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 Trip...
Molecular Classification <ul><li>Gene expression arrays identify five molecular subtypes  </li></ul><ul><li>that: </li></u...
Starting point <ul><li>Disease is being segmented  in rare  molecular entities according to molecular alterations </li></u...
Overcoming Resistance
Understanding the wiring diagram trastuzumab lapatinib T-DM1 Pertuzumab MM111 HER2 HR + TNBC PTEN loss PI3K mutant BRCA1 B...
Drug Development One drug for the whole Angiogenesis inhibitors Biphosphonates Stroma-targeting drugs New chemotherapies M...
Targeting HER2 <ul><li>… .. Trastuzumab </li></ul><ul><li>T-DM1  </li></ul><ul><li>Pertuzumab </li></ul><ul><li>Lapatinib ...
Neratinib in MBC – Study 201 <ul><li>Open label, multicenter  </li></ul><ul><li>Neratinib 240 mg orally QD with food, pref...
Monotherapy in MBC – Study 201 Objective response  rate = (CR + PR/evaluable pts) Clinical benefit rate = (CR + PR + SD ≥ ...
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...
Dual HER2 targeting together  with chemotherapy
Pathological CR Rates NEO-SPHERE NEO-ALTTO Trastuzumab Docetaxel Pertuzumab  Docetaxe l Trastuzumab Pertuzumab  Docetaxel ...
Dual HER2 blockade  without  chemotherapy
Trastuzumab + Pertuzumab without chemotherapy Courtesy L. Gianni
Angiogenesis
Angiogenesis <ul><li>Bevacizumab (BV), a monoclonal antibody, inhibits  </li></ul><ul><li>vascular endothelial growth fact...
General Study Designs Optional Second-line  Chemo + BV ( AVADO and RIBBON-1 only ) Chemo + No BV Chemo + BV Treat  until P...
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 4...
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 sur...
New therapeutic approaches…
Patients <ul><li>Patients with locally advanced breast cancer  </li></ul><ul><li>(and/or with distant metastases) with  </...
Aims <ul><li>To assess activity in of bevacizumab in combination with capecitabine and oral vinorelbine (sequential and co...
Treatment <ul><li>ARM A: Bevacizumab  for 2 cycles  BEVIX </li></ul><ul><li>ARM B: BEVIX </li></ul>Drug Dose Day 1 3 14 21...
Patients <ul><li>From July 2007 to December 2009 enrolled 46 patients. </li></ul><ul><li>Median age: 53 years (33-72) </li...
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 ...
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...
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 <ul><li>Develop more effective ways to antagonize estrogen. </li></ul><ul><li>Understand m...
Clinical Clues to Mechanisms of Resistance <ul><li>Loss of ER expression. </li></ul><ul><li>Multiple responses to sequenti...
Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology,  2011 ER Liver biopsy Primary Negativ...
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 cance...
New drugs in Luminal B Breast cancers:  two scenarios PI3KCA mutations FGFR1 amplification Orphan molecular diseases (ATK ...
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...
PARP Inhibition With Chemotherapy for  TN Breast Cancer:  Where Are We? <ul><li>Striking early results; phase III negative...
Back to the future …. <ul><li>Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 e...
Neo-adjuvant chemotherapy with platinum-compounds: Phase II trials  Garber JE 2006 CDDP N = 28  Gronwald J 2009 CDDP N = 2...
Phase II Study of Weekly Cisplatin and Metronomic  Cyclophosphamide and Methotrexate in Second Line  Triple-negative Metas...
Weekly Cisplatin and Metronomic Dosing  of Cyclophosphamide and Methotrexate G. S. Bhattacharyya, et al. ESMO/ECCO 2009 A ...
Weekly Cisplatin and Metronomic Dosing  of Cyclophosphamide and Methotrexate <ul><li>The average cost of this regimen is $...
Targeting hallmarks of cancer
Conclusions <ul><li>Oncogenic events can be shared across molecular  </li></ul><ul><li>classes </li></ul><ul><li>Overcomin...
Thank you 2 post doc positions available at IEO
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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

    1. 1. New drugs in subsets of breast cancer Giuseppe Curigliano MD PhD Division of Medical Oncology European Institute of Oncology
    2. 2. Breast Cancer Molecular Classification Each molecular segment is very rare and presents a specific biological feature Triple negative Her2 Luminal luminal Her2 Triple negative
    3. 3. Molecular Classification <ul><li>Gene expression arrays identify five molecular subtypes </li></ul><ul><li>that: </li></ul><ul><ul><li>Overlap with clinical-pathologic characteristics </li></ul></ul><ul><ul><li>Could drive current medical treatments </li></ul></ul><ul><li>Molecular classes could be re-divided according to </li></ul><ul><li>molecular events </li></ul>
    4. 4. Starting point <ul><li>Disease is being segmented in rare molecular entities according to molecular alterations </li></ul><ul><li>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 </li></ul>
    5. 5. Overcoming Resistance
    6. 6. 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
    7. 7. 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
    8. 8. Targeting HER2 <ul><li>… .. Trastuzumab </li></ul><ul><li>T-DM1 </li></ul><ul><li>Pertuzumab </li></ul><ul><li>Lapatinib </li></ul><ul><li>Neratinib </li></ul>
    9. 9. Neratinib in MBC – Study 201 <ul><li>Open label, multicenter </li></ul><ul><li>Neratinib 240 mg orally QD with food, preferably in the morning </li></ul><ul><li>Primary endpoint : 16-week PFS rate </li></ul><ul><li>Secondary endpoints: PFS, ORR, CBR, safety, DR, PK </li></ul>Burstein HJ et al. JCO 2010;28:1301-1307. <ul><li>Adv / MBC </li></ul><ul><li>ErbB-2+ amplification (central confirmation) </li></ul><ul><li>≥ 1 measurable lesion (modified RECIST 1.0) </li></ul><ul><li>ECOG 0-2 </li></ul><ul><li>1-4 prior chemo for metastatic disease </li></ul>Arm A: Prior trastuzumab (n = 66) Arm B: trastuzumab-naive (n = 70)
    10. 10. 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%
    11. 11. Targeting HER2/neu: Overcome resistance to trastuzumab
    12. 12. Beyond trastuzumab…T-DM1
    13. 13. Beyond trastuzumab…T-DM1
    14. 14. 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
    15. 15. Dual HER2 targeting together with chemotherapy
    16. 16. 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%
    17. 17. Dual HER2 blockade without chemotherapy
    18. 18. Trastuzumab + Pertuzumab without chemotherapy Courtesy L. Gianni
    19. 19. Angiogenesis
    20. 20. Angiogenesis <ul><li>Bevacizumab (BV), a monoclonal antibody, inhibits </li></ul><ul><li>vascular endothelial growth factor (VEGF), a key </li></ul><ul><li>mediator of angiogenesis. </li></ul><ul><li>3 randomized trials (E2100, AVADO, RIBBON-1) have </li></ul><ul><li>demonstrated significantly improved progression-free survivial (PFS) for BV combined with different </li></ul><ul><li>chemotherapies as first-line metastatic breast cacner </li></ul><ul><li>(MBC) treatment. </li></ul><ul><li>PFS improved when BV combined with chemotherapy </li></ul><ul><li>regardless of hormone receptor status, sites of </li></ul><ul><li>metastases, disease-free interval (DFI), or prior adjuvant </li></ul><ul><li>taxane use. </li></ul>
    21. 21. 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
    22. 22. 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)
    23. 23. 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
    24. 24. 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
    25. 25. New therapeutic approaches…
    26. 26. Patients <ul><li>Patients with locally advanced breast cancer </li></ul><ul><li>(and/or with distant metastases) with </li></ul><ul><li>lymphangitic spread to the chest wall are </li></ul><ul><li>eligible. </li></ul><ul><li>Excluded patients with deep venous thrombosis and documented brain metastases. </li></ul>
    27. 27. Aims <ul><li>To assess activity in of bevacizumab in combination with capecitabine and oral vinorelbine (sequential and concurrent administration). Response assessed according to RECIST criteria </li></ul><ul><li>To gain insight into the mechanisms of action of bevacizumab assessing CECs and CEPs. </li></ul><ul><li>To identify a gene signature predictive of response to bevacizumab </li></ul>
    28. 28. Treatment <ul><li>ARM A: Bevacizumab for 2 cycles BEVIX </li></ul><ul><li>ARM B: BEVIX </li></ul>Drug Dose Day 1 3 14 21 Bevacizumab 15 mg x Kg   Oral Vinorelbine 55 mg/m2   Capecitabine 2000 mg/m2  
    29. 29. Patients <ul><li>From July 2007 to December 2009 enrolled 46 patients. </li></ul><ul><li>Median age: 53 years (33-72) </li></ul><ul><li>Evaluable for primary endpoint 46 </li></ul><ul><li>Median number of cycles: 5 (2-22) </li></ul>
    30. 30. 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
    31. 31. 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
    32. 32. Results 19.07.2007 18.10.2007
    33. 33. Results
    34. 34. Results Expression pattern of approximately 160 genes correlates with response to bevacizumab
    35. 35. Endocrine Resistance : Who will be the First-in-class?
    36. 36. 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
    37. 37. Overcoming Endocrine Resistance <ul><li>Develop more effective ways to antagonize estrogen. </li></ul><ul><li>Understand mechanisms of resistance and develop strategies to overcome them. </li></ul><ul><li>Develop better biomarkers to predict estrogen dependence (response to therapy). </li></ul><ul><li>Will require serial tumor biopsies. </li></ul><ul><li>Understand genetic makeup of the patient and tumor. </li></ul>
    38. 38. Clinical Clues to Mechanisms of Resistance <ul><li>Loss of ER expression. </li></ul><ul><li>Multiple responses to sequential endocrine therapies over time; “drug” resistance but not loss of E dependence. </li></ul><ul><li>Tumors with high HER2 or EGFR have lower ER and PR and less responsiveness to endo therapy. </li></ul><ul><li>Eventual loss of E dependence even though ER is still present. </li></ul>
    39. 39. 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
    40. 40. Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology, 2011
    41. 41. L. Ding,et al, Nature 464, 2010 Genome Remodeling in Breast Cancer Primary xenograft Brain metastasis breast primary
    42. 42. 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
    43. 43. 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
    44. 44. Basal-like Breast Cancer: A Disease of DNA Repair?
    45. 45. 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
    46. 46. PARP Inhibition With Chemotherapy for TN Breast Cancer: Where Are We? <ul><li>Striking early results; phase III negative </li></ul><ul><li>Presumption is that PARP inhibition interferes </li></ul><ul><li>with chemo-induced DNA repair </li></ul><ul><li>Will PARP inhibition work in non-TN populations, </li></ul><ul><li>or is genomic instability of TN disease part of the </li></ul><ul><li>explanation? </li></ul><ul><li>Is there single agent activity of PARP inhibition in TN disease? </li></ul>
    47. 47. Back to the future …. <ul><li>Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. </li></ul>Daniel P. S. et al. J Clin Oncol; 28:1145-1153 2010
    48. 48. 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
    49. 49. 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
    50. 50. 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
    51. 51. Weekly Cisplatin and Metronomic Dosing of Cyclophosphamide and Methotrexate <ul><li>The average cost of this regimen is $60.00 per month for costs of drugs </li></ul>
    52. 52. Targeting hallmarks of cancer
    53. 53. Conclusions <ul><li>Oncogenic events can be shared across molecular </li></ul><ul><li>classes </li></ul><ul><li>Overcoming therapy resistance may require inhibition of multiple escape pathways for optimal treatment. </li></ul><ul><li>Biopsies of endocrine resistant tumors from patients are needed to confirm mechanisms of resistance. </li></ul><ul><li>Second-in-class drugs to reverse resistance to be </li></ul><ul><li>developed according to molecular profiling </li></ul><ul><li>Integrated biology approach could help to improve </li></ul><ul><li>results in patients who develop resistance… </li></ul>
    54. 54. Thank you 2 post doc positions available at IEO

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