(NEO-)ADJUVANT THERAPY FOR HER-2+ EBC

Transcription

1 (NEO-)ADJUVANT THERAPY FOR HER-2+ EBC Rebecca Dent, MD FRCP (Canada) Senior Consultant, National Cancer Center Singapore Associate Professor, Duke-NUS

2 When to question a pathology report? PgR+, ER- Lobular, tubular carcinoma HER2+ Grade 1, ER+++, PgR+++, HER2+ Grade 3, ER-, ki67 <5% Grade 3 ER+++, PgR+++ Medullary carcinoma is extremely rare (ask for a second opinion) Redo HER2 on surgical specimen if grade 3, ER- or ER+ If ER and/or PgR is negative on a biopsy redo on surgical specimen Courtesy F. Penault-Llorca

3 Introduction of new treatment modalities over time has improved recurrence outcomes in the ADJUVANT setting AI, aromatase inhibitor; CMF, cyclophosphamide, methotrexate and fluorouracil; HR, hazard ratio; RR, risk ratio. 1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet 2012; 379: ; 2. EBCTCG. Lancet 2015; 386: ; 3. EBCTCG. Lancet 2005; 365: ; 4. Jackisch C, et al. SABCS 2015; Poster PD5-01; 5. Slamon D, et al. SABCS 2015; Oral presentation S5-04; 6. Slamon D, et al. N Engl J Med 2011; 365:

4 Consistent & significant benefit of adjuvant trastuzumab

5 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 , 0.67 <0.001 SABCS 2005 Disease-free survival HER-2 Pos & Her-2 Neg Patients Patients (%) HERA (New Engl J Med, 2005) The right subpopulation The right drug An imp treatment effect! year trastuzumab Observation year Events DFS HR 95% CI p value No. at risk , 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

6 Four pivotal trials (>12,000 patients) established 18 cycles (1 year) of adjuvant trastuzumab as the SoC for HER2-positive ebc IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; SoC, standard of care. 1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353: ; 2. Gianni L, et al. Lancet Oncol 2011; 12: ; 3. Slamon D, et al. N Engl J Med 2011; 365: ; 4. Perez EA, et al. J Clin Oncol 2011; 29:

7 SEQUENTIAL CHEMO H SEQUENTIAL CHEMO H CONCOMITANT CHEMO + H These adjuvant trials demonstrated consistent DFS and OS benefit with 1 year of trastuzumab versus observation Study FU (yrs) N DFS HR HERA CT* ± RT H (1 year) vs. CT* ± RT BCIRG AC TH vs. AC T TCH vs. AC T Joint analysis 7 9 (NCCTG N9831/ NSABP B-31) AC PacH vs. AC Pac NCCTG N AC Pac H vs. AC Pac * Selected from a list of approved regimens consisting of 4 cycles. AC, doxorubicin plus cyclophosphamide; CT, chemotherapy; DFS, disease-free survival; FU, follow-up; H, trastuzumab; OS, overall survival; Pac, paclitaxel; RT, radiotherapy; T, docetaxel; TCH, docetaxel, carboplatin Favours trastuzumab Favours chemo alone Increase in DFS of 36% to 58% ~Increase in DDFS 1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353: ; 2. Smith I, et al. Lancet 2007; 369:29 36; 3. Gianni L, et al. Lancet Oncol 2011; 12: ; 4. Goldhirsch A, et al. Lancet 2013; 382: ; 5. Cameron D, et al. Lancet 2017; 389: ; 6. Slamon D, et al. SABCS 2015; Oral presentation S5-04; 7. Romond EH, et al. N Eng J Med 2005; 353: ; 8. Perez EA, et al. J Clin Oncol 2011; 29: ; 9. Perez EA, et al. J Clin Oncol 2014; 32: ; 10. Perez EA, et al. J Clin Oncol 2011; 29: OS Favours trastuzumab HR Favours chemo alone

8 Perez, SABCS 2009

9 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

10 Optimal Chemotherapy regimen? (anthracyclines: to give or not give!) 10

11 BCIRG 006 AC x 4, Docetaxel x4 + H followed by 40 weeks H HER2+ by FISH Node positive or High Risk (loosely defined Normal EF R AC x 4, Docetaxel x4 N=3223 TCH x 6 followed by 34 weeks of H Hypotheses: 1) Earlier H would be better; 2) Anthracyline would be unnecessary 11

12 % alive and disease-free BCIRG-006: Disease free survival final analysis (10.3yrs) AC-T AC-TH TCH Patients Events HR (95% C.I.) P (reference) ( ) < ( ) % 73.0% 67.9% Time (months) San Antonio Breast Cancer Symposium, December 8-12, 2015 Slamon et al, SABCS 2015 BCIRG 007 Docetaxel +/- Carbo = No added benefit of carbo 12

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

14 CLEOPATRA: Exposure to docetaxel in patients from Asia Docetaxel dose reductions below 75 mg/m 2 occurred in 47% of patients from Asia compared with13% of patients from other regions. HT n = 269 Other regions PHT n = 282 HT n = 128 But did not adversely affect efficacy in patients from Asia, with PFS and overall survival being comparable with that of patients from other regions. Asia PHT n = 125 Median number of all study treatment cycles (range) 15.0 (1 50) 18.0 (1 56) 15.0 (1 46) 20.0 (1 50) Median number of docetaxel cycles (range) 8.0 (1 27) 7.0 (1 35) 9.0 (1 41) 9.0 (1 30) Median docetaxel dose intensity, mg/m 2 /week Docetaxel dose escalation to 100 mg/m 2, n (%) 56 (20.8) 47 (16.7) 5 (3.9) 1 (0.8) Docetaxel dose reduction to <75 mg/m 2, n (%) One dose reduction to <75 mg/m 2 Two dose reductions to <75 mg/m 2 * Docetaxel permanently discontinued No, n (%) Yes, n (%) 32 (11.9) 31 (11.5) 1 (0.4) 97 (36.1) 172 (63.9) 166/172 (96.5) 42 (14.9) 39 (13.8) 3 (1.1) 78 (27.7) 204 (72.3) 194/204 (95.1) 57 (44.5) 56 (43.8) 1 (0.8) 45 (35.2) 83 (64.8) 79/83 (95.2) 62 (49.6) 61 (48.8) 1 (0.8) 31 (24.8) 94 (75.2) 91/94 (96.8) Data cut-off: May 2011 * Includes patients with initial dose escalation to 100 mg/m2 followed by two subsequent dose reductions H, trastuzumab; P, pertuzumab; T, docetaxel Swain SM, et al. The Oncologist 2014; 19:1 9 14

15 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

16 What about duration of trastuzumab? 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)

17 Overall Survival (%) Disease-free survival (%) DFS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MEDIAN FU & 734 DFS EVENTS % 86.7% 81.6% 81.0% 75.8% 76.0% Trastuzumab 2 years Trastuzumab 1 year HERA TRIAL Accrual (n=5102) 20 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 % 96.5% 92.6% 91.4% Trastuzumab 2 years Trastuzumab 1 year 86.4% 87.6% 20 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

18 DFS (%) PHARE failed to show non-inferiority of 6 months vs. 1 year of trastuzumab treatment 42.5 months MFU Events 2-yr DFS (95% CI) HR (95% CI) P value Trastuzumab 1 yr % ( ) Trastuzumab 6 mo % ( ) 1.28 (1.05, 1.56) No. at risk Months H 1 yr H 6 mo Cox model stratified by ER status and concomitant chemotherapy Pivot X, et al. Lancet Oncol 2013; 14:

19 Short-HER: Study Design EUDRACT number: NCI ClinicalTrials.gov number: NCT n = 1250 pts Non-inferiority study: HR = 1.29, Alpha: 0.05 (one tail) Power: 80% Stratification factors: HR status, Nodal status Radiotherapy and hormonal therapy started at the completion of ChemoRx, when indicated Presented by: Carey K. Anders, MD

20 SHORTHer Primary Objective of DFS 5.2 yrs Follow-up N = HR = 1.15 ( ); 0.78 probability 5yr DFS (87.5% LONG vs. 85.4% SHORT) Stage III vs I+II Subset Analyses: Ratio of HRs (90%CI) p-value 2.30 (1.35, 3.94) < Number at risk A long B short Months from randomization A long B short Nodal status N2+N3 vs N0+N (1.33, 3.83) < HR>1.0 favors LONG No difference in 5 yr OS (95.1 vs 95%) Presented by: Carey K. Anders, MD

21 ShortHER: Cardiac Adverse Events HR= 0.32 (95% CI 0.21;0.50) p< p< P< Months from randomization A Long Cumulative hazard estimates B Short Long N=627 Short N=626 Grade N(%) N(%) 2 69 (11.0) 22 (3.5) 3 12 (1.9) 5 (0.8) 4 1 (0.2) 0 Total 82 (13.1) 27 (4.3) Presented by: Carey K. Anders, MD

22 TAKE HOME MESSAGES Duration of adjuvant trastuzumab: DON T CHANGE YOUR PRACTICE Duration of adjuvant trastuzumab: STORY NOT FINISHED Any subgroup of pts needing shorter or longer duration? Wait for other trial results & longer FU of PHARE and ShortHER In total about pts enrolled to answer duration question! Need to identify strategies to de-escalate!

23 APT (Tolaney) trial: Adjuvant paclitaxel and trastuzumab for low-risk HER2- positive breast cancer NOTE: This is a single-arm, single-centre study, and thus unable to provide definitive data on treatment benefit * Loading dose of 4 mg/kg IV trastuzumab on Day 1; Radiation and hormonal therapy was initiated after completion of paclitaxel; Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks. ER, oestrogen receptor; q1w, every week; q3w, every 3 weeks. Tolaney SM, et al. N Engl J Med 2015; 372:

24 APT (Tolaney) trial: IDFS rates in small, node-negative tumours PR, progesterone receptor Tolaney SM, et al. ASCO 2017; Poster 511.

25 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

26 Fatima? Clinical Conclusions

27 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!!)

28 Case 1 57F Clinical Self detected mass (no palpable axillary lymph nodes) 3.5cm, Grade 3, ER+ 70% PR + 40%, HER2 + What would offer this patient: 1. Go straight to surgery if operable - then adjuvant therapy 2. Neoadjuvant therapy

29 Case 1 continued What regimen would you offer her in neoadjuvant setting? 1. TCH x 6 (Taxotere/Carbo/Herceptin) 2. TCHP x 6 (Taxotere/Carbo/Herceptin/Pertuzumab) x 6 3. AC TH 4. AC- THP 5. Taxane + Pertuzumab/Trastuzumab x 4 cycles if good response - > proceed to surgery

30 Case 2 35F previously well Right breast 4 cm clinical, G2, ER - PR -, her2 +, Core biopsy right axill LN + Treated with AC-THP Patient had complete clinical response Went for Wide Local excision and pathology showed a complete pathological response (pcr) with no residual invasive disease in breast and axilla What would you do? 1. Complete adjuvant pertuzumab/trastuzumab for total 1 year 2. Continue adjuvant trastuzumab only for total 1 year 3. No further systemic treatment

31

32 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):

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

34 TRIALS EVALUATING Dual HER2 Blockade STRATEGY A STRATEGY B EGF NeoALTTO Cherlob LPT NSABP B-41 CALGB ALTTO Advanced Disease Neoadjuvant setting Adjuvant setting Cleopatra PERUSE PHEREXA NeoSPHERE TRYPHAENA WSG-ADAPT KRISTINE APHINITY Alvaro Moreno-Aspitia et al, ASCO 2017

35 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.

36 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.

37 Conclusions Updated results of the NeoALTTO study confirms - > pts who achieve a pcr have a better EFS and OS Difference mainly observed in the hormone receptor negative group EFS and OS after 6 years did not differ significantly between the 3 treatment groups NeoALTTO is underpowered to detect modest treatment differences with respect to EFS and OS

38 ALTTO trial

39 ALTTO trial DISEASE-FREE SURVIVAL (DFS) ANALYSIS MCBS: No Evaluable Benefit * *Bracketed data in all KM curves represent results of the Primary Analysis ASCO 2014 ALTTO investigators Presented by: A. Moreno-Aspitia et al, ASCO 2017

40 HER2-positive disease and intrinsic subtype Subtype Clinically HER2+ HER2-Enriched 66% Luminal B 20% Basal-like 14% Combined analysis TCGA + METABRIC: Clinical HER2 and molecular HER2 are overlapping but different Luminal A 7% Prat et al, JNCI

41 Intrinsic Subtypes by Hormone Receptor Carey, JCO

42 pcr by intrinsic subtype 100% 90% 80% 70% 60% 50% 40% 30% 20% P= % 36% 34% 80% 37% 71% 40% 41% 38% HER2E (n=82) LumA (n=80) LumB (n=80) 52% 22% This may be why effect larger in HR- than HR+ Note ~ 70% pcr rate with 12 weeks TH (APT regimen) in HER2-E 10% 9% 0% Overall THL TH TL Carey, JCO 2015 Carey, JCO

43 NeoSphere NeoSphere Study Design A randomized, multicenter, open-label phase II study HER2+ patients with operable (T2 3, N0 1, M0) or locally advanced (T2 3, N2 3, M0 or T4a c, any N, M0) or inflammatory (T4d, any N,M0) breast cancer Chemo-naïve & primary tumors >2cm (N=417) TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) S U R G E R Y Study dosing: q3w x 4 Primary endpoint: Comparison of pcr rates in breast (ypt0/is) ( (TH vs THP - TH vs HP - THP vs TP) Secondary endpoints: pcr in breast and nodes (ypt0/is ypn0), Clinical response rate, Time to clinical response, Breast conservation surgery rate and Safety Gianni L. et al. Lancet Oncol 2012

44 pcr, % 95% CI NeoSphere Pathological Complete Response in Breast (ypt0/is) p= p= p= N=107 N=107 N=107 N=96 TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel p values from Cochran-Mantel-Haenszel test and adjusted for multiplicity Gianni L. et al. Lancet Oncol 2012

45 NeoSphere NEOSPHERE PFS, DFS Results Hazard Ratio 95% CI PFS (B vs. A) 0.69 [0.34, 1.40] DFS (B vs. A) 0.60 [0.28, 1.27] DFS (pcr vs. non-pcr) 0.68 [0.36, 1.26] In NEOSPHERE, PFS and DFS results are consistent with the primary endpoint pcr PFS and DFS were pre-specified secondary endpoints and were not powered for statistical comparisons The definition of PFS in NEOSPHERE is the same as is commonly used for event-free survival (EFS).

46 Patients may benefit from continuation into the adjuvant setting irrespective of pcr outcome Potential outcomes following neoadjuvant therapy pcr: No malignant cells found on pathological examination in breast and axilla No pcr: Residual macroscopic or microscopic disease present in breast and axilla Regardless of how a patient responds to therapy in the neoadjuvant setting, it is important to continue treatment following surgery pcr, pathologic complete response.

47 APHINITY: Phase III study to assess pertuzumab plus trastuzumab in the adjuvant setting 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 * Standard anthracycline or non-anthracycline (TCH) regimens were allowed F O L L O W - U P 10 Y E A R S Primary endpoint: IDFS Secondary endpoints: IDFS with second non-breast primary cancers included, DFS, OS, RFI, DRFI, safety and HRQoL Stratification factors: Chemotherapy regimen, HR status, nodal status, geographic region, Protocol version (A vs. B) DRFI, distant relapse-free interval; HRQoL, health-related quality of life; RFI, relapse-free interval. von Minckwitz G, et al. N Engl J Med 2017; 377:

48 APHINITY has broader eligibility criteria than previous Herceptin adjuvant trials Inclusion criteria HER2-positive status confirmed by a central review (IHC 3+ or FISH-/CISH-positive) Node-positive, any tumour size except T0 Node-negative* - Tumour size >1 cm OR - For tumours >0.5 and 1 cm, at least 1 of: - histologic/nuclear grade 3 OR - ER- and PR-negative OR - age <35 Baseline LVEF 55% Exclusion criteria Prior invasive breast cancer Non-operable breast cancer Metastatic disease (stage IV) Previous non-breast malignancies (except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin) Previous or current anti-cancer therapy or previous radiotherapy for any malignancy Cardiac dysfunction or serious medical condition von Minckwitz G, et al. N Engl J Med 2017; 377: * Protocol A only. CISH, chromogenic in situ hybridisation; ER, oestrogen receptor; FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; PR, progesterone receptor

49 Proportion event-free APHINITY met the primary efficacy objective: IDFS year 98.6% 98.8% 2 years 96.4% 95.7% 3 years 94.1% 93.2% 4 years 92.3% 90.6% IDFS PERJETA Herceptin (n = 2400) Placebo Herceptin (n = 2404) Events, n (%) 171 (7.1) 210 (8.7) Stratified HR (95% CI) 0.81 (0.66, 1.00) p value * Median FU, months No. of patients at risk Time (months) Stratification factors are: nodal status and protocol version, intended adjuvant chemotherapy and central hormone receptor status * The p value shown in this table is based on stratification factor data taken from the ecrf. In a sensitivity analysis based on stratification factor data from the IxRS system (FDA Preferred Analysis), the p value from the stratified log-rank test was Hazard ratio was estimated by Cox regression. von Minckwitz G, et al. N Engl J Med 2017; 377:

50 APHINITY: Node-positive Subgroup Absolute difference: 3 % EFFICACY BY NODAL STATUS Number needed to treat: 56 The slides are the property of BIG. Permission required for reuse G. von Minckwitz et al, ASCO APHINITY: Node-negative Subgroup Absolute difference: 0 % G. von Minckwitz et al, ASCO 2017, NEJM 2017 The slides are the property of BIG. Permission required for reuse G. von Minckwitz et al, ASCO

51 APHINITY: Hormone Receptor-negative Subgroup Absolute difference: 3 % Number needed to treat: 63 EFFICACY BY HR STATUS The slides are the property of BIG. Permission required for reuse G. von Minckwitz et al, ASCO APHINITY: Hormone Receptor-positive Subgroup Absolute difference: 1.5 % G. von Minckwitz et al, ASCO 2017, NEJM 2017 The slides are the property of BIG. Permission required for reuse G. von Minckwitz et al, ASCO

52 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 APHINITY trial *A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed G. von Minckwitz et al, ASCO 2017, NEJM 2017 The slides are the property of BIG. Permission required for reuse 63 DUAL BLOCKADE COST: $$$$ APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival expected: 89.2% Provisional MCBS: B Numberneeded to treat: 112 The slides are the property of BIG. Permission required for reuse G. von Minckwitz et al, ASCO 2017, NEJM 2017 The slides are the property of BIG. Permission required for reuse 52 65

53 How does the APHINITY population compare with those of other key adjuvant HER2-positive ebc trials?* Proportion of trial population HERA 1 BCIRG Joint Analysis 3 BETH 4 ALTTO 5 APHINITY 6 Node-positive 57% 71% 93% 52% 52% 63% HR-negative 48% 46% 45% 41% 43% 36% HR-positive 50% 54% 55% 59% 57% 64% Tumour size >2cm 49% 60% 60% 51% 50% 60% Total N * Chemo + H arm only 1. Piccart-Gebhart MJ, et al. N Eng J Med 2005; 353: ; 2. Slamon D, et al. N Eng J Med 2011; 365: ; 3. Perez EA, et al. J Clin Oncol 2014; 32: ; 4. Slamon D, et al. SABCS 2013; 5. Piccart M, et al. J Clin Oncol 2016; 34: von Minckwitz G, et al. N Engl J Med 2017; 377:

54 How do DFS rates in HER2-positive ebc studies change over time? Overall HERA 1 BCIRG-006 2,3 Joint analysis 4,5 APHINITY 6 Study arm H TCH AC-TH AC-TH H + chemo PH + chemo DFS, % (overall) 2 years years years years years years Jackisch C et al. SABCS 2015 (Abstract PD5-01); 2. Slamon D, et al. NEJM 2011; 365: ; 3. Slamon D, et al. SABCS 2015; 4. Perez EH, et al. JCO 2011; 29: ; 9. Perez EH, et al. JCO 2014; 32: ; 6. von Minckwitz G, et al. N Engl J Med 2017; 377:

55 EU LABEL PERTUZUMAB NEW NEOADJUVANT INDICATION FOR PETUZUMAB Neoadjuvant Treatment of Breast Cancer NEW EU LABEL 28/07/2015 PERTUZUMAB is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence Metastatic Breast Cancer PERTUZUMAB is indicated for use in combination with trastuzumab and docetaxel in adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-her2 therapy or chemotherapy for their metastatic disease.

56 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 Guidelines in progress re: adjuvant pertuzumab + trastuzumab! Interesting RR of 2 anti-her-2 agents alone (with no chemotherapy but NOT FULLY CONFIRMED IN THE LARGE ADJUVANT TRIALS)

57 De-escalation in Preop Setting? 57

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 Nitz et al. Annals of Oncology

61 Clinical Practice? Await trials, but data supports further development of de-escalation strategies 61

62 Randomization (1:1) 2-year follow-up for idfs 5-year follow-up for idfs Overall survival ExteNET: study design HER2+ breast cancer IHC 3+ or ISH amplified (locally determined) Prior adjuvant trastuzumab + chemotherapy N=2840 Neratinib x 1 year 240 mg/day Part A Part B Part C Lymph node +/, or residual invasive disease after neoadjuvant therapy Stratified by: nodal status, hormone receptor status, concurrent vs sequential trastuzumab Placebo x 1 year Primary endpoint: invasive disease-free survival (idfs) Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS recurrences, OS, safety Other analyses: biomarkers, health outcome assessments (FACT-B, EQ-5D) Endocrine adjuvant therapy given to patients with HR-positive tumors according to local practice Chan et al. Lancet Oncol 2016 Clinicaltrials.gov identifier: NCT M. Martin et al, ESMO 2017

63 Invasive disease-free survival (%) ExteNET: 5-year analysis: idfs % 95.5% 2.4% 94.3% 91.7% 2.6% 92.2% 90.2% 2.0% Absolute difference: 3.5 % 91.2% 89.1% 2.1% 90.2% 87.7% 2.5% No. at risk Neratinib Placebo 50 Treatment Neratinib Placebo Months after randomization Intention-to-treat population. Cut-off date: March 1, 2017 HR (95% CI) = 0.73 ( ) Two-sided P = M. Martin et al, ESMO 2017

64 Invasive disease-free survival (%) Invasive disease-free survival (%) ExtNET: idfs by hormone receptor status Absolute difference: 5.6 % Absolute difference: 0 % HR-positive subgroup HR-negative subgroup % 96.1% 95.4% 91.7% 93.6% 89.8% 92.6% 88.5% 91.2% 86.8% % 94.7% 92.8% 91.8% 90.8% 90.4% 89.9% 89.3% 88.9% 88.8% HR (95% CI) = 0.60 ( ) Two-sided P = HR (95% CI) = 0.95 ( ) Two-sided P = Neratinib Placebo Neratinib Placebo No. at risk Months after randomization No. at risk Months after randomization Neratinib 816 Placebo Neratinib 604 Placebo Intention-to-treat population. Cut-off date: March 1, 2017 M. Martin et al, ESMO 2017 M. Martin et al Lancet Oncology Nov 2017

65 ExteNET: Side Effects N % Neratinib (n=14080) Placebo (n=1408) All grades G3-4 All grades G3-4 Diarrhea 1343 (95.4) 562 (39,9) 499 (35,4) 23 (1,6) Dose reduction: 26% Tx termination: 17% What does G 3 diarrhea mean? - > 7 stools daily - incontinence; -hospitalization indicated - limiting self care ADL Chan i wsp. Abst.508 Courtesy of Dr Aleksandra Łacko

66 Clinical Practice?

67 MANAGEMENT OF HER-2 + EBC: Lessons learned from the trastuzumab era & Questions unanswered Consistent & significant benefit of adjuvant trastuzumab Optimal duration still not clear, 1 year remains standard 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?