Meeting

Prevalence of EGFR Mutations by Smoking Status

EGFR mutation status (exons 19 and 21) determined in 2142 adenocarcinoma samples from Memorial Sloan- Kettering Cancer Center

Incidence of EGFR mutations in tumors– 52% of never smokers– 15% of former smokers– 6% of current smokers

D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070.

EGFR Mutations Detected

Never (n = 302)

Current (n = 20)

Former (n = 181)

36%

4%

60%

Gefitinib as first line therapy for EGFR mutated NSCLC: Legacy of the IPASS (IRESSA Pan-Asia Study) trial

Presented By Daniel Costa at 2014 ASCO Annual Meeting

EGFR TKIs as first line therapy for EGFR mutated NSCLC: <br />gefitinib (NEJ 002) and erlotinib (EURTAC) vs chemotherapy

Presented By Daniel Costa at 2014 ASCO Annual Meeting

Trial Treatment N RR, % Median PFS, Mos Median OS, Mos

TKI Chemo TKI Chemo TKI Chemo

NEJ002[1] Gefitinib vs carboplatin/paclitaxel

230 74 31 10.8 5.4 30.5 23.6

WJTOG3405[2] Gefitinib vs cisplatin/docetaxel

172 62 32 9.2 6.3 30.9 Not reached

OPTIMAL[3] Erlotinib vs carboplatin/gemcitabine

165 83 36 13.1 4.6 NR Not reported

EURTAC[4] Erlotinib vs platinum-based

doublet174 58 15 9.7 5.2 NR Not

reported

Prospective Trials of EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients

1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 4. Rosell R, et al. ASCO 2011. Abstract 7503.

Evidence-based use of EGFR TKIs (gefitinib, erlotinib and afatinib) for EGFR-L858R or exon 19 deletions mutated advanced NSCLCs as first line systemic therapy

Presented By Daniel Costa at 2014 ASCO Annual Meeting

Slide 5

Presented By Leena Gandhi at 2014 ASCO Annual Meeting

Crizotinib in Patients With Advanced ALK-Positive NSCLC

Crizotinib (PF-02341066)– Dual selective inhibitor of ALK and c-MET

• ATP-competitive inhibitor• Orally available small molecule

– Potent inhibition of cell growth and induction of apoptosis in NSCLC cell lines

– Demonstrated safety in dose-escalation study

1. Tan W, et al. ASCO 2010. Abstract 2596.

RESPONSES SEEN TO CRIZOTINIB, AN ALK AND C-MET INHIBITOR, IN ALK-REARRANGED NSCLC PATIENTS ON PHASE I TRIAL

Presented By Leena Gandhi at 2014 ASCO Annual Meeting

EML4-ALK FUSION???

Slide 10

Presented By Leena Gandhi at 2014 ASCO Annual Meeting

Kinase inhibitors in driver oncogene mutant cancers: <br />EGFR TKIs in comparison to other approved inhibitors

Presented By Daniel Costa at 2014 ASCO Annual Meeting

TARGETED THERAPY FOR ONCOGENIC DRIVER ALTERATIONS

Presented By Leena Gandhi at 2014 ASCO Annual Meeting

The immunoediting hypothesis suggests that clinically evident cancer arises when the control mechanisms of the immune system are breached thus leading to escape and a

cascade of tumor proliferation associated with relative immune paresis.

Patrick M. Forde et al. The Oncologist 2013;18:1203-1213

©2013 by AlphaMed Press

CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma

Yuan J et al. PNAS 2008;105:20410-20415

Polyfunctional NY-ESO-1 antigen-specific T cells secreted higher levels of IFN-γ after anti-CTLA-4 antibody treatment.

Immune checkpoint modulation for advanced NSCLC.

Patrick M. Forde et al. The Oncologist 2013;18:1203-1213

©2013 by AlphaMed Press

Why Perform Molecular Testing?

Outcomes of Molecular Testing

For predictive and prognostic value

Predictive: Who is likely to do better with a particular therapy?

Prognostic: Who is likely to do better or worse, independent of therapy?

To improve clinical outcomes

Give best treatments first (eg, consider timing of EGFR TKI)

Provide access to agent (eg, crizotinib for ALK-positive NSCLC)

Identify subsets who might benefit from targeted therapy (eg, cetuximab)

To facilitate clinical research

May improve patient outcomes Better understanding of molecular oncology

Diagnosis Tumor is resected and measured

Stage IA+B: Observation

Stage II-IIIA: Adjuvant therapy

Early-Stage NSCLC Treatment Protocol

Who to treat? 27% of stage IA and 42% of stage IB patients recur and die

– Q: How to identify individuals at higher risk? 41% of patients with stage II NSCLC are cured with surgery alone and

do not need adjuvant treatment– Q: How to identify patients that can be cured by surgery alone?– Q: How can patient selection among those given adjuvant

therapy improve HR and cure rate?

Importance of Molecular Staging

LUNG

COMPROBACION POR IHQ

thyroid transcription factor 1

RESPONSE TO TK

EGFR MUTATION ANALYSYSCENTRAL & CARIBBEAN

CDDP

TK

PEMETREXED

CETUXIMAB

Muchas GraciasThank you