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New York (NY): Random House, 1998. 214 pp., illus. ISBN 0-679-45702-X A 2008 Lifetime Television movie, directed by Dan Ireland, starring Harry Connick,

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Presentation on theme: "New York (NY): Random House, 1998. 214 pp., illus. ISBN 0-679-45702-X A 2008 Lifetime Television movie, directed by Dan Ireland, starring Harry Connick,"— Presentation transcript:

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2 New York (NY): Random House, 1998. 214 pp., illus. ISBN 0-679-45702-X A 2008 Lifetime Television movie, directed by Dan Ireland, starring Harry Connick, Jr. The film is based on the true life story of Dr. Dennis Slamon.

3 10.1200/JCO.2011.40.2545 Targeted Agents for HER2+ Breast Cancer Targeted Agents for HER2+ Breast Cancer

4 Pertuzumab Trastuzumab Pertuzumab Fisher, et al. J. Mol. Biol. 2010;402:217-229.

5 OS (after an additional year of follow-up) Lancet Oncol 2013; 14: 461–71 Published Online April 18, 2013

6 FDA On June 8, 2012, the U. S. Food and Drug Administration approved pertuzumab injection (PERJETA, Genentech, Inc.) for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of HER2, and thereby blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. EMA march 4, 2013 The European Medicines Agency (EMA) has approved Roche’s PERJETATM ( pertuzumab ) RG1273 for patients with previously untreated HER2-positive metastatic breast cancer (mBC). PERJETA is approved in combination with Herceptin® (trastuzumab) and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease

7 EMILIA OS: Second Interim Analysis Data cutoff July 31, 2012; median follow-up: 18.6 mos. Verma S, et al. N Engl J Med. 2012;367:1783-1791. 100 80 60 40 20 0 0 OS (%) 2481012141630 Mos 6 18202224 2628 T-DM1 Lapatinib-capecitabine Pts at Risk, n Lapatinib- capecitabine T-DM1 496 495 471 485 453 474 435 457 403 439 368 418 297 349 240 293 204 242 159 197 133 164 86 111 63 86 17 28 7 13 4545 36 3234 110 136 27 38 45 62 51.8% (95% CI: 45.9-57.7) 78.4% (95% CI: 74.6-82.3) 85.2% (95% CI: 82.0-88.5) 64.7% (95% CI: 59.3-70.2) Median, MosEvents, n Cap + Lap25.1182 T-DM130.9149 Stratified HR: 0.68 (95% CI: 0.55-0.85; P =.001) Efficacy stopping boundary P =.0037 or HR: 0.73

8 FDA On Feb. 22, 2013, the U. S. Food and Drug Administration approved approved Kadcyla ( ado-trastuzumab emtansine ), a new therapy for patients with HER2-positive, late-stage* (metastatic) breast cancer. This application is currently under review by the EMA

9 ClinicalTrials.gov. NCT01120184. PD Trastuzumab + Taxane (n=364) Trastuzumab + Taxane (n=364) T-DM1 + Pertuzumab (n=364) T-DM1 + Pertuzumab (n=364) T-DM1 + Placebo (n=364) T-DM1 + Placebo (n=364) Patients with HER2+, previously untreated MBC (N=1092) Patients with HER2+, previously untreated MBC (N=1092) Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC Primary endpoints: PFS as assessed by IRF, AEs – Superiority design with a noninferiority analysis – Interim futility analysis: option to drop experimental arm Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR

10 MM-302 Nanotherapeutic encapsulation of liposomal doxorubicin with an anti-HER2 antibody fragments coupled to its surface. Upon administration of MM-302, the immunoliposome allows for specific delivery of doxorubicin to tumors overexpressing the HER2 receptor. Once inside the cancer cell, the liposome breaks down and releases doxorubicin intracellularly, promoting cell death. Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-09.

11 Recombinant antibody fragments Fv Fc VH IgG 150 KDa Fab 50 KDa scFv

12 MM-302

13 MM-302

14 MM-302

15 10.1200/JCO.2011.40.2545 Targeted Agents for HER2+ Breast Cancer Targeted Agents for HER2+ Breast Cancer

16 ARRY-380 is an orally active, small molecule, reversible- selective inhibitor of the HER-2 tyrosine kinase receptor with antitumor activity in HER2-positive breast cancer in vitro and in vivo. In multiple preclinical tumor models, ARRY-380 was well tolerated and demonstrated significant dose-related tumor growth inhibition that was superior to trastuzumab and lapatinib. ARRY-380 http://www.arraybiopharma.com/_documents/Publication/PubAttachment430.pdf

17 http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf

18 These findings led to a phase I trial which found ARRY-380 to be well tolerated, with rash and diarrhea as the most frequent adverse effects ARRY-380 http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf

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20 http://www.arraybiopharma.com/_documents/Publication/PubAttachment506.pdf

21 Neratinib Inhibitors of EGFR-receptors Gajria D Chandarlapaty S. Expert Rev Anticancer Ther. 2011;11(2):263-75 Neratinib (HKI-272) oral, multitargeted, irreversible inhibitor of HER1, HER2 and HER4

22 Randomized Phase II: Neratinib vs Lapatinib + Capecitabine in Locally Advanced or MBC Most commonly observed severe AEs: diarrhea and hand–foot syndrome – 28% in the neratinib arm vs 10% of the patients in the L + C arm experienced grade 3/4 diarrhea ResponsenMedian Survival, Mos95% CIP Value PFS Neratinib1174.53.1-5.7.231 L + C1166.85.9-8.2 OS Neratinib11719.718.2-NE.280 L + C11623.618.0-NE Martin M, et al. SABCS 2011. Abstract S5-7.

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26 AFATINIB Afatinib has demonstrated preclinical activity in HER2-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. The most common treatment-related adverse events of EGFR-TKIs in general, and afatinib in particular, are gastrointestinal and cutaneous side effects, specifically diarrhea and rash The recommended phase II dose of afatinib is 50 mg orally daily based on phase I trials in patients with advanced solid tumor malignancies Afatinib is in Phase III clinical development in breast cancer, NSCLC and head and neck cancer OncoTargets and Therapy 2013:6

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28 This study is ongoing, but not recruiting participants. Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-16.

29 Anti HER2 mAbs MGAH22 TrasGEX Ertumaxomab Anti HER3 mAbs ………. Novel Monoclonal Antibodies

30 Anti HER2 mAbs MGAH22 TrasGEX Ertumaxomab Anti HER3 mAbs ………. Novel Monoclonal Antibodies

31 MGAH22 www.macrogenics.com

32 Chimeric IgG1 anti-HER2 antibody based on mouse clone 4D5, the precursor to trastuzumab. Engineered to maintain the antigen-binding properties of the original antibody while optimizing its interactions with human Fc ϒ Rs. The optimized Fc domain confers enhanced ADCC against all HER2+ tumor cells tested, including cells resistant to trastuzumab’s anti-proliferative activity or expressing low HER2 levels. MGAH22

33 MGAH22

34 Anti HER2 mAbs MGAH22 TrasGEX Ertumaxomab Anti HER3 mAbs ………. Novel Monoclonal Antibodies

35 TrasGEX Biosimilar or biobetter? Significantly improved ADCC-activity promising a significantly better therapeutic outcome for all patients eligible for treatment with Trastuzumab. Simultaneously, the fully human nature of Tras-GEX’ host cell lines avoids the common immunogenic reactions against host-derived non-human components. Biosimilars are structural imitations of the originator, whereas biobetters are improvements to the originator biological molecule

36 TrasGEX TrasGEX Phase II is estimated to start in Q3 / 2013.

37 Anti HER2 mAbs MGAH22 TrasGEX Ertumaxomab Anti HER3 mAbs ………. Novel Monoclonal Antibodies

38 IgG Anti-CD3 Anti-HER2 Fc Fab IgG Fv Fc Bispecific Trifunctional mAb “An antibody which behaves like a man with a wife and a mistress” Rev. Med. Virol. 2009; 19: 181–183 “An antibody which behaves like a man with a wife and a mistress” Rev. Med. Virol. 2009; 19: 181–183 Ertumaxomab Clin Cancer Res 2006;12:3085-3091

39 HER2 Tumor cells T cells CD3 Accessory cell (macrophage, dendritic cell, NK cell…) Fcγ receptor I/III I/III Cytokine activation and coreceptor activation Cytokine activation and coreceptor activation Phagocytosis ADCC Phagocytosis ADCC Porin mediated lysis Ertumaxomab Clin Cancer Res 2006;12:3085-3091

40 HER-2 Low Expressing Hormone- Refractory Phase II Study of Single Agent Trifunctional Antibody Ertumaxomab (Anti-HER-2 & Anti-CD3) in HER-2 Low Expressing Hormone- Refractory Advanced Breast Cancer Patients (ABC). Cardoso F et al. http://www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_1066&terms= Results: Of the planned 40 pts, 28 were enrolled. Recruitment was prematurely terminated due to a strategic change in the sponsor's clinical development program. Eight of 26 evaluable patients (30.8%) had SD at day 70. The median TTP in the evaluable population was 65.5 days (95%, CI: 43-98). The most frequently observed AEs were pyrexia (74.1%), headache (40.7%), chill (33.3%), and vomiting (29.6%). AEs were mostly of mild or moderate intensity and the majority (73.8%) resolved within one day.

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42 Anti HER2 mAbs MGAH22 TrasGEX Ertumaxomab Anti HER3 mAbs ………. Novel Monoclonal Antibodies

43 + + + + + + + + + ++ Signaling activity + + + + HomodimersHeterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 Tzahar E., et al. Mol Cell Biol. 1996. Sergina NV, et al. Nature. 445:437-441. HER2:HER3 Dimers May Provide an Escape Mechanism From Trastuzumab

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46 The maximum administered dose was 20 mg/kg q2w. The most frequent AEs related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained ≥ 9 weeks in 19.2% in part 1 and ≥ 10 weeks in 25.8% in part 2. CONCLUSIONS: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. PK data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing. U3-1287 (AMG-888)

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49 A Phase 1/2 study evaluating MM-121 in combination with erlotinib is ongoing in patients with non-small cell lung cancer, as well as a Phase 1 dose escalation trial testing the safety and pharmacokinetics of MM-121. MM-121

50 MM-121

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52 Domain VH - 15 KDa Domain VL - 15 KDa IgG Fv Fab Fc Recombinant antibody fragments VH scFv 28 KDa Cytosol Nucleus Intrabody IntracellularLocalizationDomainIntracellularLocalizationDomain

53 Fv Fc VH IgG Fab Recombinant antibody fragments Flexibody Tandem antibody “TandAb” Triabody 75 KDa Tetrabody 100 KDa

54 Diabody 55 KDa Monospecific Recombinant antibody fragments Bispecific Diabody Fv Fc VH IgG 150 KDa Fab 50 KDa

55 Fv Fc VH IgG 150 KDa Fab 50 KDa modified human serum albumin modified human serum albumin Anti-HER3 Anti-HER2 MM-111 MM-111 is a bispecific antibody fusion protein consisting of two human single-chain variable fragment (scFv) antibodies linked by modified human serum albumin (HSA).

56 MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing HER2-directed therapies to treat resistant tumors MM-111 Mol Cancer TherMol Cancer Ther 2012 Mar;11(3):582-93.

57 On average, it takes between nine and 17 years, and only one in approximately 19,817 candidate compounds actually becomes a drug. DEVELOPING A NEW DRUG http://www.eisai.com/ir/individual/knowledge.html

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