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MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight session - New drugs in subsets of breast cancer
 

MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight session - New drugs in subsets of breast cancer

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  • The docetaxel+BV7.5 arm in AVADO was excluded from the pooled analysis. PFS data for patients who received non-protocol anti- cancer therapies prior to disease progression were censored. The primary analysis of PFS was based on IRF assessment for E2100 and on investigator assessment for AVADO and RIBBON-1.
  • Bv=bevacizumab, CI=confidence interval. BV administered at 10 mg/kg/2wk in E2100 and bevacizumab 15 mg/kg/3wk in AVADO and RIBBON-1. Non-Bv=chemotherapy alone in E2100 and chemotherapy+placebo in AVADO and RIBBON-1. Data cutoff date was April 30, 2009 for AVADO and February 23, 2009 for RIBBON-1.

MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight session - New drugs in subsets of breast cancer MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight session - New drugs in subsets of breast cancer Presentation Transcript

  • New drugs in subsets of breast cancer Giuseppe Curigliano MD PhD Division of Medical Oncology European Institute of Oncology
  • Breast Cancer Molecular Classification Each molecular segment is very rare and presents a specific biological feature Triple negative Her2 Luminal luminal Her2 Triple negative
  • Molecular Classification
    • Gene expression arrays identify five molecular subtypes
    • that:
      • Overlap with clinical-pathologic characteristics
      • Could drive current medical treatments
    • Molecular classes could be re-divided according to
    • molecular events
  • Starting point
    • Disease is being segmented in rare molecular entities according to molecular alterations
    • Implication: Optimal development of targeted agent requires the enrichment of trials in patients presenting the candidate molecular alteration, ie a molecular selection needs to be done before inclusion in phase I/II trial
  • Overcoming Resistance
  • Understanding the wiring diagram trastuzumab lapatinib T-DM1 Pertuzumab MM111 HER2 HR + TNBC PTEN loss PI3K mutant BRCA1 BRCA2 Tamoxifen AI Estrogen degrading FGFR Cabozantinib MM121 Anti-PI3K, AKT and mTOR Anti-PI3K β PARP inhib. Platinum Salts anti-EGFR PARP inhibitors FGFR ampl FGR inh
  • Drug Development One drug for the whole Angiogenesis inhibitors Biphosphonates Stroma-targeting drugs New chemotherapies Modulation of drug sensitvity (incl IGF1r Iinh) Cancer vaccines Low benefit for the whole Second-in class In a specific subtype: To do better To reverse resistance Molecular Niche Global trials Expected effect mTOR inhibitors small TKI Pertuzumab/trast CHK1 inh ? Trastuzumab T-DM1 PARP inh ? Cisplatin? Subtype-specific First-in class AI + everolimus? TKI ? or new subdivision according to molecular events TAM Small population High sensitivity
  • Targeting HER2
    • … .. Trastuzumab
    • T-DM1
    • Pertuzumab
    • Lapatinib
    • Neratinib
  • Neratinib in MBC – Study 201
    • Open label, multicenter
    • Neratinib 240 mg orally QD with food, preferably in the morning
    • Primary endpoint : 16-week PFS rate
    • Secondary endpoints: PFS, ORR, CBR, safety, DR, PK
    Burstein HJ et al. JCO 2010;28:1301-1307.
    • Adv / MBC
    • ErbB-2+ amplification (central confirmation)
    • ≥ 1 measurable lesion (modified RECIST 1.0)
    • ECOG 0-2
    • 1-4 prior chemo for metastatic disease
    Arm A: Prior trastuzumab (n = 66) Arm B: trastuzumab-naive (n = 70)
  • Monotherapy in MBC – Study 201 Objective response rate = (CR + PR/evaluable pts) Clinical benefit rate = (CR + PR + SD ≥ 24 weeks /evaluable pts by independent review) Burstein HJ et al. JCO 2010;28:1301-1307. Independent Assessment Prior Trastuzumab (n = 63) No prior Trastuzumab (n = 64) Objective Response Rate (95% CI) 24% (14-36) 56% (43-68) Clinical Benefit Rate (95% CI) 33% (22-46) 69% (56-80) Partial Response 24% 55% Stable Disease <24 wks ≥24 wks 33% 10% 20% 13% Progressive Disease 27% 8% Unknown 6% 3%
  • Targeting HER2/neu: Overcome resistance to trastuzumab
  • Beyond trastuzumab…T-DM1
  • Beyond trastuzumab…T-DM1
  • Dual HER2 blockade in neoadjuvant trials NEOSPHERE TRASTUZUMAB + PERTUZUMAB N = 417 Europe, Asia, N + S America Median age ~ 50 Operable ~ 60% Inflammatory 6 to 9% N = 450 Europe, Asia, Canada, South America Median age ~ 50 Operable 100% Inflammatory 0% HR+ 47% HR- 53% HR+ 48% HR- 52% NEOALTTO TRASTUZUMAB + LAPATINIB
  • Dual HER2 targeting together with chemotherapy
  • Pathological CR Rates NEO-SPHERE NEO-ALTTO Trastuzumab Docetaxel Pertuzumab Docetaxe l Trastuzumab Pertuzumab Docetaxel Trastuzumab Pertuzumab ITT 29% 24% 46% 17% Trastuzumab Paclitaxel Lapatinib Paclitaxel Trastuzumab Lapatinib Paclitaxel ITT 29% 25% 51%
  • Dual HER2 blockade without chemotherapy
  • Trastuzumab + Pertuzumab without chemotherapy Courtesy L. Gianni
  • Angiogenesis
  • Angiogenesis
    • Bevacizumab (BV), a monoclonal antibody, inhibits
    • vascular endothelial growth factor (VEGF), a key
    • mediator of angiogenesis.
    • 3 randomized trials (E2100, AVADO, RIBBON-1) have
    • demonstrated significantly improved progression-free survivial (PFS) for BV combined with different
    • chemotherapies as first-line metastatic breast cacner
    • (MBC) treatment.
    • PFS improved when BV combined with chemotherapy
    • regardless of hormone receptor status, sites of
    • metastases, disease-free interval (DFI), or prior adjuvant
    • taxane use.
  • General Study Designs Optional Second-line Chemo + BV ( AVADO and RIBBON-1 only ) Chemo + No BV Chemo + BV Treat until PD RANDOMIZE Previously Untreated MBC RIBBON-1 Capecitabine, Taxane, or Anthracycline AVADO Docetaxel E2100 Paclitaxel
  • Progression-Free Survival, Pooled Population Non-BV (n=1008) BV (n=1439) Median, mo 6.7 9.2 HR (95% CI) 0.64 (0.57–0.71)
  • Objective Response Rate* *Includes only patients with measurable disease at baseline. Non-BV (n=788) BV (n=1105) 50 0 45 40 35 30 25 20 15 10 5 32 49
  • Overall Survival, Pooled Population Non-BV (n=1008) BV (n=1439) Median, mo 26.4 26.7 HR (95% CI) 0.97 (0.86–1.08) 1-yr survival rate (%) 77 82
  • New therapeutic approaches…
  • Patients
    • Patients with locally advanced breast cancer
    • (and/or with distant metastases) with
    • lymphangitic spread to the chest wall are
    • eligible.
    • Excluded patients with deep venous thrombosis and documented brain metastases.
  • Aims
    • To assess activity in of bevacizumab in combination with capecitabine and oral vinorelbine (sequential and concurrent administration). Response assessed according to RECIST criteria
    • To gain insight into the mechanisms of action of bevacizumab assessing CECs and CEPs.
    • To identify a gene signature predictive of response to bevacizumab
  • Treatment
    • ARM A: Bevacizumab for 2 cycles BEVIX
    • ARM B: BEVIX
    Drug Dose Day 1 3 14 21 Bevacizumab 15 mg x Kg   Oral Vinorelbine 55 mg/m2   Capecitabine 2000 mg/m2  
  • Patients
    • From July 2007 to December 2009 enrolled 46 patients.
    • Median age: 53 years (33-72)
    • Evaluable for primary endpoint 46
    • Median number of cycles: 5 (2-22)
  • N % Patients 46 ER+/PgR+ - 18 39 ER-/PgR- 28 61 HER2 Status Positive 8 17 Triple negative 21 46 Prior CT regimens 0 1 15 13 33 28 2 5 11 ≥ 3 13 28 No metastatic sites Only local disease 2 4 1 11 24 2 12 26 ≥ 3 21 46
  • Results ARM A (Bevacizumab alone) ARM A BEVIX ARM B BEVIX N % N % N % Activity 18 18 28 CR/PR 2 11 7 39 13 46 SD 4 22 5 27 14 50 PD 12 67 6 33 1 4
  • Results 19.07.2007 18.10.2007
  • Results
  • Results Expression pattern of approximately 160 genes correlates with response to bevacizumab
  • Endocrine Resistance : Who will be the First-in-class?
  • ER Function Growth Growth Factors HER-3 HER-2 T EGFR T ERK1,2 AKT ER ER ER ER AIB1 N-COR AIB1 N-COR ER
  • Overcoming Endocrine Resistance
    • Develop more effective ways to antagonize estrogen.
    • Understand mechanisms of resistance and develop strategies to overcome them.
    • Develop better biomarkers to predict estrogen dependence (response to therapy).
    • Will require serial tumor biopsies.
    • Understand genetic makeup of the patient and tumor.
  • Clinical Clues to Mechanisms of Resistance
    • Loss of ER expression.
    • Multiple responses to sequential endocrine therapies over time; “drug” resistance but not loss of E dependence.
    • Tumors with high HER2 or EGFR have lower ER and PR and less responsiveness to endo therapy.
    • Eventual loss of E dependence even though ER is still present.
  • Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology, 2011 ER Liver biopsy Primary Negative Positive Total Negative 43 (74.1%) 15 (25.9%) 58 (100%) Positive 22 (11.2%) 175 (88.8%) 197 (100%) Total 67 188 255
  • Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology, 2011
  • L. Ding,et al, Nature 464, 2010 Genome Remodeling in Breast Cancer Primary xenograft Brain metastasis breast primary
  • New drugs in Luminal B Breast cancers: two scenarios Scenario I: First-in-class drug for the whole luminal B breast cancer: Intracellular kinase inhibitors: mTOR inhibitors (everolimus) Tyrosine kinase inhibitors: EGFR, IGF1R inhibitors Retrospective identification of predictors
  • New drugs in Luminal B Breast cancers: two scenarios PI3KCA mutations FGFR1 amplification Orphan molecular diseases (ATK amp, JAK2 amp, FGFR2 amp) IGF1R expression Scenario II: biology-driven trials in small segments drugs specific to biologically-defined subsets of ER+ breast cancer: FGFR1 inhibitors in FGFR1 amplified breast cancers PI3K inhibitors in PI3KCA mutated breast cancers
  • Basal-like Breast Cancer: A Disease of DNA Repair?
  • PARP1 inhibitors Compound Route Phase Ongoing Trials Iniparib (BSI-201) Intravenous I–III Breast Veliparib Oral I-II Breast, ovarian Olaparib Oral I–II Breast, ovarian
  • PARP Inhibition With Chemotherapy for TN Breast Cancer: Where Are We?
    • Striking early results; phase III negative
    • Presumption is that PARP inhibition interferes
    • with chemo-induced DNA repair
    • Will PARP inhibition work in non-TN populations,
    • or is genomic instability of TN disease part of the
    • explanation?
    • Is there single agent activity of PARP inhibition in TN disease?
  • Back to the future ….
    • Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive.
    Daniel P. S. et al. J Clin Oncol; 28:1145-1153 2010
  • Neo-adjuvant chemotherapy with platinum-compounds: Phase II trials Garber JE 2006 CDDP N = 28 Gronwald J 2009 CDDP N = 25 Torrisi R 2008 ECF -> P N = 30 Ryan PD 2009 CDDP + BEV N = 51 22 15 40 72 triple negative triple negative triple negative BRCA-1 mutation % pCR
  • Phase II Study of Weekly Cisplatin and Metronomic Cyclophosphamide and Methotrexate in Second Line Triple-negative Metastatic Breast Cancer G. S. Bhattacharyya, et al. ESMO/ECCO 2009 Metastatic Ca Breast - ER/PR/HER-2neu negative Post anthracycline and taxanes No brain metastases Cisplatin 20mg/m 2 + Cyclophosphamide 50mg per day + Methotrexate 2.5 mg twice a day on day 1 and 2 of every week CM
  • Weekly Cisplatin and Metronomic Dosing of Cyclophosphamide and Methotrexate G. S. Bhattacharyya, et al. ESMO/ECCO 2009 A (66) B (60) CR 8% (5) 5% (3) PR 55% (36) 28% (17) SD 27% (18) 30% (18) Time to progression 13mo 7mo (9mo to 24mo) (6mo to 14mo) Median overall survival 16mo 12mo Survival at the end of 3 years 10 4
  • Weekly Cisplatin and Metronomic Dosing of Cyclophosphamide and Methotrexate
    • The average cost of this regimen is $60.00 per month for costs of drugs
  • Targeting hallmarks of cancer
  • Conclusions
    • Oncogenic events can be shared across molecular
    • classes
    • Overcoming therapy resistance may require inhibition of multiple escape pathways for optimal treatment.
    • Biopsies of endocrine resistant tumors from patients are needed to confirm mechanisms of resistance.
    • Second-in-class drugs to reverse resistance to be
    • developed according to molecular profiling
    • Integrated biology approach could help to improve
    • results in patients who develop resistance…
  • Thank you 2 post doc positions available at IEO