This document discusses heterogeneity in non-small cell lung cancer (NSCLC) and the importance of personalized treatment based on molecular profiling. It presents four hypothetical patients with stage IV NSCLC who differ in their clinical features, molecular characteristics, and appropriate therapies. For example, a younger female never-smoker with an EGFR mutation should receive an EGFR tyrosine kinase inhibitor, while an older male smoker with a KRAS mutation may not benefit from such targeted therapies. The document emphasizes that molecular testing is needed to determine the optimal treatment for each patient's specific cancer.

2. ClinicalCareOptions,LLCinPartnershipwithOncologyToday
20
20092013

3. Updates in Community Oncology 2011: A Focus on Non-Small-Cell Lung Cancer
20142015

5. “ 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

6. Patients With the Same Diagnosis and Clinical Features
(Stage IV NSCLC)
65-yr-old male
smoker,
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

7. 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 male
smoker,
squamous
KRAS Mt

8. ALK fusion
54-yr-old male
never-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 male
smoker,
squamous
KRAS Mt

9. Non-small-cell lung cancer (NSCLC)
Presented By Daniel Costa at 2014 ASCO Annual Meeting

10. Only a fraction of molecular aberrations are clinically relevant
Presented By David Gerber at 2014 ASCO Annual Meeting

11. Competition is fierce
Report, Medicines in Development for Cancer, PhRMA, www.phrma.org,
136
136

12. GENOMICA EN CANCER DE PULMON
OBJETIVOS DE LA CONFERENCIA
1. 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…..

13. 30 million ptes living with cancer 2015
CA&C: 255,900 CASES
173
134

18. 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 30
Meses
Cisplatino/paclitaxel (R)
Cisplatino/gemcitabine
Cisplatino/docetaxel
Carboplatino/paclitaxel (R)
distributionfunctionSVida
1930 1940 1950 1960 1970 1980 1990 2000 2010
Sv ½ 7.9m
TR: 19%
Carcinoma Pulmonar
Historia . E1594 (n=1155)

19. . Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Evading
apoptosis
Self-sufficiency in
growth signals
Tissue invasion
and metastasis
Limitless replicative
potential
Sustained
angiogenesis
Insensitivity to
antigrowth signals
Cancer
cells
Fundamental Hallmarks of Cancer

22. Updates in Community Oncology 2011: A Focus on Non-Small-Cell Lung Cancer
History of Therapy in Advanced NSCLC:
FDA Approval Dates
First line
Second line
Third line
Maintenance
Not approved
1970 1980 1990 2000
Median
OS (mos)
12+
~ 6
~ 2-4
BSC Single-agent platinum Doublets
Bevacizumab + PC
Carboplatin*
1989
Erlotinib
Pemetrexed
2004
Docetaxel
1999
Paclitaxel
Gemcitabine
1998
Vinorelbine
1994
Docetaxel
2002
Bevacizumab
2006
Gefitinib
2003
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.

23. . Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Evading
apoptosis
Self-sufficiency in
growth signals
Tissue invasion
and metastasis
Limitless replicative
potential
Sustained
angiogenesis
Insensitivity to
antigrowth signals
Cancer
cells
Fundamental Hallmarks of Cancer

25. Numerous driver mutations have been identified in NSCLC
Presented By David Gerber at 2014 ASCO Annual Meeting

26. KRAS mutations are the most common genomic alteration in lung adenocarcinoma
Presented By David Gerber at 2014 ASCO Annual Meeting

28. Epidermal growth factor receptor (EGFR) pathway
Presented By Daniel Costa at 2014 ASCO Annual Meeting

31. 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%

33. 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

34. 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

35. 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
doublet
174 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.

36. 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

38. Slide 5
Presented By Leena Gandhi at 2014 ASCO Annual Meeting

40. 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.

41. 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

42. EML4-ALK FUSION???

44. Slide 10
Presented By Leena Gandhi at 2014 ASCO Annual Meeting

46. 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

47. TARGETED THERAPY FOR ONCOGENIC DRIVER ALTERATIONS
Presented By Leena Gandhi at 2014 ASCO Annual Meeting

50. 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

52. 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.

53. Immune checkpoint modulation for advanced NSCLC.
Patrick M. Forde et al. The Oncologist 2013;18:1203-1213
©2013 by AlphaMed Press

55. 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

56. 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

59. LUNG
COMPROBACION POR IHQ
thyroid transcription
factor 1

60. RESPONSE TO TK
EGFR MUTATION ANALYSYS
CENTRAL & CARIBBEAN

61. CDDP
TK
PEMETREXED
CETUXIMAB