Osp PertiniSEugenioCTO Therapeutic approach to HER 2 breast cancer in metastatic setting Lisa Carey SABCS 2018 La malattia HER2 positiva Trastuzumab Key Phase III HER2 Positive MBC Trials ID: 1045520
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1. GIULIANA D’AURIAUOC Oncologia ASL Roma 2Osp Pertini-S.Eugenio-CTOTherapeutic approach to HER 2 breast cancer in metastatic setting
2. Lisa Carey, SABCS 2018
3. La malattia HER2 positiva: Trastuzumab
4. Key Phase III HER2 Positive MBC TrialsPresented By Carlos Barrios at 2019 ASCO Annual Meeting
5. 8-year follow-up of the CLEOPATRA trial (OS)Swain et al, Abstr. 1020, ASCO 2019
6. Mark D. Pegram 2018 ASCO EDUCATIONAL BOOK
7. Awada, ESMO Breast 2019
8. Awada, ESMO Breast 2019
9. OUTLINEMargetuximabNeratinibPyrotinibNew drugs and combinations
10. Margetuximab: Fc-engineered to Activate Immune ResponsesPresented By Hope Rugo at 2019 ASCO Annual Meeting
11. ADCC
12. Study CP-MGAH22-04 (SOPHIA) Design1,2Presented By Hope Rugo at 2019 ASCO Annual Meeting
13. ITT Population: Prior Cancer TherapyPresented By Hope Rugo at 2019 ASCO Annual Meeting
14. PFS Analysis in ITT PopulationPresented By Hope Rugo at 2019 ASCO Annual Meeting
15. Planned* Exploratory PFS Analyses by FcR Genotypes (CBA) Presented By Hope Rugo at 2019 ASCO Annual Meeting
16. SOFIA TRIALPresented By Carlos Barrios at 2019 ASCO Annual Meeting
17. NALA study designPresented By Cristina Saura at 2019 ASCO Annual Meeting
18. Baseline characteristicsPresented By Cristina Saura at 2019 ASCO Annual Meeting
19. Centrally confirmed PFS (co-primary endpoint)Presented By Cristina Saura at 2019 ASCO Annual Meeting
20. Prespecified restricted means analysis – PFSPresented By Cristina Saura at 2019 ASCO Annual Meeting
21. NALA summary of resultsSwain et al, Abstr. 1020, ASCO 2019
22. NALA safety considerationsSwain et al, Abstr. 1020, ASCO 2019
23. NALA TRIALPresented By Carlos Barrios at 2019 ASCO Annual Meeting
24. PHENIX Study Design<br /> Pyrotinib combined with capecitabine in women with HER2+ metastatic breast caNcer prevIously treated with trastuzumab and taXanes: a randomized phase 3 study<br />Presented By Zefei Jiang at 2019 ASCO Annual Meeting
25. Slide 8Presented By Zefei Jiang at 2019 ASCO Annual Meeting
26. Slide 9Presented By Zefei Jiang at 2019 ASCO Annual Meeting
27. Slide 14Presented By Zefei Jiang at 2019 ASCO Annual Meeting
28. PHENIX TRIALPresented By Carlos Barrios at 2019 ASCO Annual Meeting
29. Anti-HER2 directed TKIs in DevelopmentPresented By Carlos Barrios at 2019 ASCO Annual Meeting
30. OUTLINEMargetuximabNeratinibPyrotinibNew drugs and combinations
31. Slide 26Presented By Sunil Verma at 2019 ASCO Annual Meeting
32. Anti-HER2 directed Antibody Drug Conjugates in DevelopmentPresented By Carlos Barrios at 2019 ASCO Annual Meeting
33. Bystander effectHigh potency of payloadStable linker-payloadPayload with short systemic half-lifePayload with a different mechanism of actionHigh drug-to-antibody ratio (~1:8)Tumor-selective cleavable linkerIwata et al. ASCO 2018. Trastuzumab Deruxtecan (DS-8201a): Structure and Mechanism of Action
34. Tamura et al, Lancet Oncology 2019N = 111Efficacy of DS-8201a in HER2+ mBC: Phase I study
35. Accrual complete as of September 2018ClinicalTrials.gov NCT03248492DESTINY-Breast01 study: DS-8201a in HER2+ MBC with prior T-DM1
36. Study NameDescription/PopulationCT.gov Identifier and EUDRA CT IdentifierRecruitment StatusDESTINY-Breast02DS-8201a vs investigator’s choice inHER2-positive unresectable and/or MBC previously treated with standard of care anti-HER2 therapies including T-DM1NCT03523585*2018-000221-31RecruitingDESTINY-Breast03DS-8201a vs. T-DM1 in HER2-positive unresectable and/or MBCNCT03529110*2018-000222-61RecruitingDESTINY-Breast04DS-8201a vs. physician’s choice in HER2-low, unresectable and/or MBCNCT03734029*2018-003069-33RecruitingClinicalTrials.gov accessed 26APR2019Ongoing Phase III Trials: DS-8201a in MBC
37. SYD-985: Trastuzumab DuocarmazineHER2-targeting ADC based on trastuzumabProtease cleavable linker with a DNA alkylating toxin duocarmycinToxin incorporated into the linker as an inactive prodrugProteolytic cleavage: release of the membrane permeable active toxin
38. Saura C, et al. ASCO 2018HER2+ (n=48): ORR 33%Efficacy of SYD-985 in MBC: Phase I study
39. Phase III: Tulip Trial (n=345)CT.gov: NCT03262935HER2+ MBC≥2 HER2-Rx regimensSYD985 (1.2 mg/kg Q3W)Physician's choice (as per SOC) Primary endpoint: PFSSecondary endpoints: OS, ORR, PRO
40. Slide 20Presented By Sunil Verma at 2019 ASCO Annual Meeting
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44. monarcHER: ConclusionsIn the randomized phase II monarcHER trial, the primary endpoint of median PFS was significantly prolonged with abemaciclib + trastuzumab + fulvestrant vs trastuzumab + CT in patients with hormone receptor–positive/HER2-positive advanced BC previously treated with HER2-directed therapiesMedian PFS: 8.32 vs 5.69 mos; HR: 0.673; P = .0506 (prespecified α = 0.20)Median PFS did not improve with abemaciclib + trastuzumab vs trastuzumab + CTConfirmed best ORR significantly higher with abemaciclib + trastuzumab + fulvestrant vs trastuzumab + CT in ITT population (32.9% vs 13.9%; P = .0042) and in subgroup with measurable disease (35.7% vs 16.2%; P = .0111)Safety profile generally tolerable with no new signals observedInvestigators concluded that abemaciclib has shown clinical activity in hormone receptor–positive/HER2-positive advanced BCSlide credit: clinicaloptions.comTolaney. ESMO 2019. Abstr LBA23.
45. E Ciruelos,et al. Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TexasN=15PFS6 Rates:Cohort A: 33,3% (5/15), Cohort B: 40.0% (6/15) Cohort B2: 53.3% (8/15)Median PFS in cohorts B1+B2, Luminal vs Non-Luminal (defined by PAM50) :12.4 vs. 4.1 months(HR=0.30; p-value=0.025). CBR6 in Luminal vs Non-Luminal :73% vs. 25% (p=0.022) Safety:Grade 1-2 in 97.7% of ptsGrade 3-4 in 84.4% of pts, mainly neutropenia (80%) and thrombocytopenia (17%). Dose reductions were required in 60% of pts.
46. Primary endpoint of the Phase II part of the study : ORRSecondary endpoints: PFS, DCR, duration of response, duration of disease control, OS
47. Results:PDL1 + cohort (n= 46)ORR: 15,2% (CI 7-27%)Median PFS: 2,7 moMedian duration of disease control: 11,1 moMedian OS: 16,1 moPDL1 - cohort (n= 12)ORR: 012-months PFS Rates:13%12-months OS Rates: 65%12-months PFS Rates:0%12-months OS Rates: 12%
48. Stromal TILs (sTILs) from metastatic biopsy:ORR 39% (sTILs+) vs 5% (sTILs-)Toxicity: 2/58 with grade III/IV pneumonitis
49. Current Approach for Advanced HER2+ Breast CancerPresented By Carlos Barrios at 2019 ASCO Annual Meeting
50. "If I have seen further it is by standing upon the shoulders of giants."Presented By Gabriel Hortobagyi at 2019 ASCO Annual Meeting