(Neo) Adjuvant systemic therapy for HER-2+ EBC

Transcription

1 (Neo) Adjuvant systemic therapy for HER-2+ EBC F. Cardoso, MD Director, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal ESMO Board of Directors & NR Committee Chair ESO Breast Cancer Program Coordinator EORTC Breast Group Chair Non è possibile visualizzare questa immagine.

2 DISCLOSURES Consultant/Ad Board: Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck- Sharp, Merus BV, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Teva

3 MANAGEMENT OF HER-2 + BC: Lessons learned & Questions unanswered HER-2 + BC is a well identified subtype Quality of HER-2 testing essential Crucial role of patient selection Several efficacious anti-her-2 agents available (challenge: the best sequence and/or combinations) Lack of predictive markers beyond HER-2 (particularly to select among different anti-her-2 agents) Even with target/targeted drug resistance occurs

4 TARGET FOR THERAPY : HERA EXPERIENCE Patients (%) No. at risk Disease-free survival Months from randomisation Median follow-up: 1 year HR, hazard ratio; CI, confidence interval 0 Observation 1 year trastuzumab 2-year Events DFS HR 95% CI p value Simulation of HERA if conducted in unselected patients: HER2+ : HR 0.54 HER2- : HR , 0.67 <0.001 SABCS 2005 Disease-free survival HER-2 Pos & Her-2 Neg Patients Patients (%) No. at risk HERA (New Engl J Med, 2005) The right subpopulation The right drug An imp treatment effect! year trastuzumab Observation 2-year Events DFS HR 95% CI p value , Months from randomisation R. Gelber & M. Piccart Median follow-up: 1.8 years HR, hazard ratio; CI, confidence interval Simulation by Aparna Keshaviah, Sc.M. SABCS 2005

5 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

6 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

7 Adjuvant chemotherapy + trastuzumab: 6 large adjuvant BC trials, all N+ or high risk N-(>13,000 patients) NSABP-B31 (n=1960) NCCTG N9831 (n=3046) AC for 4 cycles, followed by paclitaxel for 4 cycles + Weekly T for 1 y AC q 3w for 4 cycles, followed by 12 weekly doses of paclitaxel +Weekly T for 1 y Reference Romond 2005 Romond 2005 HERA (global ex-us) (n=5090) BCIRG 006 (global) (n=3222) +Weekly T for 1 y Standard CTX + observation only Standard CTX + T 3-wkly for 1 y Standard CTX + T 3-wkly for 2 y AC for 4 cycles, followed by docetaxel for 4 cycles + T 3-wkly for 1 y Piccart- Gebhart 2005 Slamon 2006 FinHer (n=232) PACS 04 (n=528) Carbo + docetaxel for 6 cycles, + T 3-wkly for 1 y Docetaxel or vinorelbine for 3 cycles, followed by FEC for 3 cycles + Weekly T for 9 weeks FEC or ED for 6 cycles + Weekly T for 1 year Joensuu 2006 Spielmann 2007 AC/FEC Paclitaxel Trastuzumab (T) Carbo+D D or Vinorelbine FEC or ED Docetaxel (D) Standard chemotherapy (CTX) See Glossary on last slide for explanations of all abbreviations here, unless previously defined.

8 Adjuvant chemotherapy ± trastuzumab trials: disease-free survival HR Absolute benefit at 4y/3y a p Median FU yrs Reference Combined US (n=3968) b % < Perez 2007 HERA (n=3401) %* < Smith 2007 BCIRG AC-DT (n=1074) % < Slamon 2006 BCIRG DCarboT (n=1075) % Slamon 2006 FinHER (n=232) % Joensuu 2006 PACS-04 (n=528) % n.s. 4 Spielmann Favours trastuzumab *Benefit at 3 y a Absolute difference in percentage of patients with DFS at 4 or 3 years b Combined US: Joint analysis of NSABP Exception: B-31 and NCCTG PACS04!! N9831 A, doxorubicin; C, cyclophosphamide; Carbo, carboplatin; D, docetaxel; T, trastuzumab; DFS, disease-free survival; FU, follow-up; HR, hazard ratio 1 Favours chemotherapy only Increase in DFS of 36% to 58% ~Increase in DDFS 2

9 Adjuvant chemotherapy ± trastuzumab trials: overall survival Combined US (n=3969) b HERA (n=3401) HR Difference at 4y/3y a 3.2% 2.7%* p Median FU yrs 3 2 Reference Perez 2007 Smith 2007 BCIRG AC-DT (n=1074) % Slamon 2006 BCIRG DCarboT (n=1075) % Slamon 2006 FinHER (n=232) %* Joensuu 2006 PACS-04 (n=528) % n.s. 4 Spielmann Favours trastuzumab *Benefit at 3y a Absolute difference in percentage of patients with OS at 4 or 3 years b Combined US: Joint analysis of NSABP B-31 and NCCTG N Favours chemotherapy only Reduction in mortality risk of 34% to 59% Exception: PACS04!!! 2 * Benefit at 3 y

10 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

11 TRIALS EVALUATING ADJUVANT TRASTUZUMAB DURATION 1 vs. 2 years: HERA 9 weeks: FinHER (Finland) 1 year vs. 3 ms: E 2198 (US) 1 year vs. 9 weeks: ShortHER 1 year vs. 9 weeks: SOLD 1 year vs. 6 ms: PHARE (France) 1 year vs. 6 ms: HeCOG (Greece) 1 year vs. 6 ms: Persephone(UK)

12 HERA TRIAL DESIGN ACCRUAL (N=5102) Women with locally determined HER2- positive invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF 55% Randomization OBSERVATION n=1698 After ASCO 2005, option of switch to Trastuzumab 1 year Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n= years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n=1701 CT, chemotherapy; RT, radiotherapy Goldhirsch & Gelber et al, ESMO 2012, LBA 6

13 DFS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS Disease-free survival (%) % 81.6% 86.7% 75.8% 81.0% 76.0% Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) year Years from randomization No. at risk Trastuzumab 2 years Trastuzumab 1 year Goldhirsch & Gelber et al, ESMO 2012, LBA 6 OS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS No added benefit for 2 years Independent of ER status Higher cardiac toxicity for 2 years Overall Survival (%) % 92.6% 86.4% 96.5% 91.4% 87.6% Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) year Years from randomization No. at risk Trastuzumab 2 years Trastuzumab 1 year Goldhirsch & Gelber et al, ESMO 2012, LBA 6

14 Protocol of Herceptin Adjuvant with Reduced Exposure PHARE Study design Clinical exam LVEF trastuzumab6 months R Stratification 1. ER pos / neg 2. Chemo: conco/ seq 3384 pts randomised trastuzumab up to 12 months 1690 patients stop trastuzumab (i.e. 6 months) 1690 patients mos Mammography Up to 60 mos R: Randomization after informed consent Pivot et al, ESMO 2012, LBA 5

15 Probability Disease Free Survival Events HR 95%CI p-value H 12m 176 H 6m ( ) Months At risk H-12m H 6m H-12m H-6m Pivot et al, ESMO 2012, LBA 5 * Cox model stratified by ER status and concomitant chemotherapy Probability Overall Survival 42.5mos. median FU Events HR 95%CI p-value H 12m 66 H 6m ( ) Months At risk H-12m H 6m H-12m H-6m Pivot et al, ESMO 2012, LBA 5 * Cox model stratified by ER status and concomitant chemotherapy

16 TAKE HOME MESSAGES Duration of adjuvant trastuzumab: DON T CHANGE YOUR PRACTICE Duration of adjuvant trastuzumab: STORY NOT FINISHED Role of concurrent administration Any subgroup of pts needing shorter or longer duration? Wait for other trial results & longer FU of PHARE In total about pts enrolled to answer duration question! Really needed? Can we be smarter in trial design? Can sponsors be more flexible?

17 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

18 Meta-analysis: Neoadjuvant anthracyclines/taxanes with or without trastuzumab All cooperative neoadjuvant trials in Germany between 1998 and 2006 using anthra/taxanes (N=4913) plus GeparQuattro and TECHNO trials (N=1721) using trastuzumab for HER2+ tumors Goals: Total 6634 pts Overall pcr rate Effects according to treatment: - Trastuzumab - Dose-Density - Duration - Concurrent versus sequential Von Minckwitz et al, SABCS 2008, Abstract 79

19 Meta-analysis: pcr rate based on treatment In patients with HER2+ tumors: Trastuzumab (N=671) No Trastuzumab (N=736) P-value pcr rate 41% 23% <.001 Other characteristics associated with high rate of pcr (multivariate analysis): Younger age (P<.001) Ductal (P<.001) Histological grade 3 (p<.001) Positive HER2 (P<.001) Negative HR (P<.001) Tumor size (P<.001) Conventional dosage (vs. dd) (P<.001) No significant difference between concurrent vs. sequential therapy (P=.329) Von Minckwitz, SABCS 2008, Abstract 79

20

21 NOAH: Phase III, Open-Label Trial of Neoadjuvant Trastuzumab HER2-positive LABC (IHC 3+ or FISH+) HER2-negative LABC (IHC 0/1+) n = 115 n = 113 n = 99 Trastuzumab + chemotherapy a Chemotherapy a Chemotherapy a Surgery followed by radiotherapy b Trastuzumab continued to week patients crossed over to trastuzumab a CT: AP x 3 followed by P x 4, followed by CMF x 3 b HR+ pts received adjuvant tamoxifen Gianni L, et al. Lancet. 2010;375(9712):

22 NOAH: Event-Free Survival (EFS) and OS in HER2-Positive Population (ITT) EFS OS Gianni L, et al. Lancet. 2010;375(9712):

23 Neoadjuvant therapy for HER-2+ breast cancer Anti-HER-2 agent in neoadjuvant or adjuvant setting? NO DIRECT COMPARISON ADJUVANT VS. NEOADJUVANT INDIRECT EVIDENCE (Higher pcr rates!!)

24 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

25 Perez, SABCS 2009

26 There is a strong trend for a 25% reduction in the risk of an event with starting trastuzumab concurrently with taxane relative to sequentially: 5 yr DFS: 80% vs. 84% (final results would need too long FU) Perez, SABCS 2009

27 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

28 BCIRG 006 Trial Design AC T 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 HER2+ (Central FISH) N+ or high risk N AC TH 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 1 year Trastuzumab N=3222 Stratified by nodes and hormonal receptor status TCH Slamon D, et al. Cancer Res. 2009;69(24 Suppl): Abstract x Docetaxel and Carboplatin 75 mg/m 2 AUC 6 1 year Trastuzumab

29 DFS in all patients DFS in patients without TOP2A co-amplification DFS in patients with TOP2A co-amplification Slamon D et al. N Engl J Med 2011;365:

30 Therapeutic Index for Critical Clinical Events Slamon D et al. N Engl J Med 2011;365:

31 CLINICAL IMPLICATIONS OF BCIRG 006 We don t know how safe it is to withhold anthracyclines and in which pts (trial not powered to show equivalence; trial hypothesis (TCH better) not proven!) TCH associated with less cardiotoxicity and less leukemia (associated with A or C??!!) ONLY POSSIBLE CLINICAL RECOMMENDATION: TCH is a very good option and should be chosen when cardiac risk factors or c.i. for anthracyclines are present

32 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

33 TRIALS EVALUATING DUAL BLOCKADE IN THE NEOADJUVANT SETTING NeoALTTO: Trastuzumab + Lapatinib NSABP B-41: Trastuzumab + Lapatinib CherLob: Trastuzumab + Lapatinib NeoSphere: Trastuzumab + Pertuzumab TRYPHAENA : Trastuzumab + Pertuzumab

34 NeoALTTO Study Design Invasive operable HER2+ BC T >2 cm (inflammatory BC excluded) LVEF 50% N = 450 Stratification T 5 cm vs T>5 cm ER or PgR+ vs ER & PgR- N0-1 vs N 2 Conservative surgery or not R A N D O M I Z E Lapatinib Paclitaxel Trastuzumab Paclitaxel Lapatinib Trastuzumab Paclitaxel 6 wks +12 wks S U R G E R Y F E C X 3 Lapatinib Trastuzumab Lapatinib Trastuzumab 34 wks IBC exclusion criteria 52 weeks of anti-her2 therapy Baselga J, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-3.

35 NeoALTTO: Overall Clinical Response at 6 weeks (w/o chemo) and at surgery P<.001 P =.049 P =.49 P<.001 L N = 154 L = lapatinib; T = trastuzumab T N = 149 L+T N = 152 At Week 6 (w/o chemo) L N = 154 T N = 149 At surgery L+T N = 152 Baselga J, et al. Cancer Res. 2010;70(24 Suppl): Abstract S3-3.

36 NeoALTTO trial

37 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 EVENT-FREE SURVIVAL (EFS) ANALYSIS All patients Tests for interaction according to HR status Lap + Tras vs. Tras p=0.48 Lap vs. Tras p=0.56 Martine Piccart, SABCS This presentation is the intellectual property of the presenter. Contact martine.piccart@bordet.be for permission to reprint and/or distribute

38 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 OVERALL SURVIVAL (OS) ANALYSIS All patients Tests for interaction according to HR status Lap + Tras vs. Tras p=0.54 Lap vs. Tras p=0.90 Martine Piccart, SABCS 2013 This presentation is the intellectual property of the presenter. Contact martine.piccart@bordet.be for permission to reprint and/or distribute

39 ALTTO trial

40 Benefit NOT CONFIRMED! ALTTO trial

41 NSABP B-41 Schema Tissue for Biomarkers Tissue for Biomarkers Operable Breast Cancer HER-2 neu Positive R AC WP+T AC WP+L AC WP+T+L WP=Weekly Paclitaxel S U R G E R Y Trastuzumab for a total of 1 year Accrued 529 patients from July 16, 2007 to June 30, 2011

42 NSABP B-41 Summary Treatment Regimens Neither the addition of lapatinib to trastuzumab (AC WP+T+L) nor the substitution of lapatinib for trastuzumab (AC WP+L) demonstrated statistical superiority to trastuzumab (AC WP+T) for RFI or OS in protocol specified pair-wise comparisons Exploratory analyses suggest the three treatment arms are different in long-term outcomes (p=0.049 for RFI and p=0.07 for OS) Exploratory analyses of RFI by HR status showed similar trends in patients with HR-negative and those with HR-positive tumors

43 NeoSphere Study Design Patients with operable or locally advanced/ inflammatory* HER2-positive breast cancer Chemo-naïve and primary tumors >2 cm (N = 417) TH (n = 107) docetaxel + trastuzumab THP (n = 107) docetaxel + trastuzumab + pertuzumab HP (n = 107) trastuzumab + pertuzumab TP (n = 96) docetaxel + pertuzumab Study dosing: q3w x 4 S U R G E R Y FEC q3w x 3 Trastuzumab q3w cycles 5-17 FEC q3 x 3 Trastuzumab q3w cycles 5-17 Docetaxel q3w x 4 FEC q3w x 3 Trastuzumab q3w cycles 5-17 FEC q3w x 3 Trastuzumab q3w cycles 5-21 BC, breast cancer; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel *Locally advanced = T2-3, N2-3, M0 or T4a-c, any N, M0; operable = T2-3, N0-1, M0; inflammatory = T4d, any N, M0 Gianni L, et al. Cancer Res.2010;70(24 Suppl): Abstract S3-2.

44 NeoSphere: pcr Rates (ITT Population) P =.0198 P =.0141 P =.003 pcr, % ±95% CI CI, confidence interval; H, trastuzumab; P, pertuzumab; pcr, pathologic complete response; T, docetaxel Gianni L, et al. Cancer Res.2010;70(24 Suppl): Abstract S3-2.

45 APHINITY: Phase III Adjuvant Study HER2+ EBC S U R G E R Y N=4805 Patients with HER2+ EBC R A N D O M I Z A T I O N Chemotherapy plus trastuzumab and pertuzumab Chemotherapy plus trastuzumab and placebo anti-her2 treatment for 52 weeks Primary endpoint: idfs Large global trial, completed recruitment Q Anthracycline or non-anthracycline based chemo allowed idmc and Independent Cardiac Review Committee Results expected 2016 COR_045

46 Neoadjuvant Benefit: pcr (%) Chemo (includes Anthra and Taxane) Neoadjuvant Anti-Her 2 Studies Chemo Chemo+H Chemo+L Chemo+ H+L Chemo+ H+P H+L+ AI(ER+ve) H+P Presented by: Dr. Sunil Verma

47 Neoadjuvant Her 2 Trials Updated DFS Results NeoALLTO (2014): Chemo + L vs. Chemo + T vs. Chemo + L + T 3y EFS: 78% vs. 76% vs. 84% (NS) 3y OS: 93% vs. 90% vs. 95% (NS) NeoSphere (2016): Chemo + T vs. Chemo + T+P 5y DFS 81% vs. 84% (NS) de Ezambuia et al. Lancet Oncol Sep;15(10): Gianni et al. Lancet Oncol.2016 May (epub ahead of print) Presented by: Dr. Sunil Verma

48 TRIALS EVALUATING DUAL BLOCKADE IN THE NEOADJUVANT SETTING Main conclusions In general trastuzumab + CT better than the other anti- HER-2 agent + CT Dual blockage beneficial particularly in ER negative disease, in terms of pcr rates Interesting RR of 2 anti-her-2 agents alone (with no CT) NOT CONFIRMED IN THE LARGE ADJUVANT ALTTO TRIAL (Waiting for APHINITY)

49 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

50 Tolaney S, NEJM 2015 De-Escalation

51 Tolaney S, NEJM 2015 pt1-pt3 pn0 HER2+

52 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration Neoadjuvant or adjuvant setting Concomitant vs. sequential with CT Optimal CT regimen (anthracyclines: to give or not give!) The principle of dual blockade (neo and adjuvant) Without CT or less CT in certain cases? Extended anti-her2 therapy

53 Timing of Distant Recurrences in relation to Adjuvant Trastuzumab < 2% of patients relapse on adjuvant trastuzumab and < 5% in the year following Romond EH, N Engl J Med 2005; 353: NSABP B-31 and NCCTG N9831 Courtesy G. Curigliano

54 ExteNET HER2+ Stage II-IIIC node positive BC following CT + 12 months of trastuzumab (adj) (N=2821) R Neratinib 240 mg orally daily for 1 year Placebo Orally daily for 1 year DFS DFS CT, chemotherapy; adj, adjuvant; DFS, disease-free survival; BC, breast cancer. Press release - Puma Biotechnology July 22nd, 2014 Extended DFS by 33% compared with placebo (HR = 0.67; P =.0046)

55 ExteNET Intention-to-treat population % 95.6% 93.9% 91.6% 2.3% Disease-free survival (%) P-value = HR (95% CI) = 0.67 ( ) Neratinib Placebo No. at risk Neratinib Placebo Months after randomization Chan et al. Lancet Oncol 2016

56 ExteNET Neratinib (n=1408) Placebo (n=1408) n (%) All grades Grade 3 4 All grades Grade 3 4 Diarrhea 1343 (95.4) 562 (39.9) 499 (35.4) 23 (1.6) Nausea 605 (43.0) 26 (1.8) 303 (21.5) 2 (0.1) Fatigue 382 (27.1) 23 (1.6) 283 (20.1) 6 (0.4) Vomiting 369 (26.2) 47 (3.3) 113 (8.0) 5 (0.4) Abdominal pain, general 340 (24.1) 24 (1.7) 144 (10.2) 3 (0.2) Headache 278 (19.7) 8 (0.6) 275 (19.5) 6 (0.4) Abdominal pain, upper 212 (15.1) 11 (0.8) 96 (6.8) 3 (0.2) Rash 211 (15.0) 5 (0.4) 100 (7.1) 0 Decreased appetite 170 (12.1) 3 (0.2) 40 (2.8) 0 Muscle spasms 159 (11.3) 1 (0.1) 45 (3.2) 1 (0.1) Dizziness 146 (10.4) 3 (0.2) 128 (9.1) 3 (0.2) Arthralgia 86 (6.1) 2 (0.1) 162 (11.5) 4 (0.3) Chan et al. Lancet Oncol 2016

57 OTHER NEOADJUVANT TRIALS IN HER-2+ EBC

58 ADAPT HER2+/HR+ TRIAL International, prospective, randomized phase II trial Wk 12 Pts with ER+ and/or PgR+, HER2+, ct1c - ct4a-c, cn, cm0 BC and adequate organ function, LVEF 50%, normal ECG (N = 375) T-DM1 3.6 mg/kg Q3W (n = 119) T-DM1 3.6 mg/kg Q3W + ET* (n = 127) Trastuzumab 8 mg/kg loading dose, then 6 mg/kg Q3W + ET* (n = 129) Surgery *Tamoxifen if premenopausal; aromatase inhibitor (of investigator s choice) if postmenopausal. Standard chemotherapy (1-yr trastuzumab) recommended after surgery or 12-wk biopsy (if clinical non-pcr). Primary endpoint: pcr (no invasive carcinoma in breast/nodes) Secondary endpoints: dynamic testing evaluation, EFS, OS, safety 1. Harbeck N, et al. SABCS Abstract S Hofmann D, et al. Trials. 2013;14:261.

59 ADAPT Trial 12-wk T-DM1 increased pcr rate vs trastuzumab + ET in women with HER2+/HR+ EBC 41% vs 15%, respectively (P <.001) Addition of ET to T-DM1 did not raise pcr rate Menopausal status had minimal bearing on results Tolerable safety profile with low toxicity Early response significantly associated with increased pcr rate Detectable after 3 wks Authors conclude further investigation of T-DM1 in pts with EBC warranted Harbeck N, et al. SABCS Abstract S5-03.

60 ADAPT HER2+/HR-: Design ER / PR negative (<1%) and HER2+ by central pathology ct1c - ct4a-c all cn M0 Adequate organ function LVEF > 50%; LVEF within normal institutional limits by echocardiography; normal ECG N. Harbeck, ASCO 2016

61 ADAPT HER2+/HR-: Conclusions WSG ADAPT HER2+/HR- is a unique phase II trial in focusing only on HER2+ HR- early breast cancer (ebc) 90.5% pcr rate with T+P+Pac is substantial Adding chemotherapy to dual blockade more than doubles pcr rate in HER2+ HR- ebc 34.4% pcr rate with P + T is clinically meaningful (e.g. frail patients, small tumors) Early response at 3-weeks seems to be positively correlated with pcr. Yet, missing data does not allow any definite conclusions N. Harbeck, ASCO 2016

62 KRISTINE Study Design Centrally confirmed HER2-positive, operable, locally advanced or inflammatory breast cancer Tumor >2cm N=432 R A N D O M I Z A T I O N TCH+P T-DM1+P Docetaxel Carboplatin Trastuzumab Pertuzumab 6 cycles of neoadjuvant therapy T-DM1 Pertuzumab S U R G E R Y Trastuzumab Pertuzumab 12 cycles of adjuvant HER2-therapy a T-DM1 Pertuzumab F O L L O W - U P Primary endpoint: pcr by local assessment (ypt0/is, ypn0) Stratification factors: local HR status, geographic location, and clinical stage at presentation a Adjuvant chemotherapy was recommended for patients in the T-DM1+P arm who had residual disease in lymph node(s) or in the breast (>1cm). 6 2

63 Primary Endpoint: pcr (ypt0/is, ypn0) Difference: % CI: -20.5, -2.0 Stratified 2-sided P value: b 56% 44% 123/221 99/223 a pcr rate and 95% CI are shown. Patients with missing or unevaluable pcr status were considered nonresponders: TCH+P, 7 (3.2%); T-DM1+P, 18 (8.1%). Treatment discontinuation in the neoadjuvant phase for progressive disease: TCH+P, 0% of patients; T-DM1+P, 7% of patients. b Cochran-Mantel-Haenszel Chi-square. Presented by: Dr Sara Hurvitz 7 6 pcr by Central ER/PR Receptor Status ER and PR negative Difference (95% CI): 19.0 ( 33.3, 4.6) ER and/or PR positive Difference (95% CI): 8.6 ( 20.5, 3.2) 73% pcr (%) a 54% 44% 35% 60/82 45/83 56/128 46/131 TCH+P T-DM1+P TCH+P T-DM1+P a ypt0/is, ypn0; patients with missing or unevaluable pcr status were considered nonresponders. Twenty patients had unknown ER/PR status by central analysis. Presented by:

64 Maintenance of HRQoL and Physical Function Maintenance of HRQoL a HR (95% CI): 0.60 ( ) Maintenance of physical function a HR (95% CI): 0.47 ( ) Deterioration-Free Survival (%) Time (mo.) T-DM1+P (n=200) TCH+P (n=191) 6 Deterioration-Free Survival (%) Time (mo.) T-DM1+P (n=200) TCH+P (n=191) 6 a Data are based on the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and QLQmodified breast cancer module (BR23). Maintenance of health-related quality of life (HRQoL) and physical function were assessed as the time to deterioration defined as the time from baseline to first 10-point (or greater) decrease. Only data from the neoadjuvant treatment phase including pre-surgery visit are used. Patients of the ITT population with a baseline assessment and at least 1 post-treatment assessment are included in this analysis. Presented by:

65 6 5 Conclusions Neoadjuvant TCH+P achieved a superior pcr rate compared with T- DM1+P (56% vs 44%) Neoadjuvant TCH+P was associated with a higher BCS rate (53% vs 42%) Neoadjuvant T-DM1+P had a more favorable safety profile Lower incidence of grade 3 adverse events (13% vs 64%), serious adverse events (5% vs 29%), and adverse events leading to treatment discontinuation (3% vs 9%) Neoadjuvant T-DM1+P was associated with longer maintenance of patient-reported HRQoL and physical function Upcoming phase III T-DM1 data in EBC: KATHERINE T-DM1 vs trastuzumab adjuvant in patients without pcr; KAITLIN T-DM1+P vs HP+taxane adjuvant.

66 OTHER ADJUVANT TRIALS IN HER-2+ EBC

67 Katherine (POST-NEOAJUVANT) Neoadjuvant CT + trastuzumab Residual invasive cancer R T-DM1 Trastuzumab Primary endpoint : IDFS 1400 patients; recruitment ongoing

68 KAITLIN HER2+ Node+ or Node-, ERand T>2cm R AC x 4 or FEC x3 AC x 4 or FEC x3 TAXANE TRASTUZUMAB PERTUZUMAB T-DM1 PERTUZUMAB IDFS HO 89,5% 93,1% 1300/2500 women recruited PUT ON HOLD AFTER MARIANNE TRIAL RESULTS 68

69 MANAGEMENT OF HER-2 + EBC: Unanswered questions Optimal duration for all patients Neoadjuvant or adjuvant setting Optimal anti-her-2 agent and optimal combination with CT Dual blockade in the adjuvant setting Without CT in certain cases? Small N0 tumors; elderly pts; minor cardiac problems?? Mechanisms of resistance & predictive markers (beyond HER-2)

70 BACK-UP

71 The magnitude of improvement in pcr rate did not predict EFS and OS effect Cortazar P et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014

72 Association between pcr and EFS by BC subtype Cortazar P et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014