1. Advances and Emerging Therapy for Lung Cancer
Rachel E. Sanborn, M.D.
Providence Cancer Center

2. Early-Stage Disease

3. Definitive Therapy Surgical resection is preferred
Survival with resection alone:
Stage I: %
Stage II: 50%

4. Adjuvant Therapy for Resected Disease

5. Adjuvant Chemotherapy, 1
4 cycles of Cisplatin-based therapy
Improves 5-year survival 4-17%
Benefit in patients with nodal or later-stage disease
Less benefit in stage I tumors

6. Adjuvant Chemotherapy, 2
Carboplatin-based therapy
No survival benefit

7. Adjuvant Chemotherapy, Questions
Will addition of targeted agents improve survival?
Will predictive markers help to guide who needs or benefits from adjuvant therapy?

8. Adjuvant Therapy--Questions
Which agents?
Stage I disease?
How far out to treat before “window of opportunity” is lost?

9. Locally-Advanced Disease: Mediastinal Nodal Involvement or Invasive Tumors

10. Neoadjuvant Therapy

11. Neoadjuvant Therapy
Smaller phase III trials (60 pts), both stopped early
Stage IIIA
Survival advantage with neoadjuvant chemotherapy
Med survival 26 mo vs 8 mo; P<0.001
64 mo vs 11 mo; P<0.008
Rosell et al, NEJM 1994; Roth et al, JNCI 1994

12. SWOG 9900 Arm A: Carboplatin/Paclitaxel X3 cycles R ANDOM I Z E
Resectable NSCLC,
354/600 Planned Patients
Surgery
Arm B:
Surgery Alone
Pisters et al, ASCO 2005; abstr 7012

13. SWOG 9900, Early Results Chemo + Surgery Surgery P
Med PFS 31 mo 20 mo 0.26
Overall Survival 47 mo 40 mo 0.47
Pisters et al, ASCO 2005; abstr 7012

14. Neoadjuvant Therapy
For patients with advanced but potentially resectable disease, possible benefit to survival
Possible increase in surgical resectability rate
Some trial interpretation confounded by adjuvant therapy, adjuvant radiation
Is benefit equivalent to adjuvant therapy?

15. Definitive Therapy for Unresectable Disease: Combined Modality Therapy

16. Initial Combination Trial
Randomized to Radiation vs
Chemo Radiation
Increased median survival from
9.7 months to 13.8 months
Increased 3-Y OS from 11% to 26%
Dillman et al, NEJM 1990

17. Chemo/RT Combinations
Chemo/RT combination shown better than sequential (Cisplatin-based combination)
Median survival increased from 13.3 mo to 16.5 mo
5-Y OS increased from 8.9% to 15.8%
Furuse et al, JCO 1999

18. Concurrent vs Sequential Tx
Fig 1. Overall survival in patients with NSCLC according to treatment group
Furuse, K. et al. J Clin Oncol; 17:

19. SWOG 9019 Stage IIIB only, 50 patients
Cisplatin/Etoposide/Concurrent TRT
Median OS 15 months
5-Y OS 15%
Albain et al, JCO 2002

20. Carboplatin-based chemo/RT
Median survival 11.4 months with concurrent treatment
Median survival 14 months with induction followed by concurrent treatment
P=0.154
Results consistently inferior to cisplatin
Vokes et al, PASCO 2004

21. Consolidation: Chemo After Chemo/RT

22. SWOG 9504 Med Surv 3-Y OS 4-Y OS 5-Y OS PE/RT Docetaxel S9504 26m 40%
29%
PE/RT PE
S9019
15m
17%
Gandara et al, ASCO 2005, abstr 7059

23. SWOG 0023 R ANDOM I Z E Gefitinib Cis/Etop Concurrent RT Consolidation
Docetaxel
Placebo
Kelly et al, ASCO 2007; abstr 7513

24. Overall Survival From Randomization
Median
1 YR OS
2 YR OS N
Events
in Months
100%
Gefitinib
118 71 23
73%
46%
Placebo
125 54 35
81%
59%
80%
P = .01
60%
Overall survival from the time from randomization was 23 months for gefitinib compared to 35 months for placebo. The p value for the test of the null hypothesis is 0.01.
40%
Median FU time:
27 months
20% 0% 12 24 36 48 60
Kelly et al, ASCO 2007; abstr 7513
Months After RANDOMIZATION

25. SWOG 0023 Closed after DSMB interim analysis Gefitinib Placebo P
Median PFS 11m 10m NS
Dead from Cancer 86% 80%
Dead from Toxicity 3% 0%
Overall Survival 23m 35m
Kelly et al, ASCO 2007; abstr 7513

26. HOG Phase III; Replicating SWOG 9504
R ANDOM I Z E
Consolidation
Docetaxel
IIIA/B
243/259
Patients randomized
Cis/Etop
Concurrent RT
Observation
Hanna et al, ASCO 2007; abstr 7512

27. Overall Survival (ITT) Randomized Patients (n=147)
Observation: Median: 24.1 months ( )
3 year survival rate: 27.6%
Docetaxel: Median: 21.5 months ( )
3 year survival rate: 27.2%
P-value: 0.940
Hanna et al, ASCO 2007; abstr 7512

28. HOG, Phase III Results DSMB interim analysis
Closed after 203 pts due to futility
Docetaxel Observation P
Median PFS 12.3m 12.9m 0.94
Median Survival 24.3m 26m
Hospitalizations 28.8% 8.1%
Toxic Death 5.5%
Hanna et al, ASCO 2007; Mina et al, ASCO 2008

29. Metastatic Disease

30. Chemo or Hospice? Median survival with Best Supportive Care: 5 months
Spiro et al, Thorax 2004
BMJ Meta-Analysis, 1995
Detriment with long-term alkylating agents suggested (AKA: Old Chemo)
Cisplatin-Based Trials
10% absolute improvement in 1-Y OS, (5% to 15%)
Increased median survival 6 weeks

31. Chemo or Hospice? Median survival with Best Supportive Care: 5 months
Spiro et al, Thorax 2004
BMJ Meta-Analysis, 1995
Detriment with long-term alkylating agents suggested
Cisplatin-Based Trials
10% absolute improvement in 1-Y OS, (5% to 15%)
Increased median survival 6 weeks

32. Chemotherapy First-Line

33. Comparison Trial Cisplatin/Paclitaxel Cisplatin/Gemcitabine
Cisplatin/Docetaxel
Carboplatin/Paclitaxel
Schiller et al, NEJM 2002

34. Median Survival: 8 mo 1-Y Survival: 34% 2-Y Survival: 12%
Schiller et al, NEJM 2002

35. Median Survival: 8 mo 1-Y Survival: 34% 2-Y Survival: 12%
Schiller et al, NEJM 2002

36. Targeted Agents— Bevacizumab

37. Why Target VEGF?
Actively proliferating tumor cells express more Vascular endothelial growth factor (VEGF) than nonproliferating cells1
VEGF may act as an autocrine growth factor1
VEGF expression is upregulated in many cancer types, including NSCLC2-4
Elevated serum VEGF levels have been associated with poorer outcomes in limited- or early-stage disease2,5-7
KEY POINT: Tumor-derived signals result in high levels of VEGF expression, which correlates with poor prognosis and malignant progression.
Mandatory Slide
ADDITIONAL INFORMATION
Vascular endothelial growth factor (VEGF) is implicated in tumor biology because it is upregulated by tumor-derived signals1-5 and is overexpressed by many tumor types, including NSCLC.4,6,7 High VEGF levels are also correlated with malignant progression and poorer outcomes in limited-and early-stage disease7-10
As observed in tumor malignancy in general, the process of angiogenesis may play a critical role in tumor growth and metastasis of lung cancer.11 A large body of scientific research suggests a strong association between VEGF and increased microvessel density (one of the primary measurements of angiogenesis) in lung cancer. Moreover, VEGF and microvessel density have been shown to correlate with a range of prognostic parameters, including tumor size and metastasis, cancer recurrence, and overall and disease-free survival
REFERENCES
Shweiki et al. Proc Natl Acad Sci U S A :768–772.
Rak et al. Cancer Metastasis Rev. 1995;14:263–277.
Kieser et al. Oncogene. 1994;9:963–969.
Ravindranath et al. J Androl. 2001;22:432–443.
Horiguchi et al. Endocrine. 2004;24:141–146.
Lantuejoul et al. J Pathol. 2003;200:336–347.
Yuan et al. Int J Cancer Pred Oncol. 2000;89:475–483.
Shimanuki et al. Lung. 2005;183:29–42.
Hasegawa et al. Intern Med. 2005;44:26–34.
Mineo et al. J Clin Pathol. 2004;57:591–597.
Hicklin et al. J Clin Oncol. 2005;23:1011–1027.
1. Mattern et al. Br J Cancer. 1996;73:931– Yuan A et al. Int J Cancer Pred Oncol. 2000;89:475–483.
3. Lantuejoul et al. J Pathol. 2003;200:336– Ravindranath et al. J Androl. 2001; 22:432– Shimanuki et al. Lung. 2005;183:29–42.
6. Hasegawa et al. Intern Med. 2005;44:26– Mineo et al. J Clin Pathol. 2004;57:591–597.

38. VEGF: A Key Mediator of Angiogenesis
Environmental factors
(Hypoxia, pH)
Growth factors
Hormones
(EGF, bFGF, PDGF,
IGF-1, IL-1, IL-6, estrogen)
Genes involved in tumorigenesis
(p53, p73, src, ras, vHL, bcr-abl)
Increased VEGF levels
Binding and activation of VEGFR P P
Endothelial cell
activation P P
KEY POINT: A number of environmental, hormonal, and genetic factors can lead to VEGF overexpression.
ANGIOGENESIS
Proliferation
Survival
Migration
Mandatory Slide
ADDITIONAL INFORMATION
VEGF plays a key role in the regulation of angiogenesis1
Many environmental factors, including hypoxia and low pH, stimulate the expression of VEGF1
Hormones (eg, progesterone, estrogen), growth factors (eg, epidermal growth factor [EGF], transforming growth factor-beta [TGF-], basic fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], insulin-like growth factor [IGF]-1), and cytokines (eg, interleukin [IL]­1, IL-6) also stimulate VEGF expression1
In addition to exogenous factors, many tumorigenic mutations lead to VEGF upregulation1,2
This can include mutations in cellular oncogenes, such as src, ras, and bcr-abl
Mutations in tumor suppressor genes such as p53, p73, and vHL also lead to upregulation of VEGF
VEGF then binds and activates its receptors, stimulating signaling cascades involving phospholipase C, the nonreceptor tyrosine kinase src, phosphatidylinositol-3-kinase, and ras guanosine triphosphatase (GTP-ase) activating protein3
Downstream signaling events lead to inhibition of apoptosis, stimulation of mitosis, and cytoskeletal changes associated with motility and vascular permeability3
REFERENCES
1. Dvorak. J Clin Oncol. 2002;20:4368–4380.
2. Ebos et al. Mol Cancer Res. 2002;1:89–95.
3. Ferrara et al. Nat Med. 2003;9:669–676.
bFGF, basic fibroblastic growth factor; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor.
1. Dvorak. J Clin Oncol. 2002;20:4368–4380; 2. Ebos et al. Mol Cancer Res. 2002;1:89–95; 3. Ferrara et al. Nat Med. 2003;9:669–676.

39. Summary of Anti-VEGF Proposed Mechanisms of Action Based on Preclinical Models1
May regress existing microvasculature1,2
KEY POINT: Based on preclinical models, anti-VEGF agents are thought to have a triple MOA that includes regression of existing microvasculature, normalization of surviving vasculature, and inhibition of vessel regrowth and neovascularization. 2
May normalize surviving mature vasculature3-5
Mandatory Slide
ADDITIONAL INFORMATION
This is a graphic representation and summary of the triple mechanism of action (MOA) of anti-VEGF agents, along with the consequences of their actions
May regress existing microvasculature1,2
Direct and rapid changes include a significant reduction in microvascular density, as seen in preclinical models1-3
May normalize surviving mature vasculature3-5
Reversal of structural and functional abnormalities may improve the vasculature’s capacity for drug delivery, as seen in preclinical models3-5
May inhibit vessel regrowth and neovascularization2,3,6
Genentech is pursuing research to expand the understanding of the MOA of bevacizumab and other monoclonal antibodies that bind to VEGF
REFERENCES
Lee et al. Cancer Res. 2000;60:5565–5570.
Inai et al. Am J Pathol. 2004;165:35–52.
Gerber et al. Cancer Res. 2005;65:671–680.
Jain. Science. 2005;307:58–62.
Tong et al. Cancer Res. 2004;64:3731–3736.
Hicklin et al. J Clin Oncol. 2005;23:1011–1027. 3
May inhibit vessel regrowth and neovascularization2,3,6
1. Lee et al. Cancer Res. 2000;60:5565–5570; 2. Inai et al. Am J Pathol. 2004;165:35–52; 3. Gerber et al. Cancer Res. 2005;65:671–680; 4. Jain Science. 2005;307:58–62; 5. Tong et al. Cancer Res. 2004;64:3731–3736; 6. Hicklin et al. J Clin Oncol. 2005;23:1011–1027.

40. Avastin® (bevacizumab)
Recombinant humanized monoclonal IgG1 antibody
Recognizes all isoforms of VEGF-A and blocks VEGF function
Half-life is approximately 20 days (range, 11 to 50 days)
KEY POINT: Bevacizumab is a recombinant humanized monoclonal immunoglobulin (IgG) antibody that binds all isoforms of VEGF-A.
Mandatory Slide
ADDITIONAL INFORMATION
Bevacizumab is a recombinant humanized mAb of the lgG1 isotype1
Bevacizumab binds all isoforms of VEGF(-A)2
At least 4 different VEGF isoforms, with different molecular weights (121, 165, 189, and 206 kDa) and heparin-binding properties, are created by alternative splicing of the VEGF(-A) gene.
The estimated half-life of bevacizumab is 20 days (range, 11 to 50 days)1
Blockade of VEGF with bevacizumab inhibited VEGF-induced proliferation of endothelial cells in vitro and tumor growth in vivo3
REFERENCES
1. Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.
2. Ferrara et al. Nat Med. 2003; 9:669–676.
3. Presta et al. Cancer Res. 1997;57:4593–4599.
Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.

41. Randomized Phase II/III
Arm A:
Carboplatin/Paclitaxel
+Placebo
R ANDOM I Z E
Advanced Non-Squamous NSCLC,
855 Patients
Bev until
progression
Arm B:
Carboplatin/Paclitaxel
+Bevacizumab
Sandler et al, NEJM 2006

42. Exclusion Squamous cell carcinoma Central tumors
Brain mets (Actively screened for prior to enrollment)
Hemoptysis
Anticoagulation (Except ASA 81mg)
Sandler et al, NEJM 2006

43. Phase III: Overall Survival
1.0
12 mo 24 mo Median
PC 44.4% 15.4% mo
0.8
BV/PC 51.0% 22.0% mo
Median 12.3 mo
HR: 0.80, P = .013
0.6
Proportion surviving
Median 10.3 mo
0.4
0.2
KEY POINT: Overall survival was significantly prolonged by the addition of bevacizumab to paclitaxel and carboplatin.
0.0
Mandatory Slide
ADDITIONAL INFORMATION
A significantly higher percentage of patients in the bevacizumab group were alive at 12 months (51% vs 44.4%) and 24 months (22% vs 15.4%)
The median overall survival was 12.3 months vs 10.3 months for the bevacizumab plus PC group vs PC alone
The hazard ratio was 0.80, with a 20% relative reduction in the risk of death; P = .013
REFERENCES
Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006. 6 12 18 24 30 36 42 48
Patients at risk PC
444
318
190
104 36 9 5 1
BV/PC
434
340
216
127 54 25 8 3
Months
Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.

44. Carbo/Tax/Bevacizumab: Toxicities
HTN
Neutropenia
Hemorrhage
Proteinuria
Thromboembolism

45. PCB Conclusions
Significant gains in survival for patients treated with bevacizumab
Carboplatin/Paclitaxel/Bevacizumab has become new treatment standard for many cooperative groups
(For this patient population)
Sandler et al, NEJM 2006

46. Targeted Agents— Cetuximab

47. The HER Family of Receptors
EGF
TGF
Amphiregulin
Betacellulin
HB-EGF
Epiregulin
NRG2
NRG3
Heregulins
Betacellulin
Heregulins
Ligand-binding
domain
Transmembrane
HER1 is also known as EGFR, or erb-b1, and is a member of a family of membrane receptor tyrosine kinases known as the HER family, which also includes HER2, HER3, and HER4.
These receptors have different ligand-binding affinities, as shown in this slide.
Epidermal growth factor (EGF) and transforming growth factor alpha (TGF) are the 2 most important ligands of HER1.
The neuregulins (NRGs) are important ligands for HER3 and HER4.
In normal cells, HER2 is intrinsically devoid of any ligand-binding activity. It is an important signaling partner of HER1 and HER3, and functions as a coreceptor.
Ligand binding leads to receptor interaction, and the resulting stearic change activates the intrinsic kinase activity of these HER family receptor tyrosine kinases.
The activated kinase phosphorylates itself and its partner on conserved tyrosine residues and initiates a signal transduction cascade, that eventually activates key regulators like mitogen-activated protein kinase (MAPK) and PI3K.
All HER family proteins, with the exception of HER3, have intrinsic kinase activity.
Since 1984, it has been recognized that HER1 can be overexpressed in lung cancer.
HER2 appears to be less frequently expressed in NSCLC; expression levels of HER1 and HER2 are independent.
Considerably less information is available on the expression of HER3 and HER4 in lung cancer. Patterns of coexpression of HER3 and HER4 are not well defined.
Tyrosine
kinase
domain
HER1
erb-b1 EGFR
HER2
erb-b2 neu
HER3
erb-b3
HER4
erb-b4
Roskoski. Biochem Biophys Res Commun. 2004;319:1.
Rowinsky. Annu Rev Med. 2004;55:433.
Franklin WA, Veve R, Hirsch FR, et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol. 2002;29(suppl4):3-14.
Roskoski R Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:1-11.
Rowinsky EK. The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:

48. Potential Consequences of EGFR Dysregulation
Signaling
cascades
EGFR
PI3K
MAPK
Nucleus
Gene activation Cell cycle progression M G1 S G2
Myc
Fos
Jun P
Invasion
Angiogenesis
Metastasis
Proliferation
Cell surface receptors bind ligands that activate the receptor and regulate cell functions.
EGFR can bind EGF as well as several other ligands (eg, TGF).
The binding of ligand results in 2 receptors joining together in a process known as dimerization.
Upon dimerization, the intracellular tyrosine kinase domains of the receptor may transphosphorylate the dimer partner, initiating a signaling cascade. Subsequent transduction of the signal to the nucleus leads to regulation of genetic functions, such as gene activation/suppression and cell cycle regulation.
In malignancies, such as NSCLC, overexpression or dysregulation of EGFR may increase the signaling response and result in
Cell cycle progression leading to cellular proliferation.
Decreased apoptotic response leading to increased cellular survival even in the presence of abnormal cell functions resulting from toxic stimuli such as radiation or chemical damage.
Production of cell factors that promote angiogenesis and further cellular proliferation.
Increased invasiveness and metastasis.
Survival
Apoptosis
MAPK = mitogen-activated protein kinase.
Roskoski. Biochem Biophys Res Commun. 2004;319:1.
Rowinsky. Annu Rev Med. 2004;55:433.
Roskoski R Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:1-11.
Rowinsky EK. The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:

49. Epidermal Growth Factor Receptor
EGFR expression upregulated in a number of cancers
Most NSCLC found to express EGFR
Inhibition of EGFR can induce apoptosis and reduce tumor proliferation

50. EGFR-Targeted Approaches
TOXIN
There are a number of ways to target EGFR dysregulation.
Antibodies against EGFR can act as receptor antagonists and prevent ligand binding, eg, cetuximab.
Antibodies may prevent receptor dimerization, eg, trastuzumab (HER2).
Antibodies against ligand also block binding, and this approach may be useful when 1 ligand binds to several receptors.
Using a small molecule that specifically targets and either reversibly or irreversibly inhibits the tyrosine kinase activity is an approach that may block signaling by all active EGFR forms, including those receptors with mutated or deleted extracellular domains.
Erlotinib and gefitinib are 2 ATP-competitive inhibitors of the EGFR tyrosine kinase.
Mutations in the tyrosine kinase domain that lead to increased growth factor signaling correlate with increased clinical responsiveness to these TKIs. These mutations may result in increased sensitivity to erlotinib and gefitinib.
Further prospective studies are required to better understand the prognostic and predictive value of EGFR tyrosine kinase domain mutations.
Conjugates of a ligand and a cytotoxic agent (eg, TP-38 and DAB389EGF) or an antibody and a cytotoxic agent (eg, scFv-14e1-ETA fusion toxin) are another approach that may have the advantage of killing the cell after internalization, in addition to inhibiting tyrosine kinase activity.
Anti-EGFR
blocking
antibodies
Antiligand
blocking
antibodies
Tyrosine
kinase
inhibitors
Ligand-
toxin
conjugates
HER dimerization
inhibitors
Adapted from Noonberg and Benz. Drugs. 2000;59:753.
Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs. 2000;59:
Erbitux® [package insert]. Branchburg, NJ, and Princeton, NJ: ImClone Systems and Bristol-Myers Squibb Company; 2004.
Sampson JH, Akabani G, Archer G, et al. Clinical outcome and distribution measure of a recombinant chimeric protein composed of transforming growth factor alpha and a mutated Pseudomonas exotoxin (TP-38) via convection-enhanced microinfusion on a phase I study for malignant brain tumor. Proc Am Soc Clin Oncol. 2003;22:99. Abstract 397.
Frankel AE, Liu TF, Thorburn AM, Tatter SB, Willingham MC. Recombinant toxin DAB389EGF produces regressions of human glioma xenografts in nude mice. Proc Am Soc Clin Oncol. 2004;23:220. Abstract 3101.
Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(suppl 4):2-8.

51. Cisplatin/Vinorelbine/Cetuximab
Randomized Phase III trial
Cis/Vinorelbine
With or without Cetuximab
Cetuximab till disease progression
Pirker et al, PASCO 2008

52. Cetuximab Toxicity with Chemo
Rash
Febrile neutropenia
No difference in treatment-related mortality
Pirker et al, PASCO 2008

54. Conclusions
Cetuximab added to first line chemotherapy with CV demonstrated superior survival over CV alone in patients with EGFR detectable advanced NSCLC
Would other platin-based combinations have a more acceptable toxicity profile?

55. Conclusions
Cetuximab added to first line chemotherapy with CV demonstrated superior survival over CV alone in patients with EGFR detectable advanced NSCLC
Would other platin-based combinations have a more acceptable toxicity profile?
Further refining patient selection may increase the current modest survival benefit
EGFR FISH
KRAS mutation

56. Chemotherapy Second-Line

57. Second-Line Therapy
Chemotherapy with newer agents (docetaxel) given second-line:
Improved survival from 4.6 months (Best supportive care)
To 5.9 months
1-Y survival from 11% to 19%
Shepherd et al, JCO 2000

58. Docetaxel Survival Curve
Improvement in overall QOL, pain, appetite, and fatigue with Docetaxel compared with BSC
Shepherd et al, JCO 2000

59. Pemetrexed Median Survival: 8.3 months 1-Y Survival: 29.7% Arm A:
R ANDOM I Z E
Recurrent NSCLC,
571 Patients
Median Survival:
7.9 months
1-Y Survival:
29.7%
Arm B:
Docetaxel
Hanna et al, JCO 2004

60. Pemetrexed Median Survival: 8.3 months 1-Y Survival: 29.7% Arm A:
R ANDOM I Z E
Recurrent NSCLC,
571 Patients
Median Survival:
7.9 months
1-Y Survival:
29.7%
Arm B:
Docetaxel
Hanna et al, JCO 2004

61. Targeted Agents— Erlotinib

62. Proposed Mechanism of Action of EGFR-Targeted TKIs
Inhibit EGFR kinase activity P P
Phosphorylation P
PI3K P
MAPK
Mandatory Slide
While their mechanism of action has not been fully characterized, it is postulated that EGFR TKIs inhibit EGFR tyrosine kinase activity by preferentially occupying the ATP binding site within the intracellular TKD.
Bind at a higher affinity than the ATP substrate
Prevent receptor phosphorylation and signal activation
The prevention of signal transduction within the tumor cell may have several potential antitumor effects
Decreases activation of antiapoptotic genes, thereby increasing the rate of apoptosis
Decreases activation of genes promoting cell cycle progression
Reduces angiogenic signals
The potential net effects are tumor growth inhibition and tumor shrinkage.
While HER1 TKIs downregulate MAPK and PI3K activity, they do not directly inhibit these kinases per se. They are thought to elicit their biologic activity by inactivating the tyrosine kinase activity of EGFR, which results in the inhibition of downstream cascades such as MAPK and PI3K. No
signaling
BCL2
BAX M G1 G2 S
Tumor cell survival
Apoptosis
G1 arrest
Tumor cell proliferation
Arteaga. Semin Oncol. 2003;30(suppl 7):3.
Arteaga. Semin Oncol. 2003;30(suppl 7):3.

63. Erlotinib single agent trial
Arm A:
Erlotinib
R ANDOM I Z E
Advanced NSCLC,
731 Patients
1-2 Prior Chemo Regimens
Arm B:
Placebo
Shepherd et al, PASCO 2004

64. Erlotinib single agent trial
Arm A:
Erlotinib
R ANDOM I Z E
Overall Survival
Erlotinib 6.7 mo
Placebo 4.7 mo
P<0.001
Advanced NSCLC,
731 Patients
1-2 Prior Chemo Regimens
Arm B:
Placebo
Shepherd et al, PASCO 2004

65. Erlotinib Single Agent Survival
Shepherd et al, PASCO 2004

66. Erlotinib in Combination
Study
Patients
Median Survival
Median TTP
TALENT1 (Gem/Cis with Erlotinib or placebo)
1172
301 days v 309 days
167 days v 179 days
TRIBUTE2 (Carbo/Tax with Erlotinib or placebo)
1059
10.8m v 10.6m
5.1m v 4.9m
1. Gatzmeier et al, PASCO Herbst et al, PASCO 2004

67. Chemotherapy for Metastatic Disease
First, second, third-line therapy:
Improves survival
Improves quality of life

68. What next? Histology-derived treatment selection
Treatment/Prognosis driven by molecular profiles
Ongoing efforts to understand interactions between targeted agents and chemo

69. Small Cell Lung Cancer

70. Small Cell Lung Cancer 10-15% new lung cancers are SCLC
Decreasing proportion over time
~32,000 cases yearly

71. SCLC--Staging Limited stage Extensive stage
Involving the ipsilateral hemithorax within a single radiation port
May encompass contralateral hilar nodes
“Not metastatic”, no malignant effusion
Extensive stage
Presence of obvious metastases
Malignant effusion

72. Survival Limited Stage Median survival 3 months without treatment
Median survival months with treatment
~25% 5-year survival*
*Turrisi et al, NEJM, 1999

73. Survival Limited Stage Extensive Stage
Median survival 3 months without treatment
Median survival months with treatment
~25% 5-year survival*
Extensive Stage
Median survival 6 weeks without treatment**
Median survival with treatment 8-11 months***
<5% 2-year survival
*Turrisi et al, NEJM, 1999; **Green et al, Am J Med 1969; ***Aisner et al, JCO 1996

74. Conclusions, SCLC
SCLC is a highly aggressive and rapidly fatal disease
Significant gains in life expectancy and QOL have been made with chemotherapy and radiation
Despite previous gains, plateaus in survival have been reached, and further gains with conventional therapy will be modest at best

75. Lung Cancer: So are we crazy?
Despite pessimism, advances HAVE been made in survival and QOL in treatment of lung cancer
Further advances will require rationally-designed agents and careful monitoring for efficacy

76. Clinical Trials Help to Provide Answers