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Emerging Medical Treatments and Future Directions

Emerging Medical Treatments and Future Directions. Stefano Iacobelli Cancer Clinic & Laboratory of Molecular Oncology. On behalf of the Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO). Breast C ancer Facts.

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Emerging Medical Treatments and Future Directions

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  1. Emerging Medical Treatments and Future Directions Stefano Iacobelli Cancer Clinic & Laboratory of MolecularOncology On behalf of the Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)

  2. Breast Cancer Facts • Over 1 million new breast cancer cases are reported each year • ~ 10% of new diagnosed BC patients are locally advanced or metastatic disease, and 20-60% of the remaining patients develop systemic relapse • ~ 40% of the patients will die of breast cancer • Reason: Development of drug resistance in metastatic disease • Metastatic breast cancer remains an incurable disease However… Gueth U et al. Oncology 2009

  3. Paclitaxel Capecitabine Docetaxel Trastuzumab Gemcitabine Advances in Medical Treatment 1980 1985 1990 1995 2000 2005 Tamoxifen CMF Doxorubicin Mitoxantrone Epirubicin Vinorelbine Aromatase Inhibitors Fulvestrant Albumin-Bound Paclitaxel Bevacizumab ER+ or PR+ Lapatinib HER2+ Ixabepilone

  4. The use of newer therapeutic agents has been associated with improved survival in MBC over time Chia SK et al. Cancer 2007

  5. Three Key Clinical Advances All In Targeted Therapies • HER-2 • VEGF (R) • PARP

  6. Molecular Targets and Therapies Being Developed for Breast Cancer Normanno N et al. Endocr Rel Cancer 2009

  7. Trastuzumab represents the foundation of treatment of HER2+ Breast Cancer • However • In advanced breast cancer, primary resistance to • Trastuzumab is frequent (60–70% of pts with Trastuzumab • monotherapy; 30–50% of pts with Trastuzumab plus • chemotherapy) • Eventually, all advanced breast cancer patients become • resistant to Trastuzumab within months or years • CNS is a frequent metastatic site and Trastuzumab is • ineffective for CNS MTS ( CSF levels 300-fold lower than in • the serum)

  8. Molecular mechanisms of Trastuzumab resistance Altered Target Steric hindrance of receptor by cell surface proteins (MUC4)1 Truncated form of receptor (p95)2 Mutations in HER23 Increased circulating HER2 ECD Alternative pathway signaling IGF1R overexpression4 VEGF overexpression5 Alternative HER signaling HER1/HER3 heterodimers or HER1/HER1 homodimers Increased levels of ligand (heregulin, EGF, TGFα)6 Costitutive activation of downstream effectors Reduced level of PTEN7 Reduced p27kip1 8 Increased AKT activity9 1 Nagy P et al. Cancer Res 2005 4 Nahta R et al. Cancer Res 2005 7 Nagata Y et al. Cancer Cell 2004 8 Nahta R et al. Cancer Res 2004 5 du Manoir JM et al. Clin Cancer Res 2006 2 Scaltriti M et al. J Natl Cancer Inst 2007 6 Motoyama AB et al. Cancer Res 2002 9 Berns K et al. Cancer Cell 2007 3Prempree C et al. JCO 24: 611s, 2006

  9. Targeting HER2-beyond trastuzumab • Newer mAbs targeting the HER receptor family - PERTUZUMAB - ERTUMAXOMAB • TKIs to HER2- receptor family - LAPATINIB - NERATINIB - JNJ-28871063 • Trastuzumab-DM1 FISH + IHC 3+

  10. Different sites of action of various drugs acting on the HER-2 receptor signaling pathway Vora T et al. 2009

  11. Pertuzumab • Humanized monoclonal antibody targeting the HER2 extracellular domain II • Prevents HER2 heterodimerization • Potent inhibitor of HER-mediatedsignalling pathways • The combination of Pertuzumab with Trastuzumab has been shown to induce greater ADCC, receptor down-regulation and growth inhibition of tumor cells Spiridon CI et al. Clin Cancer Res 2002

  12. Phase II Trial of Pertuzumab and Trastuzumab in Patients With HER2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy Toxicities - Grade 1 or 2 diarrhea (64%) fatigue (33%) nausea (27%) - Only four G3 treatment-related event (2 cases of diarrhea, 1 central line infection, and 1 pruritic rash). - no clinically significant cardiac events Trastuzumab weekly (4 mg/kg loading dose, then2 mg/kg every week) or every 3 wks (8 mg/kg loading dose,then 6 mg/kg every 3 wks) Pertuzumab every 3 weeks (840mg loading dose, then 420 mg every 3 wks) median PFS 5.5 months (range, 0.9 to 17.0 months) Baselga J, J Clin Oncol 2010

  13. CLEOPATRA: Phase III study of Trastuzumab + Pertuzumab in HER2+ MBC Herceptin + docetaxel + placebo 1:1 randomisation Untreated HER2+ MBC n=800 Herceptin + docetaxel + pertuzumab An international Phase III randomised, double-blind, placebo-controlled study (approximately 250 sites worldwide) • End points: • Progression-free survival • Overall survival • Quality of life • Biomarker analysis Expected to be completed by March 2012

  14. Ertumaxomab • Ertumaxomab is a trifunctional, bispecific mAb targeting HER2 and CD3 • It binds to HER2 positive tumor cells, T cells and fcγ receptor positive accessory immune cells (macrophages, dendritic cells and NK cells) • This tri-cell structure causes co-stimulation of T-cells resulting in the release of cytokines and lytic enzymes (e.g. perforin) and phagocytosis of tumor cells by the fcγ receptor positive cells Zeidler RBr J Cancer 2000

  15. Phase I Trial of the Trifunctional Anti-HER2 Anti-CD3 Antibody Ertumaxomab in MBC Kiewe P et al. Clin Cancer Res 2006 17 patients with HER2 positive MBC Toxicities Infusion Reactions 6-h infusion Strong Th1 immune response Doses up to 100 μg can be safely infused with close monitoring of pts. The observed clinical responses (ORR, 5/15) are encouraging and indicate antitumor efficacy

  16. Lapatinib inhibits EGFR and HER2 *Kiapp (nM); ‡cKiapp (nM); gefitinib and erlotinib are ErbB1 inhibitors The slow off-rate, bound EGFR structure, and dual ErbB1 and Erb2 inhibition profile differentiate Lapatinib from the other agent

  17. MAPK pathway (Ras/Raf/MEK/ERK) MAPK pathway (Ras/Raf/MEK/ERK) PI3K/Akt pathway PI3K/Aktpathway Lapatinib Acts Intracellularly, Directly Inhibiting Downstream Signals Ligands Other ErbB ErbB2 Lapatinib Proliferation Cellcycle, Survival

  18. Patients with ErbB2-positive locally advanced or metastatic breast cancer that progressed after prior anthracycline, taxane and trastuzumab (N=399) RANDOMISATION Lapatinib 1250 mg po qd continuously + capecitabine 2000 mg/m2/d po days 1–14 q 3 wk Capecitabine 2500 mg/m2/day po days 1–14 q 3 wk Treatment continued until progression po = oral; qd = once daily; q 3 wk = once every 3 weeks EGF 100151: Phase III, randomised, controlled study of lapatinib plus capecitabinevscapecitabine alone Cameron et al. Breast Can Res Treat 2008; Geyer et al. N Engl J Med 2006

  19. EGF 100151 study: Lapatinib plus capecitabine: significantly longer TTP in difficult to treat population Cameron et al. Breast Can Res Treat 2008

  20. EGF100151 StudyMost Frequent Adverse Events All Grades L = Lapatinib; C = capecitabine Cameron et al. Breast Can Res Treat 2008

  21. Cancer Res 2007 Lapatinib inhibits p-Akt in a dose- and time-dependent manner in PTEN-null MDA-MB-468 BC cells Low (1+) High (3+) Negative (0) Phase II trial of Lapatinib alone in IBC

  22. Lapatinib is active against tumours expressing p95ErbB2 variant • An estimated 30% of BCs overexpressing HER2 co-espress p95HER2 • Preclinical evidence demonstrated that Lapatinib retains activity in models expressing p95HER2 Pedersen K et al. Mol Cell Biol 2009 Scaltriti et al. J Natl Cancer Inst 2007

  23. EGF 104900: Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory MBC Lapatinib 1500 mg/day p.o. (n=148) Crossover if PD after 4wk therapy (N = 73) HER2+ MBC pretreated with Trastuzumab, Anthra, Taxane (n=296) R Lapatinib 1000 mg/day + Trastuzumab 4 2 mg/kg IV qw (n=148) Primary endpoint: PFS based on RECIST criteria Secondary endpoints: ORR, CB, OS, QoL, safety Blackwell KL et al. J Clin Oncol 2010

  24. EGF 104900: Survival Analyses Blackwell KL et al. J Clin Oncol 2010 The median PFS was 8.1 vs 12 wks lapatinib alone vs combination arm HR 0.73 (95% CI, 0.57 to 0.93; P.008) Improvement in PFS for the combination arm

  25. Neratinib (HKI-272) • Oral, pan-HER (ie, HER1, HER2, and HER4) TKI • In a phase I study, MDT was 320 mg/day. Common AEs were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), and vomiting (29%) Rabindran SK et al. Cancer Res 2004

  26. Phase II study of Neratinib in pts with Advanced HER2 positive Breast Cancer Advanced HER2 + BC (N=136) Neratinib 240 mg Prior trastuzumab treatment (n = 66) Neratinib 240 mg No prior trastuzumab treatment (n = 70) Primary end point: 16-week PFS rate Burstein HJ et al. J Clin oncol 2010

  27. Efficacy analysis and safety Tumor Responses Diarrhea was the most frequent grades 3 to 4 AE Burstein HJ et al. J Clin oncol 2010

  28. JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain Barrier BT474 ErbB2-overexpressing breast carcinoma model L J Drug plasma and tissue distribution of JNJ-28871063 and lapatinib in nude mice bearing A431 Xenografts mTTP Emanuel SL et al. Mol Pharmacol 2008 mTTP N87 intracranial model 5 x104 cells were injected intracranially, and animals (n=10) were treated with vehicle or 200 mg/kg JNJ-28871063 daily for 50 days JNJ-28871063 significantly extended survival by 31.3%

  29. Trastuzumab-DM1 (Tmab-MCC-DM1) • Immunotoxin: Ab delivery of the toxin; internalization via • endocytosis induces toxin release inside the tumor • T-DM1 combines biological activity of trastuzumab with • targeted delivery of DM1 • DM-1: maytansine (potent microtubule destabilizing agent) • Activity in trastuzumab resistant cancer cell lines • • SK-OV-3 (Her2 2 +): ovarian carcinoma • • Calu-3 (Her2 3 +): lung adenocarcinoma • • BT-474-EI (Her2 3 +): breast tumor cells • • MKN7 (Her2 2 +): gastric carcinoma • In a phase I study, T-DM1 was well-tolerated at the MDT of 3.6 mg/kg IV q21, with no cardiac toxicity. Grade 3-4 toxicities were thrombocytopenia and neutropenia. ORR was 44%. Beeram M et al. ASCO 2008 (Abstr 1028) Lewis Phillips GD et al. Cancer Res 2008

  30. A phase II study of Trastuzumab-DM1 in pts with HER2 positive MBC Endpoints Progression within 60 daysof HER2-directed therapy Trastuzumab only (n = 45) Trastuzumab + Lapatinib (n = 67) ORR, safety/ Tolerability,PFS HER2+ (IHC 3+ or FISH+) MBC (N = 112) Trastuzumab-DM1*q3w *3.6 mg/kg as 30- to 90-min continuous infusion. Vukelja S, et al. SABCS 2008. Abstract 33. Vogel C, et al. ASCO 2009. Abstract 1017.

  31. Trastuzumab-DM1 in HER2-Positive MBC: Treatment History Vogel C, et al. ASCO 2009. Abstract 1017.

  32. Trastuzumab-DM1 in HER2+ MBC: Antitumor Activity * CR, PR, or SD for ≥ 6 mos. Subgroups analysis Vogel C, et al. ASCO 2009. Abstract 1017.

  33. Trastuzumab-DM1 in HER2-Positive MBC: PFS Median Follow-up 9.5 months IRF (N = 112) median: 4.9 1.0 INV (N = 112) median: 4.9 0.8 0.6 Proportion Event Free 0.4 0.2 0 10 12 14 0 2 4 6 8 PFS (Mos) Vogel C, et al. ASCO 2009. Abstract 1017.

  34. Trastuzumab-DM1 in HER2-Pos MBC: AEs Vogel C, et al. ASCO 2009. Abstract 1017.

  35. Response Rates for Novel HER2-Targeting Agents after Progression on Trastuzumab P<0.0001

  36. Angiogenesis Inhibitors • Monoclonal Antibodies - BEVACIZUMAB • Primarly antiangiogenic multitargeted TKIs - PAZOPANIB - AXITINIB - SUNITINIB

  37. First-line T herapy of MBC with Bevacizumab Added to Paclitaxel Improved PFS +/- Bevacizumab 10 mg/kg q2w HR = 0.51 Miller K et al. N Engl J Med 2007

  38. RIBBON-2: A randomized phase III trial of Bevacizumab with cht for II line HER2neg MBC • Three prior Phase III trials (E2100, AVADO, and RIBBON-1) have established a consistent improvement in PFS with the combination of Bevacizumab with various cht as first-line treatment for MBC • A previous Phase III study (AVF2119) in pts with heavily pre-treated MBC, in which bevacizumab was combined with Capecitabine, did not meet the primary end-point of PFS, but resulted in a significant increase in ORR • RIBBON-2 was designed to evaluate the clinical benefit of combining Beva with various cht used to treat MBC in II line Bevacizumab 15 mg/kg q3w or 10 mg/kg q2w Brufsky A et al. SABCS 2009

  39. Brufsky A et al. SABCS 2009 RIBBON-2 is the first positive phase III study of bevacizumab in second-line MBC

  40. A Phase II study of GW786034 (pazopanib) in pts with recurrent or metastatic breast cancer • Background • Pazopanib is an oral small molecule tyrosine kinase inhibitor of VEGFR1, 2, and 3, PDGFRα and β, and KIT • A phase I study reached doses up 2000 mg/d • DLT in 1/3 patients at 200 mg/d (grade 3 fatigue) • Activity was seen with daily doses of > 800 mg Taylor SK et al. ASCO 2009 • Elegibility • Metastatic or recurrent BC • Up to 2 lines of cht • If HER2 positive, must be trastuzumab refractory • If ER+, must be hormone refractory • No prior bevacizumab • Primary Endpoint • Anti-tumor efficacy: RR (RECIST)

  41. Taylo SK et al. ASCO 2009 • This trial did not meet the criteria to go to stage 2 based on ORR • Pazopanib appears to have similar activity of other VEGF inhibitors in advanced pretreated breast cancer, bevacizumab and sunitinib (CBR 26%, TTP 5.3 months, vs. bevacizumab, CBR 16%, TTP 2.4 mo.; and sunitinb, CBR 17%, TTP 2.3 mo.) • These results suggest that there is minor cytotoxic as well as clear cytotoxic activity of pazopanib in advanced breast cancer, and it may be useful in studies of combination therapy • Pazopanib was well tolerated (G>3 Leuko-neutropenia; hypertension; AST, ALT) Burstein et al. JCO 2008 Cobleigh et al. Semin Oncol 2003

  42. A randomized, phase II study of axitinib (AG-013736) in combination with docetaxel compared to DOC plus placebo in MBC Rugo HS et al. ASCO 2007 Abstr 1003 • Axitinib (AG-013736) a potent TKI targeting all VEGFR isoforms, PDGFR and c-KIT1 • Previous phase I study identified appropriate doses of docetaxel and axitinib2 (DOC 80 mg/m2 q3w with axitinib 5 mg twice daily ) Randomized 2:1 Docetaxel 80 mg/mq q3w + Axitinib 5 mg twice daily n=112 Pts with MBC not pretreated with cht for metastatic disease n=168 Primary Endpoint: TTP Docetaxel 80 mg/mq q3w + Placebo n=56 2Rugo HS et al. ASCO 2005 Abstr 1067 1Sloan B et al. Curr Opin Investig Drugs 2008

  43. Results Toxicities Docetaxel and axitinib associated with a higher incidence of grade 3/4 febrile neutropenia, fatigue, stomatitis, hypertension, and thromboembolic events Axitinib has promising anti-tumor activity for pts with breast cancer

  44. A Phase III Trial of Sunitinib (SU) Vs. Capecitabine (C) in Pts with Previously Treated HER2-Negative Advanced Breast Cancer (ABC) Barrios C et al. SABCS 2009 Abs 46 Randomized 1:1 Sunitinib 37.5 mg daily (231) HER2 negative ABC resistant to Anthra and Taxane (n=464) Capecitabine 1250 mg/mq x2 /die d1-14 q21 (233) mPFS 2.8 vs. 4.2 mos for SU vs. C (p<0.001) ORR 9.1 vs. 12.9 . Trial stopped for futility Sunitinib is not superior to Cap given as monotherapy. Cap was better tolerated than SU. Sunitinib cannot be recommended as monotherapy on this dosing schedule

  45. PARP1-Inhibitors PARP1 structure BSI-201 AZD2281 Olaparib Poly (ADP-ribose) polymerase (PARP)

  46. PARP inhibition and tumor-selective synthetic lethality Tumor-selective cytotoxicity CELL SURVIVAL Peralta-Leal A et al, Free Radic. Biol. Med. 2009

  47. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient ABC Tutt A et al. ASCO 2009, Abst # CRA 501 Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure of ≥ 1 prior chemotherapy For advanced disease Cohort 1 (enrolled first) Cohort 2* Olaparib 400 mg po bid (MDT) 28-day cycles; n = 27 Olaparib 100 mg po bid (MDT) 28-day cycles; n = 27 • * Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg bid cohort were permitted to crossover to receive the 400 mg bid dose • MDT determined during Phase I evaluation Primary End-point: ORR by RECIST • Median 3 prior cht treatments • In higher dose cohort, two thirds had BRCA1 mutation

  48. Olaparib in Mutation Carriers: RESULTS Olaparib 400 mg bid (n=27) Olaparib 100 mg bid (n=27) ITT cohort Overall Response Rate, n (%) 11 (41)* 6 (22)* Complete Response, n (%) 1 (4) 0 Partial Response, n (%) 10 (37) 6 (22) Tutt A et al. ASCO 2009, Abst # CRA 501

  49. Phase II trial of BSI-201 in combination with gemcitabine/carboplatin in metastatic TNBC O'Shaughnessy J et al. ASCO 2009 Abs 3 Metastatic TNBC Prior chemo n = 120 RANDOMIZE Gemcitabine 1000 mg/mq d 1, 8 Carboplatin AUC 2 d 1, 8 BSI-201 5.6 mg/kg IV d 1, 4, 8, 11 Gemcitabine 1000 mg/mq d1, 8 Carboplatin AUC 2 d 1, 8 21-day cycle RESTAGING Every 2 cycles * Pts randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression

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