1. New drugs in subsets of breast cancer Giuseppe Curigliano MD PhD Division of Medical Oncology European Institute of Oncology

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

5. Overcoming Resistance

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. 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

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. Targeting HER2/neu: Overcome resistance to trastuzumab

12. Beyond trastuzumab…T-DM1

13. Beyond trastuzumab…T-DM1

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. Dual HER2 targeting together with chemotherapy

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. Dual HER2 blockade without chemotherapy

18. Trastuzumab + Pertuzumab without chemotherapy Courtesy L. Gianni

19. Angiogenesis

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. 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. 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. 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. New therapeutic approaches…

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. 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. Results 19.07.2007 18.10.2007

33. Results

34. Results Expression pattern of approximately 160 genes correlates with response to bevacizumab

35. Endocrine Resistance : Who will be the First-in-class?

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

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. Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology, 2011

41. L. Ding,et al, Nature 464, 2010 Genome Remodeling in Breast Cancer Primary xenograft Brain metastasis breast primary

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. 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. Basal-like Breast Cancer: A Disease of DNA Repair?

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

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. 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. 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

52. Targeting hallmarks of cancer

54. Thank you 2 post doc positions available at IEO