HER2 Positive Breast Cancer

Transcription

1 HER2 Positive Breast Cancer Charles E. Geyer, Jr. MD, FACP Professor of Medicine Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Associate Director of Clinical Research Massey Cancer Center Heme/Onc Fellows Lecture Series May 1, 2018

2 HER2/Neu Oncogene Discovery 1984: Neu transforming gene identified in chemically induced rat neuro-glioblastoma : HER2 amplification identified in human breast cancer : HER2 and c-erbb2 identified and found to be the same gene as neu : Neu oncogene had activating point mutation in transmembrane domain : HER2/neu amplification associated with worse prognosis in operable breast cancer 5 1 Schecter AL et al. Nature 1984;312: King CR et al. Science 1985;229: Coussens L et al. Science 1985; 230: Bargmann CI et al. Cell 1986;45: Slamon DJ et al. Science 1987; 237:

3 HER Family Receptors and Ligands EGF Epi β-cel HB-EGF HRG (NRG1) Epi HB-GF NRG1 Ligand binding domain Transmembrane Tyrosine kinase domain HER1/ EGFR HER2 HER3 HER4 Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21 Roskoski. Biochem Biophys Res Commun. 2004;319:1; Rowinsky. Annu Rev Med. 2004;55:433

4 HER Family of Receptors Ligand Binding, Dimerization, and Phosphorylation HER1 (Open) HER1 (Closed) EGF Dimerization HER2 (Open) EGF Phosphorylation Activation of Downstream Signaling Roskoski. Biochem Biophys Res Commun. 2004;319:1; Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21

5 Hierarchy of HER2 Family Dimer Formation and Signal Potency Homodimers ErbB-1 ErbB-1 ErbB-1 ErbB-3 HER2 Heterodimers ErbB-2 ErbB-2 ErbB-1 ErbB-4 ErbB-1 ErbB-2 ErbB-3 ErbB-3 ErbB-4 ErbB-4 ErbB-3 ErbB-4 ErbB-4 ErbB-2 ErbB-3 ErbB-2 Weakest Strongest Holbro T and Hynes N. Annu Rev Pharmacol Toxicol. 2004;44: Harari D and Yarden Y. Oncogene. 2000;19: Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35

6 HER Family Heterodimer Signaling Pathways Grb2 Sos Shc Grb2 Sos PI3K Ras Raf PTEN Akt MEK1/2 mtor GSK3 FKHR BAD MAPK Cyclin D1, E Cell-cycle progression p27 Survival Proliferation

7 AC or Paclitaxel alone or with Trastuzumab in HER2+ MBC (2+ and 3+ on IHC) Median TTP 7.4 months vs 4.6 months (P<0.001) Median survival 25.1 months vs 20.3 months (P=0.046) Slamon DJ et al. NEJM 344: 2001;

8 Trastuzumab with Chemotherapy as First-line Therapy for Metastatic Disease Agent(s) Administered with Trastuzumab Response Rate (%) Median Response Duration (months) Median TTF (months) Median Survival (months) Doxorubucin Cyclophosphamide Paclitaxel Docetaxel Navelbine 3 68 N/P 5.6 N/P * N/P = Not Provided 1 Slamon DJ et al. N Engl J Med 2001;344: Marty M et al. J Clin Oncol 2005;23: Burstein HJ et al. J Clin Oncol 2003;21:

9 ASCO-CAP Guidelines Definitions of HER2 Status FDA Positive ASCO-CAP Positive ASCO-CAP Equivocal* ASCO-CAP Negative IHC Membrane staining Intensity Percent staining 3+ Intense >10% 3+ Complete circumferential and intense, >10% of cells 2+ Incomplete or weak/mod > 10%, Strong/complete <10% 0 or 1+ Incomplete and Weak to None FISH Single probe assay HER2 copy number N/A Amplified 6 Equivocal 4 to <6 Non-amplified <4 Dual probe assay with HER2/CEP17 ratio >2.0 >2.0 OR <2.0 with >6 copies per cell <2.0 with >4.0 and <6.0 copies per cell < 2.0 with <4 copies per cell *Reflex testing with alternative method or chromosome 17 probe Wolff AC et al. J Clin Oncol. 2013:31;

10 Trastuzumab with Alternative Chemotherapy following Progression 54 patients First line Response rate - 43% Stable disease > 6 months - 43% Second line Response rate - 26% Stable disease > 6 months - 43% Median TTP - 6 months Beyond second line Response rate - 30% Stable disease > 6 months - 28% Median TTP - 6 months Bartsch R et al, BMC Cancer 2006;15(6):

11 GBG 26/BIG-05: Trastuzumab/ Capecitabine vs. Capecitabine in Breast Cancer Progressing during Trastuzumab Eligibility criteria: Progressive MBC or LABC HER2 positive Patients randomized: 156 Prior therapies : 1 st line metastatic setting: T + taxane 111 T ± non-taxane 42 Adjuvant: T + taxane 3 Prior anthracyclines 75 Visceral metastases 119 R A N D O M I Z E Trastuzumab (T) 6 mg/kg day 1 q 21 days Capecitabine 2500 mg/m 2 /day, days 1-14, q 21 days Capecitabine 2500 mg/m 2 /day days 1-14, q 21 days Primary endpoint: TTP Secondary endpoints: OS, ORR, CB Von Minckwitz G, et al. J Clin Oncol 2009; 27:

12 GBG 26/BIG 3-05 Capecitabine vs Capecitabine + Trastuzumab (median follow-up 15.6 months) (accrual closed with registration of lapatinib) Capecitabine Capecitabine + Trastuzumab Number patients P value Time to Progression 5.6 months 8.2 months 0.03 Response Rate 27% 48% 0.01 Overall Survival 20.4 months 25.5 months NS Von Minckwitz G, et al. J Clin Oncol 2009; 27:

13 Lapatinib Mechanism of Action Oral dual-tyrosine kinase inhibitor with specificity for the EGFR and HER2 receptors Binds reversibly to the cytoplasmic ATP-binding site of the kinases, preventing receptor phosphorylation and activation Blocks downstream signaling through homodimers and heterodimers of EGFR and HER2 Lapatinib Downstream signaling cascade Rusnak et al. Mol Cancer Ther 2001;1:85-94 Xia et al. Oncogene 2002;21: Konecny et al. Cancer Res 2006;66:

14 Lapatinib Non-Cross Resistance with Trastuzumab Traztuzumab BT474 conditioned percent Cell viability BT474 Lapatinib BT474 conditioned BT µg/ml Traztuzumab nm Lapatinib Activity of lapatinib in HER2-overexpressing cells selected for long-term growth in the presence of 100ug/mL trastuzumab Konecny, Pegram, et al., Cancer Res 2006;66:1630-9

15 Comparison with Trastuzumab Activity Trastuzumab 1 Trastuzumab 2 Lapatinib 3 4 mg/kg 2mg/kg weekly n=58 8 mg/kg 4mg/kg weekly n=53 8mg/kg 6mg/kg q3wk n= mg QD or 500 mg BID daily n=138 Objective Response (CR/PR), ITT 14 (24%) 15 (28%) 20 (19%) 39 (24%) Clinical Benefit Rate, ITT 20 (34%) 22 (42%) 35 (33%) 43 (31%) Median TTP, ITT, months Median TTF, ITT, weeks Vogel et al J Clin Oncol 2002;20: Baselga et al J Clin Oncol 2005;23: Gomez et al J Clin Oncol 2008;26:

16 Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Measurable disease by RECIST LVEF institution LLN Stratification: Disease sites Stage of disease EGF Study Design N=324 Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m 2 /d po days 1-14 q 3 wk Capecitabine 2500 mg/m 2 /d po days 1-14 q 3 wk Patients on treatment until progression or unacceptable toxicity, then followed for survival *Trastuzumab must have been administered for metastatic disease R A N D O M I Z A T I O N Geyer et al. NEJM 2006;355:

17 Time to Progression - ITT Population % of patients free from progression* No. of pts Progressed or died Median TTP, mo Hazard ratio (95% CI) P-value (log-rank, 1-sided) Lapatinib + Capecitabine Capecitabine (0.34, 0.71) Time (weeks) 70 Geyer et al. NEJM 2006;355:

18 Overall Survival - ITT Population Cumulative Survival % No. of pts Deaths Median OS Hazard ratio (95% CI) P value (log-rank, 2-sided) Lapatinib + Capecitabine NR Capecitabine 0.92 (0.58, 1.46) NR Time (weeks) Geyer et al. NEJM 2006;355:

19 100 Most Frequent Adverse Events All Grades 90 Severity % of Patients L+C 1 12 C Diarrhea 2 L+C C Nausea C L+C PPE 1 Gr 4 Gr 3 Gr 2 Gr 1 L+C 7 C Rash 1 L = lapatinib; C = capecitabine Geyer et al. NEJM 2006;355:

20 Activity of Lapatinib and Trastuzumab on HER2+ Breast Cancer Cells Konecny GE et al. Cancer Res 2006;66:

21 Phase III HER2+ Adjuvant Trial: ALTTO Surgery and Chemotherapy Completed Randomize Estimated N = 8,400 3-wkly Trastuzumab 6 mg/kg q3wks (52 wks) Lapatinib 1,500 mg daily (52 wks) Wkly Trastuzumab 2 mg/kg (12 or 18 wks) Washout (6 wks) Lapatinib 1,500 mg daily Lapatinib 1,000 mg daily + 3-wkly Trastuzumab 6 mg/kg (52 wks) (28 or 34 wks) Primary outcome measures: DFS Anti-HER2 therapy can overlap chemotherapy Dose adjustments: Lapatinib reduced to 750 mg daily when given with wkly paclitaxel and trastuzumab, due to high grade 3 toxicities, mainly diarrhea Sep 2011: Independent committee indicated that the lapatinib-alone arm is unlikely to meet the prespecified criteria to demonstrate non-inferiority to trastuzumab alone with respect to DFS - Lapatinibonly arm halted

22 NCIC MA.31/EGF Women with HER2-positive (central or local lab) MBC and no prior chemotherapy or HER2-targeted therapy in the metastatic setting Experimental Arm Standard Arm 24 Weeks: Lapatinib + Taxane Until PD: Lapatinib 24 Weeks: Trastuzumab + Taxane Until PD: Trastuzumab Primary Outcome: PFS Taxane: Paclitaxel 80 mg/m 2 IV weekly (3 of 4) or Docetaxel 75 mg/m 2 IV every 3 weeks Anti-HER2/neu therapy: Lapatinib (L) 1250 mg PO daily + taxane; monotherapy 1500 mg PO daily Trastuzumab (T): Loading dose, then 6 mg/kg IV every 3 weeks or 2 mg/kg IV weekly Gelmon KA et al. ASCO 2012 Annual Meeting. Abstract LBA671

23 NCIC MA.31/EGF PFS in Centrally Confirmed HER2 Positive Percent Median PFS TTAX/T = 13.7 months LTAX/L = 9.0 months HR = 1.48 (95% CI, ); P = No. at Risk TTAX/T LTAX/L 0 TTAX/T LTAX/L Time (months) Gelmon KA et al. ASCO 2012 Annual Meeting. Abstract LBA671

24 Trastuzumab and Pertuzumab Bind to Distinct Epitopes on HER2 Extracellular Domain Trastuzumab (4D5) Pertuzumab (2C4) Activates antibody-dependent cellular cytotoxicity Inhibits shedding and, thus, formation of p95 Inhibits HER2-mediated signaling Inhibits dimerization Potent inhibitor of HER-mediated signaling pathways Activates antibody-dependent cellular cytotoxicity Hubbard SR. Cancer Cell 2005;7:

25 CLEOPATRA Schema HER2+ MBC N = 800 1:1 randomization Docetaxel + Trastuzumab + Placebo Docetaxel + Trastuzumab + Pertuzumab An international Phase III randomized, double-blind, placebo-controlled study (approximately 250 sites worldwide) Endpoints: Progression-free survival Overall survival Biomarker analysis Baselga J, et al. NEJM 2012;366:

26 CLEOPATRA Primary Endpoint: Independently Assessed PFS Progression-free survival (%) n at risk Ptz + T + D Pla + T + D Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months Time (months) = 6.1 months 433 PFS events HR = % CI p< Baselga J, et al. NEJM 2012;366:

27 CLEOPATRA Final OS Analysis OS (%) n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) Ptz + T + D: median 56.5 months Pla + T + D: median 40.8 months Chemo alone Δ 15.7 months 1 0 S. Swain et al, N Engl J Med. 2015;372(8):724-34

28 CLEOPATRA Adverse Events (all grades) 25% incidence or 5% difference between arms Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea 184 (46.3) 272 (66.8) Neutropenia 197 (49.6) 215 (52.8) Nausea 165 (41.6) 172 (42.3) Fatigue 146 (36.8) 153 (37.6) Rash 96 (24.2) 137 (33.7) Mucosal inflammation 79 (19.9) 113 (27.8) Asthenia 120 (30.2) 106 (26.0) Peripheral edema 119 (30.0) 94 (23.1) Constipation 99 (24.9) 61 (15.0) Febrile neutropenia 30 (7.6) 56 (13.8) Baselga J, et al. NEJM 2012;366:

29 Trastuzumab-MCC-DM1 Binds to HER2 with affinity similar to trastuzumab Provides intracellular delivery of mertansine» Derivative of maytansine, a natural-product microtubule polymerization inhibitor» more potent than vincristine

30 T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011

31 T-DM1 vs. Capecitabine + Lapatinib HER2 Positive Metastatic Breast Cancer HER2-positive Locally advanced or metastatic BC Previously received trastuzumab-based therapy Primary end point: PFS Secondary end points: OS, quality of life Allowed crossover at progression T-DM1 (3.6 mg/kg) q3w Lapatinib (1250 mg/day) Days Capecitabine (2000 mg/m 2 ) Days 1 14 q3w Verma S et al. NEJM. 2012;367:

32 EMILIA PFS by Independent Review Proportion progression-free Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001) Verma S et al. NEJM. 2012;367:

33 EMILIA OS at Second Interim Analysis OS (%) % (95% CI, ) 78.4% (95% CI, ) Lapatinib/Capecitabine T-DM1 64.7% (95% CI, ) 51.8% (95% CI, ) Median PFS Months No. of Events Stratified hazard ratio (95% CI) HR was 0.62 at First Interim NS Efficacy stopping boundary, P = or hazard ratio 0.73 No. at Risk Lap + Cap T-DM Months Verma S et al. NEJM 2012;367:

34 EMILIA Non-Hematologic Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Hypokalemia Fatigue Nausea Mucosal inflammation Increased AST Increased ALT Verma S et al. NEJM 2012;367:

35 TH3RESA Study Schema HER2-positive (central) advanced BC (N~600) 2 T-DM1 3.6 mg/kg q3w IV (n~400) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane 1 Treatment of physician s choice (TPC) (n~200) PD T-DM1 (optional crossover) Stratification factors: World region, number of prior regimens for advanced BC, presence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety Wildiers H et al. ECCO 2013

36 TH3RESA PFS by Investigator Assessment Proportion progression-free TPC (n=198) T-DM1 (n=404) Median (months) No. of events Stratified HR=0.528 (95% CI, 0.422, 0.661) P< No. at risk: TPC T-DM Time (months) Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001). Wildiers H et al. ECCO 2013

37 1.0 TH3RESA First Interim OS Analysis Observed 21% of targeted events Proportion surviving No. at risk: TPC T-DM Time (months) TPC (n=198) 44 patients in the TPC arm received crossover T-DM1 treatment after documented progression. Unstratified HR=0.57 (P=0.004). Wildiers H et al. ECCO T-DM1 (n=404) Median (months) 14.9 NE No. of events Stratified HR=0.552 (95% CI, 0.369, 0.826); P= Efficacy stopping boundary HR<0.363 or P<

38 First-Line Treatment With T-DM1 vs Trastuzumab + Docetaxel Phase II N = 137 MBC patients (never received chemotherapy or HER2-targeted therapy for locally advanced or metastatic HER2- positive breast cancer) R a n d o m i z e 1:1 T-DM1 3.6 mg/kg IV q3wk Trastuzumab 6 mg/kg IV (8 mg/kg in cycle 1) + Docetaxel 75 or 100 mg/m 2 IV q3wk until disease progression or unacceptable toxicity, and then followed for survival Hurvitz S et al. European Multidisciplinary Cancer Congress 2011 Abstract

39 First-Line Treatment of HER2-Positive MBC With T-DM1 vs D + T Docetaxel + Trastuzumab T-DM1 Comparison No. Patients Efficacy Median PFS (months) ORR n (%) (95% CI) Toxicity 58.0% (45.5, 69.2) 64.2% (51.8, 74.8) Grade 3-4 events 89.4% 46.4% Treatment discontinuation due to adverse events 28.8 % 7.2% HR 0.59 ( , P = 0.035) Hurvitz S et al. European Multidisciplinary Cancer Congress 2011 Abstract 5001

40 MARIANNE Initiated Prior to Report of CLEOPATRA HER2-positive (central) LABC or MBC No prior chemotherapy for LABC/MBC >6 months from prior (neo)adjuvant vinca alkaloid or taxane chemotherapy Trastuzumab + docetaxel (8 mg/kg LD then 6 mg/kg or 75 mg/m 2 q3w) OR Trastuzumab + paclitaxel (4 mg/kg LD then 2 mg/kg + 80 mg/m 2 qw) T-DM1 + placebo (3.6mg/kg mg LD then 420 mg q3w) T-DM1 + pertuzumab (3.6mg/kg mg LD then 420 mg q3w) N = 1095 Stratification factors: World region, Prior neo-/adjuvant therapy (if Yes: prior trastuzumab/ lapatinib), Visceral disease Primary end point: PFS by independent review facility (IRF), non-inferiority and superiority assessed Key secondary end points: OS, PFS by investigator, ORR, Safety, Patient-reported outcomes Ellis P, et al. ASCO 2015

41 MARIANNE Progression-Free Survival by IRF Progression-Free Survival (%) No. at Risk HT T-DM1 T-DM1+P HT T-DM1 T-DM1+P HT T-DM1 T-DM1+P Median PFS (mo.) Events (no.) Stratified HR (97.5% CI) vs HT Stratified HR (97.5% CI) vs T-DM ( ) P= ( ) P= ( ) Time (mo.) Non-inferiority: Established if the upper limit of the 97.5% CI for the HR is below (non-inferiority margin). Ellis P, et al. ASCO 2015

42 CLEOPATRA Final OS Analysis OS (%) n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) Ptz + T + D: median 56.5 months Pla + T + D: median 40.8 months Chemo alone Δ 15.7 months 1 0 S. Swain et al, N Engl J Med. 2015;372(8):724-34

43 Innate and Adaptive Immunity of Trastuzumab Dependent on Functional FcγR Adaptive Immunity Innate immunity Bianchini G and Gianni L. Lancet Oncol 2014;15:58-68

44 NSABP B-31 - Adjuvant Trastuzumab DFS Outcome by FCGR2A and FCGR3A SNPs Genotype by treatment interaction test adjusted for ER and nodal status indicates association between FCGR3A-158 and benefit from trastuzumab (p=0.0002) Gavin PG et al, JAMA Oncol. 2017;3:

45 NRG BR-004 Schema HER2-Positive, First-line Metastatic Breast Cancer STRATIFICATION Prior adjuvant or neoadjuvant trastuzumab (yes; no) Prior adjuvant or neoadjuvant pertuzumab (yes; no) Estrogen receptor status (positive; negative) PD-L1 status (positive; negative) RANDOMIZATION Arm 1 Weekly Paclitaxel + Trastuzumab + Pertuzumab every 3 weeks until progression + Placebo every 3 weeks until progression or 2 years Arm 2 Weekly Paclitaxel + Trastuzumab + Pertuzumab every 3 weeks until progression + Atezolizumab 1200 mg every 3 weeks until progression or 2 years Weekly Paclitaxel (WP): 80 mg/m 2 IV Days 1, 8 and 15 every 3 weeks for 9 cycles

46 Stimulatory and Inhibitory Factors in Adaptive Cancer-Immunity Cycle Traz/Pert Atezolizumab Chemotherapy Chen DS and Mellman I. Immunity 2013;39:1 10

47 Cross-Talk Between Signal Transduction and Endocrine Pathways Growth factor Estrogen IGFR EGFR / HER2 Plasma membrane P P P P ER Cell survival Akt PI3-K P p90 RSK P P P MAPK SOS RAS RAF MEK P P Cytoplasm P P P ER P ER p160 CBP Basal transcription machinery Cell growth Nucleus ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S.

48 TAnDEM PFS - Anastrozole vs Anastrozole plus Trastuzumab Probability Events Median PFS 4.8 months 2.4 months 95% CI 3.7, , 4.6 p value No. at risk A+H A months Months Mackey J et al; SABCS 2006, Abstract 3

49 EGF Progression-Free Survival: HER2+ Population Letrozole (N = 108) Letrozole + Lapatinib (N = 111) Progressed or died 89 (82%) 88 (79%) Median PFS, mo Hazard ratio (95% CI) 0.71 (0.53, 0.96) p-value Johnston et al, SABCS 2008, Abstract 46

50 CLEOPATRA Final OS Analysis OS (%) n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) Ptz + T + D: median 56.5 months Pla + T + D: median 40.8 months Chemo alone Δ 15.7 months 1 0 S. Swain et al, N Engl J Med. 2015;372(8):724-34

51 NSABP B-31/NCCTG N9831 Long Term DFS 81.4% AC Ú P+H 76.8% 73.7% % Event-Free AC Ú P N Events AC P AC P+H % 64.9% 62.2% HRadj=0.60 (95% CI: ) P< % No. at risk Years from Randomization Perez EA, et al. J Clin Oncol. 2014;32(33):

52 NSABP B-31 ACàPaclitaxel with or without trastuzumab HER2+ node-positive breast cancer Initial study entry criteria included FISH+ > 2.0 or IHC 3+ HER2 testing performed at local lab site A tissue specimen sent to NSABP for later testing NSABP B-31: Central HER2 status performed as quality check after 529 patients enrolled

53 NSABP B-31 Central HER2 Assay Result Central HER2 FISH negative Central IHC negative (0-2+) Both Negative Before amendment 103/529 (19.5%) 122/528 (23.1%) 87/529 (16.4%) (any lab) After amendment (qualified lab) 104/1266 (8.2%) 177/1259 (14.1%) 87/1266 (6.8%) Total Final 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)

54 RR of ACTH/ACT for DFS (NSABP B-31) FISH+ (1588) Categories (N) FISH- (207) IHC 3+ (1488) IHC <3 (299) FISH- & IHC <3 (174) Interaction p=0.60 for FISH Interaction p=0.26 for IHC RR Note: RR adjusted for ER and nodal status

55 N9831 Outcomes by HER2 Status Perez EA, et al. J Clin Oncol. 2010;28:

56 B-47: Adjuvant Trastuzumab in HER2 Low Breast Cancer STRATIFICATION HER2 IHC Score (1+, 2+) Number of Positive Nodes (0-3, 4-9, 10+) ER / PgR Status Intended ChemoRx regimen (ACàWP, TC) RANDOMIZATION GROUP 1 ChemoRx* GROUP 2 ChemoRx* + Trastuzumab x 1year Hormonal therapy and radiation as indicated. Chemotherapy by MD Choice: *ACàWP: Doxorubicin 60mg/m2 and Cyclophosphamide 600mg/m2 q2 or 3 wks x 4 followed by qwk paclitaxel x 12 or TC: Docetaxel 75mg/m2 + Cyclophosphamide 600mg/m2 q3wk x 6

57 San Antonio Breast Cancer Symposium, December 5-9, 2017 B-47: Selected Eligibility Criteria High-risk Node Negative T2 and ER/PR negative (TNBC) T2 and ER positive and Grade 3 or RS 25 Node Positive with T1-3 IHC must be 1+, or 2+ If 2+ then ISH must be negative for gene amplification, with ratio <2.0, and HER2 gene copy of <4 per nucleus. Exclusion: Active Cardiac Disease, Hx of MI, CHF, cardiomyopathy If TC planned -- LVEF <50%, No uncontrolled HTN >150/>90 If ACx4àWP planned -- LVEF <55% 50 yr and HTN Dx (controlled or not)

58 San Antonio Breast Cancer Symposium, December 5-9, 2017 B-47: Invasive Disease-Free Survival HR 0.98 (95% CI ) P=0.90 Treatment N Events 5 year EFS ChemoRx % ChemoRx+Trast % No. at Risk ChemoRx ChemoRx+Trast

59 B-47: Overall Survival HR 1.33 (95% CI ) P=0.14 Treatment N Deaths 5 Year OS ChemoRx % ChemoRx+Trast % No. at Risk ChemoRx 1604 ChemoRx+Trast Be cautious with TCHP in HER2 equivocal patients

60 TRYPHAENA trial Study design All 3 arms were experimental Study dosing q3w: FEC: 500 mg/m 2, 100 mg/m 2, 600 mg/m 2 Carboplatin: AUC 6 Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Pertuzumab: 840 mg loading dose, 420 mg maintenance Docetaxel: 75 mg/m 2 Schneeweiss A, et al. Ann Oncol 2013:24;

61 TRYPHAENA Pathologic Complete Responses Schneeweiss A, et al. Ann Oncol 2013:24;

62 TRYPHAENA pcr by hormone receptor status Schneeweiss A, et al. Ann Oncol 2013:24;

63 APHINITY: Trial Design S U R G E R Y Central confirmation of HER2 status (N = 4805) R Randomisation and treatment within 8 weeks of surgery Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy F O L L O W - U P 10 Y E A R S *A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed von Minckwitz G, et al. N Engl J Med 2017;377(2): The slides are the property of BIG. Permission required for reuse 63

64 APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival expected: 89.2% von Minckwitz G, et al. N Engl J Med 2017;377(2): The slides are the property of BIG. Permission required for reuse 64

65 APHINITY: Node-positive Subgroup von Minckwitz G, et al. N Engl J Med 2017;377(2): The slides are the property of BIG. Permission required for reuse 65

66 APHINITY: Node-negative Subgroup von Minckwitz G, et al. N Engl J Med 2017;377(2): The slides are the property of BIG. Permission required for reuse 66

67 APHINITY: Hormone Receptor-negative Subgroup von Minckwitz G, et al. N Engl J Med 2017;377(2): The slides are the property of BIG. Permission required for reuse 67

68 APHINITY: Hormone Receptor-positive Subgroup von Minckwitz G, et al. N Engl J Med 2017;377(2): The slides are the property of BIG. Permission required for reuse 68

69 APT: Study Design HER2+ ER+ or ER- Node Negative < 3 cm P P P P P P P P P P P P Enroll T T T T T T T T T T T T WEEKLY PACLITAXEL 80 mg/m 2 + TRASTUZUMAB 2 mg/kg x 12 N=410 T T T T T T T T T T T T T FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)* Presented by: Sara M. Tolaney

70 Patient Characteristics Age < Size of Primary Tumor T1a 0.5 cm T1b > T1c > T2 > Histologic Grade I Well differentiated II Moderately differentiated III Poorly differentiated HR Status (ER and/or PR) Positive Negative N % Presented by:

71 Disease-Free Survival All patients Disease-Free Survival Point Est. 95% Conf. Interval No. of events 3-yr DFS 98.5% 97.2% to 99.7% 6 5-yr DFS 96.3% 94.4% to 98.2% 14 7-yr DFS 93.3% 90.4% to 96.2% Time (Months) Number at risk Presented by:

72 Disease-Free Survival Events DFS Event N (%) Time to event [months; mean(range)] Any recurrence or death 23 (5.7) Local/Regional Recurrence* Ipsilateral axilla (HER2+) Ipsilateral breast (HER2+) New Contralateral Primary Breast Cancer HER2+ HER2- Unknown 5 (1.2) (1.5) (12-54) 51 (37-65) (12-59) 87 (84-90) Distant Recurrence 4 (1.0) 49 (27-63) Death Non-breast cancer related 8 (2.0) 58 (13-71) Presented by:

73 ATEMPT Trial Schema San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center--December 10-14, 2013 Stage I HER2+* ER+ or ER- PS 0-1 Adequate organ fx N=500 R 3 1 Trastuzumab-DM1 q3weeks X17 N=375 Paclitaxel + Trastuzumab x12à Trastuzumab q3weeks x13 N=125 *HER2-positive defined as IHC 3+ or FISH 2.0; will be confirmed by central HER2 testing prior to study enrollment Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy Adjuvant radiation therapy can be administered concurrently with study treatment. Presented by: Sara M. Tolaney

74 Neratinib (irreversible pan-her inhibitor) after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5- year analysis of a randomised, doubleblind, placebo-controlled, phase 3 trial

75 ExteNET Overall Five Year IDFS Martin M, et al. Lancet Oncology 2017;18:

76 ExteNET Five Year IDFS by Hormone Receptor Status HR Positive HR Negative Martin M, et al. Lancet Oncology 2017;18:

77 KATHERINE Post Neoadjuvant Residual Disease Study Residual Invasive HER2 Positive Breast Cancer in Breast and/or Axillary Nodes after Neoadjuvant Chemotherapy and Trastuzumab STRATIFICATION - Clinical presentation: inoperable vs. operable - Hormone receptor: ER or PR positive vs. ER and PR negative - Preoperative therapy: Trastuzumab vs. dual HER2 targeting - Path nodal status after preoperative therapy: +/- Trastuzumab 6 mg/kg q3wk x 14 doses T-DM1 3.6 mg/kg q3wk x 14 doses Accrual patients

78 Intrinsic Subtypes of Breast Cancer in HER2+ BC Unsupervised Hierarchical Clustering Analysis Perou CM. The Oncologist 2011:16(suppl 1):61-70

79 Intrinsic Subtypes within HER2+ BC Eroles P et at. Cancer Treatment Reviews 2012:38:

80 Intrinsic Subtypes within HER2 Negative BC Eroles P et at. Cancer Treatment Reviews 2012:38:

81 PAMELA TRIAL 92% T1/2 65% Node Negative Llombart-Cussac A et al. Lancet Oncol 2017

82 PAMELA TRIAL Distribution of intrinsic subtypes at baseline All patients N=151 HR+ N=77 HR - N=74 The study determined how pcr might be impacted by the intrinsic subtype. IMPLICATION: some patients with low-risk disease, might not need chemotherapy if treated with dual HER2 blockade + endocrine therapy Llombart-Cussac A et al. Lancet Oncol 2017

83 CDK4/6 inhibitors and HER2 positive disease Cyclin D1-CDK4 pathway can mediate resistance to anti-her2 targeted therapy This resistance can be overcome using CDK4/6i Inhibition of CDK4/6 suppresses Rb phosphorylation, reduces TSC2 phosphorylation and partially attenuates mtorc1 activity à relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/ HER2 blockade. Dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of mtorc1/ S6K/S6RP activity. BT474 tumors PDX tumor Goel, Cancer Cell 2016

84 Single arm phase II study Breast cancer T 3 cm N0 M0 HR+(> 10%) HER2+ Translational: Tissue from Dx PAM50 #1 & Blood sample TPLR Neoadjuvant treatment: 18 weeks Double anti-her2 therapy TP (Trastuzumab and Pertuzumab) Uniform Endocrine Deprivation Letrozole +/- goserelin CDK 4/6 inhibitor Ribociclib Clinical evaluation/us: if concerns for PD, patient goes off trial as non-pcr Translational: Blood sample with US at wk #6 pcr rate S U R G E R Y Adjuvant treatment per physician discretion Translational: Tissue from Sx (PAM50 #2) & Blood sample 84