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Emerging Medical Treatments

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1 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)

2 Breast Cancer Facts However…
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 Advances in Medical Treatment
1980 1985 1990 1995 2000 2005 Tamoxifen CMF Doxorubicin Mitoxantrone Epirubicin Paclitaxel Vinorelbine Aromatase Inhibitors Docetaxel Gemcitabine Capecitabine Fulvestrant Trastuzumab 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
VEGF (R) PARP 5

6 Therapies Being Developed for Breast Cancer
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 5 du Manoir JM et al. Clin Cancer Res 2006 8 Nahta R et al. Cancer Res 2004 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 3 Prempree 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 Trastuzumab-DM1 FISH + IHC 3+ 9

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-mediated signalling 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 Response N=66 CR 5 (7.6%) PR 11 (16.7%) ORR 16 (24.2%) SD > 6 mos 17 (25.8%) - 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, then 2 mg/kg every week) or every 3 wks (8 mg/kg loading dose, then 6 mg/kg every 3 wks) Pertuzumab every 3 weeks (840 mg 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
1:1 randomisation Herceptin + docetaxel + placebo 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
GEFITINIB ERLOTINIB ErbB1 3.0 ± 0.2* 0.4 ± 0.1* 0.7 ± 0.1* ErbB2 13 ± 1* 870 ± 90* 1000 ± 100* ErbB4 347 ± 16‡ 1130 ± 370‡ 1530 ± 270‡ *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 Lapatinib Acts Intracellularly, Directly Inhibiting Downstream Signals
Ligands Other ErbB ErbB2 PI3K/Akt pathway MAPK pathway (Ras/Raf/ MEK/ERK) PI3K/Akt pathway MAPK pathway (Ras/Raf/ MEK/ERK) Lapatinib Proliferation Cell cycle, Survival

18 EGF : Phase III, randomised, controlled study of lapatinib plus capecitabine vs capecitabine alone Treatment continued until progression 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 po = oral; qd = once daily; q 3 wk = once every 3 weeks Cameron et al. Breast Can Res Treat 2008; Geyer et al. N Engl J Med 2006

19 EGF study: Lapatinib plus capecitabine: significantly longer TTP in difficult to treat population Cameron et al. Breast Can Res Treat 2008 Outcome Lapatinib + capecitabine (N=198) Capecitabine (N=201) Hazard ratio (95% CI) Odds ratio p-value Median TTP (weeks [months])* 27.1 (6.2) 18.6 (4.3) 0.57 (0.43, 0.77) ORR (%) 23.7 13.9 1.9 (1.1, 3.4) 0.017

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

21 Phase II trial of Lapatinib alone in IBC
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

24 HER2+ MBC pretreated with Trastuzumab, Anthra, Taxane
EGF : 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 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

25 Improvement in PFS for the combination arm
EGF : 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

26 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

27 Prior trastuzumab treatment No prior trastuzumab treatment
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

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

29 BT474 ErbB2-overexpressing breast carcinoma model
JNJ , 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 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 daily for 50 days JNJ significantly extended survival by 31.3%

30 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

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

32 Trastuzumab-DM1 in HER2-Positive MBC: Treatment History
Previous Chemotherapy and Anti-HER2 Therapy Patients (N = 112) Chemotherapeutic agents, median n (range) 3 (1-12) Previous anthracycline, n (%) 78 (69.6) Previous taxane, n (%) 94 (83.9) Median duration of previous trastuzumab therapy, mos (range) 17.8 (1-152) Previous lapatinib therapy, n (%) 67 (59.8) Median duration of previous lapatinib therapy, mos (range) 6.0 (1-24) Vogel C, et al. ASCO Abstract 1017. 32

33 Trastuzumab-DM1 in HER2+ MBC: Antitumor Activity
Response Summary Assessment IRF (N = 112) Investigator (N = 112) Best objective response, n (%) CR 3 (2.7) PR 28 (25.0) 40 (35.7) SD 54 (48.2) 43 (38.4) PD 21 (18.8) 22 (19.6) Unknown 9 (8.0) 4 (3.6) ORR, n (%) Clinical benefit,* n (%) 39 (34.8) 50 (44.6) Trastuzumab-DM1 in HER2+ MBC: Antitumor Activity Response Summary Assessment IRF Investigator Pts previously treated with trastuzumab and lapatinib (n = 67) ORR, n (%) 16 (23.9) 24 (35.8) Clinical benefit,* n (%) 30 (44.8) Pts with centrally confirmed HER2+ (n = 75) 24 (32.0) 36 (48.0) 33 (44.0) 41 (54.7) * CR, PR, or SD for ≥ 6 mos. Subgroups analysis Vogel C, et al. ASCO Abstract 1017. 33

34 Trastuzumab-DM1 in HER2-Positive MBC: PFS
Median Follow-up 9.5 months 1.0 IRF (N = 112) median: 4.9 INV (N = 112) median: 4.9 0.8 0.6 Proportion Event Free 0.4 0.2 2 4 6 8 10 12 14 PFS (Mos) Vogel C, et al. ASCO Abstract 1017. 34

35 Trastuzumab-DM1 in HER2-Pos MBC: AEs
Any AE, n (%) Grade 1 or 2 Grade 3 Grade 4 All Grades Fatigue 72 (64.3) 5 (4.5) 73 (65.2) Nausea 55 (49.1) 1 (0.9) 56 (50.0) Headache 43 (38.4) Pyrexia 39 (34.8) Epistaxis 36 (32.1) 2 (1.8) 38 (33.9) Thrombocytopenia NR 3 (2.7) Constipation 33 (29.5) Eye disorders 31 (27.7) 32 (28.6) Cough 30 (26.8) Diarrhea 29 (25.9) Hypokalemia 22 (19.6) 9 (8.0) 27 (24.1) Dyspnea 23 (20.5) 24 (21.4) Pain in extremity Vogel C, et al. ASCO Abstract 1017. 35

36 Response Rates for Novel HER2-Targeting Agents after Progression on Trastuzumab
36

37 Angiogenesis Inhibitors
Monoclonal Antibodies - BEVACIZUMAB Primarly antiangiogenic multitargeted TKIs - PAZOPANIB - AXITINIB - SUNITINIB 37

38 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

39 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

40 Brufsky A et al. SABCS 2009 RIBBON-2 is the first positive phase III study of bevacizumab in second-line MBC 40

41 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)

42 This trial did not meet the criteria to go to stage 2 based on ORR
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

43 A randomized, phase II study of axitinib (AG ) in combination with docetaxel compared to DOC plus placebo in MBC Rugo HS et al. ASCO 2007 Abstr 1003 Axitinib (AG ) 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 1Sloan B et al. Curr Opin Investig Drugs 2008 2Rugo HS et al. ASCO 2005 Abstr 1067 43

44 Axitinib has promising anti-tumor activity for pts with breast cancer
Results Outcome Docetaxel+ Axitinib (n=112) Placebo (n=56) CR (%) 0.9 PR 39.3 23.2 SD 8.9 16.1 PD 33.9 42.9 Unknown 17 17.9 ORR, n (%) 40.2 Median TTP, mos 8.2 7 P value 0.038 0.052 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

45 A Phase III Trial of Sunitinib (SU) Vs
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

46 PARP1-Inhibitors PARP1 structure Poly (ADP-ribose) polymerase (PARP)
BSI-201 AZD2281 Olaparib Poly (ADP-ribose) polymerase (PARP) 46

47 and tumor-selective synthetic lethality Tumor-selective cytotoxicity
PARP inhibition and tumor-selective synthetic lethality Tumor-selective cytotoxicity CELL SURVIVAL Peralta-Leal A et al, Free Radic. Biol. Med. 2009 47

48 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

49 Olaparib in Mutation Carriers: RESULTS
400 mg bid (n=27) Olaparib 100 mg bid (n=27) ITT cohort Overall Response Rate, n (%) 11 (41)* (22)* Complete Response, n (%) (4) 0 Partial Response, n (%) (37) 6 (22) Tutt A et al. ASCO 2009, Abst # CRA 501 49

50 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 21-day cycle BSI mg/kg IV d 1, 4, 8, 11 Gemcitabine 1000 mg/mq d1, 8 Carboplatin AUC 2 d 1, 8 RESTAGING Every 2 cycles * Pts randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression 50

51 Need confirmation in phase III trial
Striking early results Need confirmation in phase III trial Presumption is that PARPi interferes with chemo-induced DNA repair O'Shaughnessy J et al. ASCO 2009 Abs 3 51

52 Resistance to PARP-Inhibitors
With the development of any active agent, resistance is sure to come Many potential mechanisms In a BRCA2-deficient cell line, resistance to PARP inhibition has been associated with restoration of BRCA2 function Edwads et al, Nature 2008 52

53 Baselga J et al. SABCS 2009 53

54 Phase I/II Neratinib + Trastuzumab in Trastuzumab-treated MBC
Swaby et al. ASCO 2009, Abstr 1004

55 Conclusions The list of the most promising agents in MBC is far from being complete Novel molecules are being discovered and developed constantly To better optimize BC therapy in the future, clinical trials testing new agents will need to meet rigorous patient selection criteria, and secure the collection of appropriate biological material. 55

56 Rationale for Targeting HER2 in Breast Cancer
20 to 25% of BCs exhibit HER2 gene amplification or protein overexpression HER2 overexpression in BC predicts for a poor clinical outcome It deregulates downstream signaling pathways, which impact on tumor cell growth and survival. Concomitant up-regulation of the PI3K-AKT survival pathway and of NFkB that protects against apoptotic stimuli (eg, chemotherapy). Survivin also is regulated by HER2. Blockage of HER2 leads to the inhibition of these survival pathway with tumor cell apoptosis Rosen LS et al. Oncologist 2010 Spector NL et al. J Clin Oncol 2009 Bacus SS et al. Oncogene 2002 Xia W et al. Cancer Res 2006 Yakes FM et al. Cancer Res 2002


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