Targeting the Oncogenic Pathway as Opposed to the

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Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as an Example Dennis J Slamon, MD, Ph. D Professor of Medicine Chief, Division of Hematology/Oncology; Director of Clinical/Translational Research, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA Copyright © 2010, Research To Practice, All rights reserved.

Disclosures for Dennis J Slamon, MD, Ph. D Consulting Agreement Bristol-Myers Squibb Company Speakers

Disclosures for Dennis J Slamon, MD, Ph. D Consulting Agreement Bristol-Myers Squibb Company Speakers Bureau Genentech Bio. Oncology, Roche, GSK, sanofiaventis Copyright © 2010, Research To Practice, All rights reserved.

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as an Example • Similar molecular targets may be found in multiple tumor types • Does the presence of the target predict response to the targeted agent? • Trastuzumab in HER 2 -positive gastric cancer: The To. GA trial • Lessons learned from translational research in tumors overexpressing HER 2 • Are we moving toward a molecular taxonomy? Copyright © 2010, Research To Practice, All rights reserved.

HER 2 Overexpression in Diverse Tumors N Invasive breast cancer (JNCCN 2006; 4: S

HER 2 Overexpression in Diverse Tumors N Invasive breast cancer (JNCCN 2006; 4: S 1) Rate of HER 2 positivity Definition of HER 2 positivity 15 -20% IHC 3+, FISH positive or >6 HER 2 gene copies/cell NSCLC (JCO 2005: 5007) 101 22. 8% FISH positive Prostate (J Urol 2005: 2174) 279 13. 3% Serum HER 2/neu > 14 ng/m. L Recurrent/refractory ovarian or primary peritoneal carcinoma (JCO 2003: 283) 837 11. 4% IHC 2+ or 3+ overexpression 19 26% IHC 3+ Uterine papillary serous cancers (ASCO 2003; Abstract 1870) Copyright © 2010, Research To Practice, All rights reserved.

HER 2 Overexpression in Diverse Tumors N Rate of HER 2 positivity Definition of

HER 2 Overexpression in Diverse Tumors N Rate of HER 2 positivity Definition of HER 2 positivity Pancreatic cancer (GI Cancers Symposium 2010; Abstract 200) 207 26% IHC Grade >2 and/or FISH positive Ewing’s sarcoma (Eur J Cancer 2005; 41: 1349) 113 16% IHC >2+ 84 32% IHC >2+ Bladder cancer (Endocr Relat Cancer 2001; 8: 11, Cancer Res 1993; 53: 2199) 141 36% FISH positive Advanced gastric cancer (ASCO 2009; Abstract 4556) 3, 807 22. 1% IHC 3+ and/or FISH positive Osteosarcoma (Eur J Cancer 2005; 41: 1349) Copyright © 2010, Research To Practice, All rights reserved.

HER 2 Gene Amplification Is Responsible for “Pathologic/Pathogenic” Overexpression Copyright © 2010, Research To

HER 2 Gene Amplification Is Responsible for “Pathologic/Pathogenic” Overexpression Copyright © 2010, Research To Practice, All rights reserved.

Testing Issues • Integrity of the macromolecule being analyzed – degradation of DNA, RNA,

Testing Issues • Integrity of the macromolecule being analyzed – degradation of DNA, RNA, or protein • Accuracy of the reagent – variability of the antibodies • Stability of the target, eg, fixation artifacts in proteins – altering antigenic sites and recognition that the preanalytic phase cannot be controlled • Accuracy of the testing method • Heterogeneity of the sample being tested Copyright © 2010, Research To Practice, All rights reserved.

Percent of Breast Cancers in Various Expression Categories Identified by Immunostaining with 28 Different

Percent of Breast Cancers in Various Expression Categories Identified by Immunostaining with 28 Different Antibodies Copyright © 2010, Research To Practice, All rights reserved.

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as an Example • Similar molecular targets may be found in multiple tumor types • Does the presence of the target predict response to the targeted agent? • Trastuzumab in HER 2 -positive gastric cancer: The To. GA trial • Lessons learned from translational research in tumors overexpressing HER 2 • Are we moving toward a molecular taxonomy? Copyright © 2010, Research To Practice, All rights reserved.

Does the Presence of the Target Predict Response to the Targeted Agent? Sometimes… •

Does the Presence of the Target Predict Response to the Targeted Agent? Sometimes… • The tumor must rely on the oncogenic pathway as a primary means of growth – ER in hormone receptor-sensitive breast cancer • Overexpression does not necessarily indicate “over-activity” – EGFR IHC-positive versus EGFR mutation-positive NSCLC • Mechanism of target inhibition may impact tumor response – HER 2 -positive breast cancer may be resistant to trastuzumab but sensitive to lapatanib (or vice versa) Copyright © 2010, Research To Practice, All rights reserved.

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as an Example • Similar molecular targets may be found in multiple tumor types • Does the presence of the target predict response to the targeted agent? • Trastuzumab in HER 2 -positive gastric cancer: The To. GA trial • Lessons learned from translational research in tumors overexpressing HER 2 • Are we moving toward a molecular taxonomy? Copyright © 2010, Research To Practice, All rights reserved.

Molecular Biology • • p 53: 77% EGFR HER 2/neu: Bang ASCO 2009 22%

Molecular Biology • • p 53: 77% EGFR HER 2/neu: Bang ASCO 2009 22% E-cadherin FHIT p 16/p 27 COX-2 Copyright © 2010, Research To Practice, All rights reserved.

HER 2 by IHC, CISH and FISH in Patients with Gastric Cancer (n =

HER 2 by IHC, CISH and FISH in Patients with Gastric Cancer (n = 182) • HER 2 expression = 15. 9% (IHC); 3. 8% (CISH/FISH) • Rate of HER 2 amplification for intestinal-type cancer is greater than for diffuse-type cancers, p < 0. 05 • Tumors with HER 2 amplification were associated with poor mean survival rates (922 vs 3, 243 days) and 5 -year survival rates (21. 4% vs 63%, p < 0. 05) Park DI et al. Dig Dis Sci 2006; 51(8): 1371 -9. Copyright © 2010, Research To Practice, All rights reserved.

Efficacy Results from the To. GA Trial: A Phase III Study of Trastuzumab Added

Efficacy Results from the To. GA Trial: A Phase III Study of Trastuzumab Added to Standard Chemotherapy (CT) in First-Line Human Epidermal Growth Factor Receptor 2 (HER 2)-Positive Advanced Gastric Cancer (GC) Van Cutsem E et al. Proc ASCO 2009; Abstract LBA 4509. Copyright © 2010, Research To Practice, All rights reserved.

To. GA Trial Design (N = 584) Eligibility HER 2 -positive, inoperable, locally advanced

To. GA Trial Design (N = 584) Eligibility HER 2 -positive, inoperable, locally advanced or metastatic GC • • R FC Fluoropyrimidine (F) (5 -FU or capecitabine at investigator discretion) + Cisplatin (C) FCT F + C + Trastuzumab (T) 5 -FU = 800 mg/m 2/day continuous infusion d 1 -5 q 3 w x 6 Capecitabine = 1, 000 mg/m 2 bid d 1 -14 q 3 w x 6 Cisplatin = 80 mg/m 2 q 3 w x 6 Trastuzumab = 8 mg/kg loading dose 6 mg/kg q 3 w until PD Van Cutsem E et al. ASCO 2009; Abstract LBA 4509. Copyright © 2010, Research To Practice, All rights reserved.

Primary Endpoint: Overall Survival – decreased relative risk of death by 26% Median 1.

Primary Endpoint: Overall Survival – decreased relative risk of death by 26% Median 1. 0 0. 9 0. 8 0. 7 0. 6 Event 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 11. 1 0 2 4 6 Events OS HR 95% CI p-value FC + T 167 13. 8 0. 74 0. 60, 0. 91 0. 0046 FC 182 11. 1 13. 8 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) Reprinted with permission: Van Cutsem E et al. ASCO 2009; Abstract LBA 4509. Copyright © 2010, Research To Practice, All rights reserved.

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as an Example • Similar molecular targets may be found in multiple tumor types • Does the presence of the target predict response to the targeted agent? • Trastuzumab in HER 2 -positive gastric cancer: The To. GA trial • Lessons learned from translational research in tumors overexpressing HER 2 • Are we moving toward a molecular taxonomy? Copyright © 2010, Research To Practice, All rights reserved.

Lapatinib, a Dual EGFR and HER 2 Kinase Inhibitor, Selectively Inhibits HER 2 -Amplified

Lapatinib, a Dual EGFR and HER 2 Kinase Inhibitor, Selectively Inhibits HER 2 -Amplified Human Gastric Cancer Cells and Is Synergistic with Trastuzumab In Vitro and In Vivo Wainberg ZA et al. Clin Cancer Res 2010; 16(5): 1509 -19. Copyright © 2010, Research To Practice, All rights reserved.

Cell Growth Inhibition by Lapatinib In Vitro Laptanib Lapatinib selectively inhibits the growth of

Cell Growth Inhibition by Lapatinib In Vitro Laptanib Lapatinib selectively inhibits the growth of the HER 2 -amplified gastric and esophageal cancer cell lines NCIN 87 and OE 19. Reprinted with permission: Wainberg ZA E et al. Clin Cancer Res 2010; 16(5): 1509 -19, figure 1. Copyright © 2010, Research To Practice, All rights reserved.

Lapatinib Induces Apoptosis in HER 2 -Amplified Gastric Cell Lines Reprinted with permission: Wainberg

Lapatinib Induces Apoptosis in HER 2 -Amplified Gastric Cell Lines Reprinted with permission: Wainberg ZA E et al. Clin Cancer Res 2010; 16(5): 1509 -19, figure 3. Copyright © 2010, Research To Practice, All rights reserved.

Tumor volume (mm 3) Synergistic Antitumor Activity of Lapatinib and Trastuzumab in Combination (N

Tumor volume (mm 3) Synergistic Antitumor Activity of Lapatinib and Trastuzumab in Combination (N 87 Xenograft) Reprinted with permission: Wainberg ZA E et al. Clin Cancer Res 2010; 16(5): 1509 -19, figure 6. Copyright © 2010, Research To Practice, All rights reserved.

HER 2 Gene Amplification in Salivary Gland Mucoepidermoid Carcinomas HER 2 Not Amplified HER

HER 2 Gene Amplification in Salivary Gland Mucoepidermoid Carcinomas HER 2 Not Amplified HER 2 Amplification Copyright © 2010, Research To Practice, All rights reserved.

Agilent Array-CGH in Ovarian Cancer • 8/128 (6. 3%) HER 2 Amplification Lee Anderson,

Agilent Array-CGH in Ovarian Cancer • 8/128 (6. 3%) HER 2 Amplification Lee Anderson, Slamon Lab (unpublished data) Copyright © 2010, Research To Practice, All rights reserved.

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as

Targeting the Oncogenic Pathway as Opposed to the Primary Tumor Site: HER 2 as an Example • Similar molecular targets may be found in multiple tumor types • Does the presence of the target predict response to the targeted agent? • Trastuzumab in HER 2 -positive gastric cancer: The To. GA trial • Lessons learned from translational research in tumors overexpressing HER 2 • Are we moving toward a molecular taxonomy? Maybe. . . Copyright © 2010, Research To Practice, All rights reserved.

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