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

Early-Stage Disease

Definitive Therapy Surgical resection is preferred Survival with resection alone: Stage I: 60-85% Stage II: 50%

Adjuvant Therapy for Resected Disease

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

Adjuvant Chemotherapy, 2 Carboplatin-based therapy No survival benefit

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

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

Locally-Advanced Disease: Mediastinal Nodal Involvement or Invasive Tumors

Neoadjuvant Therapy

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

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

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

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?

Definitive Therapy for Unresectable Disease: Combined Modality Therapy

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

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

Concurrent vs Sequential Tx Fig 1. Overall survival in patients with NSCLC according to treatment group Furuse, K. et al. J Clin Oncol; 17:2692 1999

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

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

Consolidation: Chemo After Chemo/RT

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

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

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

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 0.013 Kelly et al, ASCO 2007; abstr 7513

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

Overall Survival (ITT) Randomized Patients (n=147) Observation: Median: 24.1 months (18.0-34.2) 3 year survival rate: 27.6% Docetaxel: Median: 21.5 months (17.-34.8) 3 year survival rate: 27.2% P-value: 0.940 Hanna et al, ASCO 2007; abstr 7512

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 0.75 Hospitalizations 28.8% 8.1% Toxic Death 5.5% Hanna et al, ASCO 2007; Mina et al, ASCO 2008

Metastatic Disease

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

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

Chemotherapy First-Line

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

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

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

Targeted Agents— Bevacizumab

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. 1995.92:768–772. 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;73:931–934. 2. Yuan A et al. Int J Cancer Pred Oncol. 2000;89:475–483. 3. Lantuejoul et al. J Pathol. 2003;200:336–347. 4. Ravindranath et al. J Androl. 2001; 22:432–443. 5. Shimanuki et al. Lung. 2005;183:29–42. 6. Hasegawa et al. Intern Med. 2005;44:26–34. 7. Mineo et al. J Clin Pathol. 2004;57:591–597.

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.

Summary of Anti-VEGF Proposed Mechanisms of Action Based on Preclinical Models 1 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.

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.

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

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

Phase III: Overall Survival 1.0 12 mo 24 mo Median PC 44.4% 15.4% 10.3 mo 0.8 BV/PC 51.0% 22.0% 12.3 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.

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

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

Targeted Agents— Cetuximab

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;55:433-457.

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;55:433-457.

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

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;59:753-767. 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.

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

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

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?

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

Chemotherapy Second-Line

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

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

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

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

Targeted Agents— Erlotinib

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.

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

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

Erlotinib Single Agent Survival Shepherd et al, PASCO 2004

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 2004 2. Herbst et al, PASCO 2004

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

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

Small Cell Lung Cancer

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

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

Survival Limited Stage Median survival 3 months without treatment Median survival 14-16 months with treatment ~25% 5-year survival* *Turrisi et al, NEJM, 1999

Survival Limited Stage Extensive Stage Median survival 3 months without treatment Median survival 14-16 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

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

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

Clinical Trials Help to Provide Answers