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Emerging Medical Treatments and Future Directions Stefano Iacobelli Cancer Clinic & Laboratory of Molecular Oncology On behalf of the Consorzio Interuniversitario.

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Presentation on theme: "Emerging Medical Treatments and Future Directions Stefano Iacobelli Cancer Clinic & Laboratory of Molecular Oncology On behalf of the Consorzio Interuniversitario."— Presentation transcript:

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  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 Gueth U et al. Oncology 2009 However…

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

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

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

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

7 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) Trastuzumab represents the foundation of treatment of HER2+ Breast Cancer

8 Altered TargetSteric hindrance of receptor by cell surface proteins (MUC4) 1 Truncated form of receptor (p95) 2 Mutations in HER2 3 Increased circulating HER2 ECD Alternative pathway signaling IGF1R overexpression 4 VEGF overexpression 5 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 PTEN 7 Reduced p27 kip1 8 Increased AKT activity 9 Molecular mechanisms of Trastuzumab resistance 9 Berns K et al. Cancer Cell Nagy P et al. Cancer Res Scaltriti M et al. J Natl Cancer Inst Prempree C et al. JCO 24: 611s, Nahta R et al. Cancer Res du Manoir JM et al. Clin Cancer Res Motoyama AB et al. Cancer Res Nagata Y et al. Cancer Cell Nahta R et al. Cancer Res 2004

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

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  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  Prevents HER2 heterodimerization  Potent inhibitor of HER-mediated signalling pathways

12 ResponseN=66 CR5 (7.6%) PR11 (16.7%) ORR16 (24.2%) SD > 6 mos17 (25.8%) Phase II Trial of Pertuzumab and Trastuzumab in Patients With HER2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy 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) - 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 Toxicities Baselga J, J Clin Oncol 2010

13 CLEOPATRA: Phase III study of Trastuzumab + Pertuzumab in HER2+ MBC 1:1 randomisation Untreated HER2+ MBC n=800 Herceptin + docetaxel + placebo 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 h infusion 17 patients with HER2 positive MBC Toxicities 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 Infusion Reactions

16 Lapatinib inhibits EGFR and HER2 LAPATINIBGEFITINIBERLOTINIB ErbB13.0 ± 0.2 * 0.4 ± 0.1 * 0.7 ± 0.1 * ErbB213 ± 1 * 870 ± 90 * 1000 ± 100 * ErbB4347 ± 16 ‡ 1130 ± 370 ‡ 1530 ± 270 ‡ *K i app (nM); ‡ cK i app (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 PI3K/Akt pathway MAPK pathway (Ras/Raf/ MEK/ERK) Lapatinib Acts Intracellularly, Directly Inhibiting Downstream Signals Ligands ErbB2 Other ErbB Proliferation Cell cycle, Survival PI3K/Akt pathway MAPK pathway (Ras/Raf/ MEK/ERK) Lapatinib

18 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/m 2 /d po days 1–14 q 3 wk Capecitabine 2500 mg/m 2 /day po days 1–14 q 3 wk po = oral; qd = once daily; q 3 wk = once every 3 weeks EGF : Phase III, randomised, controlled study of lapatinib plus capecitabine vs capecitabine alone Cameron et al. Breast Can Res Treat 2008; Geyer et al. N Engl J Med 2006

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

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

21 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 Cancer Res 2007

22 Scaltriti et al. J Natl Cancer Inst 2007 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

23

24 EGF : Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory MBC HER2+ MBC pretreated with Trastuzumab, Anthra, Taxane (n=296) Lapatinib 1500 mg/day p.o. (n=148) 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 R Crossover if PD after 4wk therapy (N = 73)

25 EGF : Survival Analyses 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 Blackwell KL et al. J Clin Oncol 2010

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

27 Advanced HER2 + BC (N=136) Neratinib 240 mg Prior trastuzumab treatment (n = 66) Neratinib 240 mg No prior trastuzumab treatment (n = 70) Phase II study of Neratinib in pts with Advanced HER2 positive Breast Cancer 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 JNJ , A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain Barrier BT474 ErbB2-overexpressing breast carcinoma model Drug plasma and tissue distribution of JNJ and lapatinib in nude mice bearing A431 Xenografts L J N87 intracranial model 5 x10 4 cells were injected intracranially, and animals (n=10) were treated with vehicle or 200 mg/kg JNJ daily for 50 days mTTP JNJ significantly extended survival by 31.3% Emanuel SL et al. Mol Pharmacol 2008

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%. Lewis Phillips GD et al. Cancer Res 2008Beeram M et al. ASCO 2008 (Abstr 1028)

31 Trastuzumab- DM1* q3w ORR, safety/ Tolerability, PFS *3.6 mg/kg as 30- to 90-min continuous infusion. Vukelja S, et al. SABCS Abstract 33. Vogel C, et al. ASCO Abstract 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) A phase II study of Trastuzumab-DM1 in pts with HER2 positive MBC

32 Trastuzumab-DM1 in HER2-Positive MBC: Treatment History Vogel C, et al. ASCO Abstract Previous Chemotherapy and Anti-HER2 TherapyPatients (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)

33 Vogel C, et al. ASCO Abstract Response Summary Assessment IRF (N = 112) Investigator (N = 112) Best objective response, n (%) CR03 (2.7) PR28 (25.0)40 (35.7) SD54 (48.2)43 (38.4) PD21 (18.8)22 (19.6) Unknown9 (8.0)4 (3.6) ORR, n (%)28 (25.0)43 (38.4) Clinical benefit,* n (%)39 (34.8)50 (44.6) * CR, PR, or SD for ≥ 6 mos. Trastuzumab-DM1 in HER2+ MBC: Antitumor Activity Response Summary Assessment IRFInvestigator Pts previously treated with trastuzumab and lapatinib (n = 67) ORR, n (%)16 (23.9)24 (35.8) Clinical benefit,* n (%)24 (35.8)30 (44.8) Pts with centrally confirmed HER2+ (n = 75) ORR, n (%)24 (32.0)36 (48.0) Clinical benefit,* n (%)33 (44.0)41 (54.7) Subgroups analysis

34 Trastuzumab-DM1 in HER2-Positive MBC: PFS Vogel C, et al. ASCO Abstract Proportion Event Free 14 PFS (Mos) IRF (N = 112) median: 4.9 INV (N = 112) median: Median Follow-up 9.5 months

35 Trastuzumab-DM1 in HER2-Pos MBC: AEs Any AE, n (%) Grade 1 or 2 Grade 3Grade 4All Grades Fatigue72 (64.3)5 (4.5)073 (65.2) Nausea55 (49.1)1 (0.9)056 (50.0) Headache43 (38.4)00 Pyrexia39 (34.8)1 (0.9)039 (34.8) Epistaxis36 (32.1)2 (1.8)038 (33.9) ThrombocytopeniaNR5 (4.5)3 (2.7)NR Constipation33 (29.5)00 Eye disorders31 (27.7)01 (0.9)32 (28.6) Cough30 (26.8)00 Diarrhea29 (25.9)00 Hypokalemia22 (19.6)9 (8.0)027 (24.1) Dyspnea23 (20.5)2 (1.8)1 (0.9)24 (21.4) Pain in extremity24 (21.4)00 Vogel C, et al. ASCO Abstract 1017.

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

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

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

39  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 RIBBON-2: A randomized phase III trial of Bevacizumab with cht for II line HER2neg MBC Brufsky A et al. SABCS 2009 Bevacizumab 15 mg/kg q3w or 10 mg/kg q2w

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

41 A Phase II study of GW (pazopanib) in pts with recurrent or metastatic breast cancer Taylor SK et al. ASCO 2009 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 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  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) Cobleigh et al. Semin Oncol 2003 Taylo SK et al. ASCO 2009 Burstein et al. JCO 2008

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-KIT 1  Previous phase I study identified appropriate doses of docetaxel and axitinib 2 (DOC 80 mg/m2 q3w with axitinib 5 mg twice daily ) 1 Sloan B et al. Curr Opin Investig Drugs Rugo HS et al. ASCO 2005 Abstr 1067 Docetaxel 80 mg/mq q3w + Axitinib 5 mg twice daily n=112 Docetaxel 80 mg/mq q3w + Placebo n=56 Pts with MBC not pretreated with cht for metastatic disease n=168 Randomized 2:1 Primary Endpoint: TTP

44 Outcome Docetaxel+ Axitinib (n=112) Docetaxel+ Placebo (n=56) CR (%)0.90 PR SD PD Unknown ORR, n (%) Median TTP, mos8.27 P value Toxicities Docetaxel and axitinib associated with a higher incidence of grade 3/4 febrile neutropenia, fatigue, stomatitis, hypertension, and thromboembolic events Results Axitinib has promising anti-tumor activity for pts with breast cancer

45 A Phase III Trial of Sunitinib (SU) Vs. Capecitabine (C) in Pts with Previously Treated HER2-Negative Advanced Breast Cancer (ABC) HER2 negative ABC resistant to Anthra and Taxane (n=464) Sunitinib 37.5 mg daily (231) Capecitabine 1250 mg/mq x2 /die d1-14 q21 (233) Randomized 1:1 mPFS 2.8 vs. 4.2 mos for SU vs. C (p<0.001) ORR 9.1 vs 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. Barrios C et al. SABCS 2009 Abs 46 Trial stopped for futility

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

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

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) Olaparib 400 mg po bid (MDT) 28-day cycles; n = 27 Cohort 2* 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 - Median 3 prior cht treatments - In higher dose cohort, two thirds had BRCA1 mutation Primary End-point: ORR by RECIST

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

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 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 21-day cycle

51  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

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

53 Baselga J et al. SABCS 2009

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

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.

56 Rationale for Targeting HER2 in Breast Cancer 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  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


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