Seventh Annual NCCTG Patient Advocate Symposium

1. 1 Seventh Annual NCCTG Patient Advocate Symposium Lung Cancer Studies Julian R Molina, MD., Ph.D.

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3. 3 2005-2009 AccrualData through April 28, 2009

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12. 12 Lung Cancer Progression

13. 13 Model of Carcinogenesis

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15. 15 Molecular Pathology

16. 16 EGFR A regulator of tumor growth. Frequently overexpressed in lung cancer.

17. 17 HER Family: Receptors and Ligands 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. Epidermal growth factor and transforming growth factor alpha (TGFa) are the 2 most important ligands for HER1/EGFR. The neuregulins (NRG1-4) 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/EGFR and HER3 and functions as a coreceptor. All HER family proteins, with the exception of HER3, have intrinsic kinase activity. Since 1984, it has been recognized that HER1/EGFR can be overexpressed in lung cancer. HER2 appears to be less frequently expressed in NSCLC; expression levels of HER1/EGFR 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. 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. Epidermal growth factor and transforming growth factor alpha (TGFa) are the 2 most important ligands for HER1/EGFR. The neuregulins (NRG1-4) 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/EGFR and HER3 and functions as a coreceptor. All HER family proteins, with the exception of HER3, have intrinsic kinase activity. Since 1984, it has been recognized that HER1/EGFR can be overexpressed in lung cancer. HER2 appears to be less frequently expressed in NSCLC; expression levels of HER1/EGFR 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.

18. 18 HER Family: Homodimers and Heterodimers Receptors in the HER family can create homo- and heterodimers. HER1/EGFR will form both homodimers as well as heterodimers with other HER family members. Although a particular receptor in the HER family may not necessarily directly bind a given ligand, dimerization allows for the phosphorylation and activation of such receptors. This plasticity of dimerization allows for more complex signaling diversity as a response to different HER family receptor ligands. Ligands will often induce certain receptor dimers. NRG-1 will preferentially induce heterodimers of HER1/EGFR with HER3 or HER4, while EGF will not. Diversity among different cell and tissue types also exists, depending on the expression and preferred partnering of the receptors and ligands. The particular cellular response to receptor stimulation is also tissue-specific. Homodimers are less proliferative and transforming than the corresponding heterodimers, with HER2-containing heterodimers being the most potent complexes. HER3 homodimers have no kinase activity. Receptors in the HER family can create homo- and heterodimers. HER1/EGFR will form both homodimers as well as heterodimers with other HER family members. Although a particular receptor in the HER family may not necessarily directly bind a given ligand, dimerization allows for the phosphorylation and activation of such receptors. This plasticity of dimerization allows for more complex signaling diversity as a response to different HER family receptor ligands. Ligands will often induce certain receptor dimers. NRG-1 will preferentially induce heterodimers of HER1/EGFR with HER3 or HER4, while EGF will not. Diversity among different cell and tissue types also exists, depending on the expression and preferred partnering of the receptors and ligands. The particular cellular response to receptor stimulation is also tissue-specific. Homodimers are less proliferative and transforming than the corresponding heterodimers, with HER2-containing heterodimers being the most potent complexes. HER3 homodimers have no kinase activity.

19. 19 HER1/EGFR: Survival Cell survival is promoted by AKT activation in response to HER1/EGFR signaling. In normal cells that have been damaged, the proapoptotic protein BAD associates with BCLXL and BCL2, abrogating the antiapoptotic properties of the latter. Damaged cells are thus signaled to undergo apoptosis. Signal transduction cascades initiated by HER1/EGFR result in the activation of PI3K. AKT, which is a downstream target of PI3K, is subsequently phosphorylated and activated. Activated AKT can phosphorylate the proapoptotic BAD protein, rendering it inactive and unable to bind to and inhibit the prosurvival proteins BCLXL and BCL2. HER1/EGFR�mediated activation of AKT tips the balance of a cancerous cell toward survival and away from apoptosis.Cell survival is promoted by AKT activation in response to HER1/EGFR signaling. In normal cells that have been damaged, the proapoptotic protein BAD associates with BCLXL and BCL2, abrogating the antiapoptotic properties of the latter. Damaged cells are thus signaled to undergo apoptosis. Signal transduction cascades initiated by HER1/EGFR result in the activation of PI3K. AKT, which is a downstream target of PI3K, is subsequently phosphorylated and activated. Activated AKT can phosphorylate the proapoptotic BAD protein, rendering it inactive and unable to bind to and inhibit the prosurvival proteins BCLXL and BCL2. HER1/EGFR�mediated activation of AKT tips the balance of a cancerous cell toward survival and away from apoptosis.

20. 20 EGFR Pathway Inhibition

21. 21 Treatment of Lung Cancer

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23. 23 Treatment of Lung Cancer Adjuvant:

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26. 26 Treatment of Advanced/Metastatic Lung Cancer

27. 27 Anti-angiogenic Targets in Lung Cancer

28. 28 Erlotinib (Tarceva�, OSI-774) Erlotinib, a quinazoline derivative Orally available, reversible and selective inhibitor of EGFR tyrosine kinase. Activity in NSCLC, head and neck and ovarian carcinomas. Two large randomized phase III studies of erlotinib in combination with chemotherapy as first-line treatment in patients with NSCLC failed to prove survival benefit. TALENT trial, 1172 patients were randomized to cisplatin/gemcitabine plus erlotinib or placebo for six cycles of chemotherapy followed by daily erlotinib or placebo. TRIBUTE trial, 1059 patients were randomized to carboplatin/paclitaxel plus erlotinib or placebo for six cycles Subset analysis revealed that never-smokers had the greatest survival benefit.

29. 29 BR.21: Phase III Trial of Erlotinib for Advanced NSCLC�Overall Survival Erlotinib significantly increased survival vs placebo during the follow-up period. Median survival was 6.7 months in the erlotinib group, vs 4.7 months in the placebo group. The hazard ratio for overall survival in the erlotinib arm relative to the placebo arm was 0.73 (95% confidence interval, 0.61-0.86) (P<0.001) One-year survival was 31% in the erlotinib group, vs 21% in the placebo group. The HR was calculated using a Cox regression model with the following covariates: Eastern Cooperative Oncology Group (ECOG) performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. The P value was derived using a 2-sided log-rank test stratified by ECOG performance status, number of prior regimens, prior platinum, and best response to prior therapy. Survival was evaluated in the intent-to-treat population (N=731). Erlotinib significantly increased survival vs placebo during the follow-up period. Median survival was 6.7 months in the erlotinib group, vs 4.7 months in the placebo group. The hazard ratio for overall survival in the erlotinib arm relative to the placebo arm was 0.73 (95% confidence interval, 0.61-0.86) (P<0.001) One-year survival was 31% in the erlotinib group, vs 21% in the placebo group. The HR was calculated using a Cox regression model with the following covariates: Eastern Cooperative Oncology Group (ECOG) performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. The P value was derived using a 2-sided log-rank test stratified by ECOG performance status, number of prior regimens, prior platinum, and best response to prior therapy. Survival was evaluated in the intent-to-treat population (N=731).

30. 30 Open NCCTG Lung Cancer Trials

31. 31 N0723: MARVEL - Phase III Biomarker Validation Study of Second-line Therapy in Patients with Advanced NSCLC Randomized to Pemetrexed Versus Erlotinib Accrual: 11 pre-registered and 9 randomized (Pre-Registration Goal: 1196, Randomization Goal: 956), opened 10/1/2008. Primary Endpoint: To evaluate whether there are differences in progression-free survival (PFS) due to treatment with erlotinib compared to pemetrexed for subsets of previously treated NSCLC patients defined by epidermal growth factor receptor (EGFR)-FISH positivity versus negativity

32. 32 N0723 Schema

33. 33 N0626: Phase II Randomized Study of Pemetrexed Combined with Sorafenib Versus Pemetrexed Alone as Second-line Therapy in Patients with Advanced NSCLC Accrual: 54 (Goal: 110), Reopened 6/27/2008 excluding patients with squamous cell histology tumors. Primary Endpoint: To compare the progression-free survival

34. 34 N0321: Phase I/II Study of PS-341 in Combination with Paclitaxel, Carboplatin, and Concurrent Thoracic Radiation Therapy for IIIA/B unresectable NSCLC Accrual: 29 (Goal: 36 Phase I; 65 Phase II), re-opened 11/04/2008 to dose level 6 (PS-341 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6); need 2 more patients enrolled to evaluate this dose level Primary Endpoint: Phase I Component: To determine the maximally tolerated dose (MTD) of PS-341/Paclitaxel/ Carboplatin, given in conjunction with fractionated daily radiation therapy. Phase II Component: To assess the 1-year survival of patients treated with this regimen.

35. 35 N0724: A Randomized Phase II Study of Oligometastatic Stage IV NSCLC Treated with Systemic Therapy Plus Either Radiotherapy to All Sites of Gross Disease or No Radiotherapy Accrual: 0 (Goal: 98) Primary Endpoint: To assess whether the addition of radiation therapy after an initial course of standard chemotherapy results in an improvement in overall survival in all eligible Stage IV NSCLC patients. Secondary Endpoint: To compare the following endpoints between the radiation therapy arm (Arm B) and the observation arm (Arm A) after standard chemotherapy: progression-free survival, time to disease progression, time to treatment failure, confirmed response rate, duration of response and adverse events.

36. 36 N0821: Phase II First-line Study of a Combination of Pemetrexed, Carboplatin, and Bevacizumab in Advanced Non-squamous NSCLC Evaluating Efficacy and Tolerability in Elderly Patients (=70 years) with Good Performance Status (PS<2) Accrual: 2 (Goal: 60) Primary Endpoint: To estimate progression-free survival at 6 months of pemetrexed, carboplatin and bevacizumab as first-line treatment in elderly patients with advanced nonsquamous NSCLC and good PS (PS<2).

37. 37 NCCTG Trials Closed in 2008

38. 38 NCCTG Trials in Development

39. 39 2009 Publications

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