(Neo-) Adjuvant chemotherapy and biological agents. Giuseppe Curigliano MD, PhD University of Milano and European Institute of Oncology

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2 (Neo-) Adjuvant chemotherapy and biological agents Giuseppe Curigliano MD, PhD University of Milano and European Institute of Oncology

3 Outline Neoadjuvant treatment in triple negative and HER2 positive early breast cancer The post-neoadjuvant setting Picking optimal adjuvant chemotherapy for TN and HER2 positive early breast cancer

4 Breast Cancer Subtypes Pathology and molecular biology Definition Ductal triple egative Basal like tu or ER negative and HER2-positive ER, PgR and HER2 negative Genomic testing ASCO/CAP Guidelines ER positive ed HER2-positive HER2-e riched tu or ASCO/CAP guidelines; ER and/or PgR positive >= 1% Genomic testing St Gallen

5 Neoadjuvant therapy The Panel strongly endorsed the use of neoadjuvant therapy for stage II or III, HER2 positive or triple-negative breast cancer as the preferred initial treatment approach, particularly when there is any suggestion that treatment response might enable de-escalation of surgery or radiotherapy. St Gallen

6 Neoadjuvant therapy Tumor de novo diagnosed THERAPY Curative intent Residual disease Pro: Conservative surgery Pathologic complete response New drug development Contras: Low rate of pcr in some subtype (ER+) Enrich by subtypes Implication for surgeon and radiation therapist In TN and HER2 positive EBC should be the preferred approach 5

7 Pathological complete response Absence of invasive tumor in breast and nodes Absence of invasive tumor in breast and nodes with residual carcinoma in situ. 6

8 pcr and outcome (N=11,955) 7 Cortazar et al, Lancet 2014

9 Clinical Heterogeneity of TNBC Subtype Gene expression profile Clinical Basal-like 1 high Ki-67; DNA damage response BRCA-associated Basal-like 2 GF pathways Higher pcr Immunomodulatory Immune genes Mesenchymal Cell motility Lower DDFS Mesenchymal stem-like Cell motility; claudin-low Luminal androgen receptor Steroid pathways Apocrine features, higher LRF; PI3Kmut Lehman BD, et al. J Clin Invest 2011;121:

10 Should all TNBC receive PST? Drugs Surgery Neoadjuvant approach Advantages Minimize surgery = no controversy Minimize chemotherapy? Disadvantages Clinical staging - less accurate Locoregional management less clear

11 (Neo)Adjuvant therapy in TN EBC Who needs more treatment? Addition of carboplatin Tumor infiltrating lymphocytes Post-neoadjuvant setting

12 Carboplatin in TN Trial n Drugs Population pcr GEICAM 94 EC-D EC-D+carbo GeparSixto 165 PM/bev PMCb/bev CALGB T-AC(bev) T/carbo-AC(bev) ADAPT-TN 336 Nab-P/wkly Gem Nab-P/wkly Carbo Al a, BCRT ; von Minckwitz, Lan et On ol ; Sikov, JCO ; Gluz, AACR-SABCS Basal-like 30% 30% TNBC (subset) 38% 59%* TNBC 46% 60%* TNBC 29% 46%* Carboplatin augments pcr in TNBC

13 Carboplatin in TN Study Objectives Primary objectives: Pathologic complete response (pcr) in breast and ipsilateral axillary lymph nodes Secondary objectives: EFS, OS, and rate of eligibility for breast conservation after therapy AC, doxorubicin plus cyclophosphamide; Cb, carboplatin; EFS, event free survival; OS, overall survival; P, paclitaxel; V, veliparib S. Loibl et al. The Lancet Oncology 2018

14 Carboplatin in TN Characteristic, n% V+Cb+P (n=316) Cb+P (n=160) P (n=158) Age, median [range], years 51 [26 79] 49 [23 76] 50 [22 75] Region North America Europe Asian Pacific 140 (44.3) 119 (37.7) 57 (18.0) 73 (45.6) 65 (40.6) 22 (13.8) 79 (50.0) 58 (36.7) 21 (13.3) gbrca status Deleterious mutation No deleterious mutation Tumor Stage T1 T2 T3-4ª Lymph Node Stage N0 N1-N2 Planned Schedule of AC Q2 weeks Q3 weeks Missing Longest Tumor Diameter > 30 mm 45 (14.2) 271 (85.8) 37 (11.7) 229 (72.5) 50 (15.8) 180 (57.0) 136 (43.0) 173 (54.7) 140 (44.3) 3 (1.0) 145 (45.9) 171 (54.1) 25 (15.6) 135 (84.4) 20 (12.5) 107 (66.9) 33 (20.6) 92 (57.5) 68 (42.5) 88 (55.0) 70 (43.8) 2 (1.2) 71 (44.4) 89 (55.6) 23 (14.6) 135 (85.4) 15 (9.5) 117 (74.1) 26 (16.5) 94 (59.5) 64 (40.5) 89 (56.3) 69 (43.7) 0 79 (50.0) 79 (50.0) S. Loibl et al. The Lancet Oncology 2018

15 Carboplatin in TN Pathologic Complete Response ypt0/tis ypn0 p=0.36 p< Intent to Perform a Breast Conserving Surgery p=0.14 p=0.13 % P a t ie n t s 5 0 % P a t ie n t s V + C b + P C b + P P V + C b + P C b + P P n=361 n=160 n=158 n=73 n=34 n= Clinical Response Rate* p<0.001 p= Minimal Residual Disease Residual Cancer Burden Class 0 or I p<0.001 p= % P a t ie n t s 5 0 % P a t ie n t s V + C b + P C b + P P V + C b + P C b + P P n=361 n=160 n=158 n=268 n=140 n=125 Error bars are 95% confidence intervals based on normal approximation. p-values were calculated from Cochran-Mantel-Haenszel test versus Arm A (V+Cb+P). *Clinical response rate after paclitaxel based treatment on serial MRI assessment S. Loibl et al. The Lancet Oncology 2018

16 Carboplatin in TN Addition of V and Cb to P followed by AC demonstrated a significant improvement in pcr compared with P followed by AC (53.2% vs 31.0%, p<0.001) confirming results of I-SPY-2. However, addition of V to Cb and P followed by AC did not show improvement in pcr compared to Cb+P followed by AC (53.2% vs 57.5%, p=0.36), demonstrating improvement in pcr was due to carboplatin, without apparent contribution from veliparib at the 50 mg BID dose. Increase in pcr with addition of carboplatin was independent of gbrca mutation status. S. Loibl et al. The Lancet Oncology 2018

17 TILs TNBC HER2+ Denkert C et al. J Clin Oncol Dec 2014

18 INFORM: preop cisplatin vs AC for BRCA Stage II/III BC with BRCA1 or 2 mutation Multicenter study 1/2 carriers AC x 4 CDDP x 4 N = 170; approximately 60 enrolled Designed to show 20% improvement in pcr with cisplatin over AC S U R G E R Y Or Biopsy Principal Investigators: Nadine Tung and Judy Garber TBCRRC and other sites B Additional Chemo

19 Neoadjuvant therapy in HER2+ EBC LESSONS LEARNED FROM NEOADJUVANT TRIALS I. First generation Trastuzumab + chemo > chemo alone

20 Trastuzumab and chemotherapy Trastuzumab + chemotherapy Chemotherapy alone MD Anderson 1 H+(T FEC) T FEC n=45 n= P=NR NOAH 2 H+ AT T CMF AT T CMF n=117 n= P< pcr (%) No evidence of residual invasive cancer, both in breast and axilla No evidence of residual disease in breast tissue pcr, pathological complete response; H, trastuzumab; T, taxane FEC, 5-fluorouracil+epirubicin+cyclophosphamide; AT, doxorubicin+paclitaxel CMF, cyclophosphamide+methotrexate+5-fluorouracil; EC, epirubicin+cyclophosphamide 1. Buzdar AU, et al. 2007,2. Gianni L, et al. 2010

21 Improved pcr rate translates into improved outcome with Trastuzumab 5-year event-free survival 5-year overall survival *EFS, Event free survival; HR, Hazard ratio; OS, Overall survival. Gianni L, et al. 2014

22 Dual HER2 blockade LESSONS LEARNED FROM NEOADJUVANT TRIALS II. Second generation Dual HER2 blockade + chemo > single HER2 blockade + chemo

23 Pertuzumab and trastuzumab 50 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) Study dosing: q3w x 4 Gianni L, et al. Lancet Oncol 2011 DOI: /S (11) S U R G E R Y pcr, % 95% CI pcr, % 95% CI T H TH P H P 24 TP ER or PR positive ER and PR negative TH THP HP TP 6

24 Overview of dual blockade

25 Dual blockade better 74% 65% 48% 45% 38% 25% 20% 15% Increase in pcr Long CHT + dual anti-her2 therapy Long CHT +Trastuzumab similar to short CHT+dual anti- HER2 Short CHT +Trastuzumab CHT alone

26 Beyond dual blockade LESSONS LEARNED FROM NEOADJUVANT TRIALS III. Third generation Identify the subset which can benefit from a chemo-sparing regimen

27 HER2+ /HR- disease % PCR rates % Dual HER2 blockade alone 62% Dual HER2 blockade + taxane 73-80% Dual HER2 blockade + taxane + other agent (anthrac., carbo) Who are these patients with HER2+ HR- disease who perhaps do not need chemo? Based on NeoSphere, NeoAltto, Tryphaena

28 HER2+ /HR- disease PIK3CA mutations/ PTEN loss Improved tailoring? TIL s Immune signatures

29 Chemofree Therapy in HER2+ patients Neosphere TBCR006 THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TBCRC 0023 Stage II/III HER2+ bc 12 weeks of HL +/-ET 24 weeks of HL +/-ET S U R G E R Y THP HP HL+ET 12 HL+ET Overall ER+ ER- 18 Gianni L, et al. Lancet Oncol 2012; Rimawi M et al. J Clin Oncol 2013; Rimawi M, et al. SABCS 2014

30 Trastuzumab Emtansine ± ET vs Trastuzumab + ET in HER2+/HR+ International, prospective, randomized phase II trial Wk 12 Pts with ER+ and/or PgR+, HER2+, ct1c - ct4a-c, cn, cm0 BC and adequate orga fu tio, 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 *Ta o ife if pre e opausal; aro atase i hi itor of i estigator s hoi e if post e opausal. 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.

31 ADAPT Trial Outcome, n/n (%) T-DM1 T-DM1 + ET pcr (ypt0 or ypt0/is, ypn0) All pts* Premenopausal women Postmenopausal women 48/117 (41.0) 22/58 (37.9) 26/59 (44.1) *P <.001 for comparison between each T-DM1 arm vs trastuzumab + ET. Lo ellularit < tu or ells or Ki de li e %i -wk biopsy. Harbeck N, et al. SABCS Abstract S /123 (41.5) 24/63 (38.1) 27/60 (45.0) Trastuzumab + ET 18/119 (15.1) 8/59 (13.6) 10/60 (16.7) Near pcr (ypt1a) 14/117 (12.0) 14/123 (11.4) 5/119 (4.2) Early response Nonresponders Responders 9/36 (25.0) 24/61 (39.3) 6/25 (24.0) 36/76 (47.4) 5/40 (12.5) 11/62 (17.7)

32 Neoadjuvant summary Neoadjuvant therapy is a standard for these two EBC subtypes Evidence-based therapy options differ from adjuvant setting pcr correlated with outcome; non-pcr: options investigated TNBC: Anthracyclines and taxanes are standard Platinum increases pcr (independent of BRCA status) HER2+: Standard CTx backbone: anthracycline+taxane vs. TCb Dual antibody blockade (T+P) are standard

33 Neoadjuvant summary pcr: Adjuvant therapy to be redefined Non-pCR: Effective additional therapy options needed Role of targeted therapies (e.g. immune therapy, PARPi, etc.) HER2+: Therapy concepts for luminal vs. non-luminal tumors Multidisciplinary concept including loco-regional therapy

34 Adjuvant therapy Treatment decision Who needs more? Which is the Best therapy? Prognostic Factors Predictive factors 33

35 Post-Neoadjuvant setting TN C. Liedtke JCO, 26, 8, 2008: pp

36 Post-Neoadjuvant setting Theory: pcr = no further therapy needed Residual disease = give more treatment

37 Post-Neoadjuvant setting Preplanned interim analysis of a randomized, open-label phase III study [1] Stratified by ER status, age, neoadjuvant chemotherapy, use of 5-FU, institution, node status Wk 24 Pts yrs of age with stage I-IIIB HER2- BC and residual disease (non-pcr, N+) after neoadjuvant chemotherapy* and surgery; ECOG PS 0 or 1; no previous oral fluoropyrimidines (N = 910) Primary endpoint: DFS Secondary endpoints: OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness Capecitabine 2500 mg/m²/day PO Days 1-14 Q3W for 8 cycles Hormonal therapy if ER/PgR+ (n = 455) Hormonal therapy if ER/PgR+ No further therapy if ER/PgR- (n = 455) *Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide. 25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet eligibility criteria. IDMC recommended extension to 8 cycles following interim safety analysis of first 50 pts receiving 6 cycles. [2] 1. Toi M, et al. SABCS Abstract S Ohtani S, et al. SABCS Abstract P

38 Post-Neoadjuvant setting Characteristic Capecitabine (n = 440) No Capecitabine (n = 445) Age, median yrs (range) 48 (25-74) 48 (25-74) Menopausal status, % Pre Post Stage, % I, IIA, IB IIIA, IIIB Hormonal receptor status, % ER+ or PgR+ ER- and PgR- Lymph nodes with metastatic disease, % Histologic effect grading by NAC, % 0, 1a, 1b 2, 3 Toi M, et al. SABCS Abstract S

39 Post-Neoadjuvant setting Capecitabine achieved significantly higher 5-yr DFS and OS in HER2- BC pts with residual disease Characteristic, % Capecitabine (n = 440) No Capecitabine (n = 445) HR (95% CI) P Value 5-yr DFS yr OS ( ) 0.60 ( ) <.01 Toi M, et al. SABCS Abstract S1-07.

40 Post-Neoadjuvant setting Masuda N, NEJM 2017

41 Triple negative BRCA mutated

42 BRAVE Protocol Triple negative IO 1 Placebo pcr TNBC Neoadj Chemo Surgery 40% 60% R Radiotherapy No pcr 2 Avelumab Principle Investigator: Pierfranco Conte

43 Escalating in TN EBC Strategy Platinum routine in neoadjuvant Rx Capecitabine in residual disease Biological subsets to tailor escalating Rx Immunotherapy/PARPi/anti androgens or other novel strategies Opinion Yes (justifiable but no known EFS advantage) An option - Stage II+ who has received anthracycline/taxane-based Rx Uncertain in non adequately treated No Not off-trial

44 Adjuvant therapy in TN Based on direct comparisons, subset analyses and considerations of toxicity/tolerability Sequential anthracycline, cyclophosphamide and taxane-based therapy An option ddac paclitaxel in high risk Alternative regimens Preferred regimen without anthracyclines: TC Preferred regimen without taxanes: AC or CMF Neoadjuvant regimens = adjuvant regimens

45 Options for Stage I Disease Chemotherapy treatment options for low risk disease: 1) simple regimen (AC, TC, CMF) 2) sequential anthracycline/taxane Enthusiasm for Chemotherapy Possible Regimens Microinvasion only Virtually none --- T1a Low to moderate None T1b Moderate to high Simple T1c High Simple or selectively sequential approach

46 De-Escalating in TN EBC Strategy Clinical low risk subsets can omit chemotherapy Biologic low risk subsets can omit / limit chemotherapy Neoadjuvant Rx to reduce surgery Treating to pcr to de-escalate systemic therapy Anthracyclines may be omitted Opinion Only in very small, nodenegative (T1a pn0) No No stage I Yes stage II+ No No (may consider in low risk)

47 Adjuvant therapy in HER2 positive EBC Optimal Adjuvant Therapy i 6 for the average patient with HER2-positive breast cancer

48 First generation trials HERA (ex-usa) BCIRG 006 (global) IHC / FISH (n=5102) Observation 1 year 2 years FISH (n=3222) 1 year 1 year NCCTG N9831 (USA) NSABP B-31 (USA) IHC / FISH (n=3505) 1 year IHC / FISH (n=2030) 1 year 1 year Standard CTx Doxorubicin + cyclophosphamide Docetaxel Docetaxel + carboplatin Herceptin Paclitaxel IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation

49 Long-term DFS benefit with adjuvant Trastuzumab for 1 year Study HERA 1 4 CT+/-RT H vs. CT+/-RT BCIRG AC TH H vs. AC T TCH vs. AC T Combined analysis 6-8 (NCCTG N9831/ NSABP B-31) AC TH H vs. AC T HR, hazard ratio Follow-up (years) N Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011, 4. Goldhirsch A, et al Slamon D, et al. 2011; 6. Romond EH, et al. 2005; 7. Perez EA, et al. 2011; 8. Perez EA, et al HR Favours 1 Favours 2 Trastuzumab HR (95% CI) observation

50 Escalation 1. Longer trastuzumab duration (Hera 2y arm) 2. Adding bevacizumab to trastuzumab (Beth) 3. Dual HER2 blockade - Lapatinib + trastuzumab (ALTTO) - Pertuzumab + trastuzumab (APHINITY) 4. T-DM1 after neoadjuvant CT + trastuzumab in case of residual disease (Katherine)

51 HERA 2 years Goldhirsch A et al. The Lancet Volume 382, No. 9897, p , 21 September 2013

52 Slamon D et al, SABCS 2-13, abstract #S1-03 Adding bevacizumab Cohort 1 Non-Anthracycline TCH Node positive or high-risk node negative HER2+ H Cohort 2 Anthracycline N= 3231 N= 278 TH FEC H Arm 1A TCH H Arm 1B TCHBev HBev TH Arm 2A H FEC Arm 2B THBev HBev FEC

53 Slamon D et al, SABCS 2-13, abstract #S1-03 Adding bevacizumab IDFS OS No Bevacizumab 92% 96% + Bevacizumab 92% 97%

54 Adding lapatinib Anti-HER2 therapy: 4 groups assigned by randomization Trastuzumab Lapatinib T x 12 wks Trastuzumab and Lapatinib 6 weeks (T) x 52 weeks (L) x 52 weeks L x 34 weeks x 52 weeks x 52 weeks 3 modalities of adjuvant CT administration per physi ia s choice Design 1 Chemotherapy Anthracycline Taxane Anti-HER2 therapy 12 to 18 weeks 52 weeks * R Design 2a 9 to 12 weeks 12 weeks * R Design 2b Docetaxel + Carboplatin 18 weeks Anti-HER2 therapy 52 weeks Anti-HER2 therapy * R: refers to the timing of randomization * R 52 weeks

55 Adding lapatinib MFU = 4.5 yrs M. Piccart et al. JCO 2015

56 Extended Neratinib 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)

57 ExteNET Intention-to-treat population % 95.6% 93.9% 91.6% 2.3% Disease-free survival (%) P-value = HR (95% CI) = 0.67 ( ) 50 Neratinib Placebo No. at risk Neratinib Placebo Months after randomization Chan et al. Lancet Oncol 2016

58 ExteNET Hormone receptor-positive Hormone receptor-negative % 96.0% 95.4% 91.2% 4.2% % 92.2% 95.0% 92.0% Disease-free survival (%) No. at risk Neratinib Placebo P = HR (95% CI) = 0.51 ( ) Months after randomization Neratinib Placebo Disease-free survival (%) No. at risk Neratinib Placebo P = 0.74 HR (95% CI) = 0.93 ( ) Months after randomization Neratinib Placebo Chan et al. Lancet Oncol 2016

59 ExteNET Invasive disease-free survival (%) No. at risk Neratinib Placebo HR (95% CI) = 0.73 ( ) Two-sided P = Treatment Neratinib Placebo % 95.5%. % % 91.7%. % Months after randomization % 90.2%. % % 89.1%. % % 87.7%. % Intention-to-treat population. Cut-off date: March 1, 2017 Martin M, et al. Presentation at European Society of Medical Oncology (ESMO) Annual Meeting, Sept Oral Presentation 149O.

60 ExteNET HR-positive subgroup HR-negative subgroup Invasive disease-free survival (%) % 96.1% 95.4% 91.7% 93.6% 89.8% HR (95% CI) = 0.60 ( ) Two-sided P = % 88.5% 91.2% 86.8% Invasive disease-free survival (%) % 92.8% 90.8% 94.7% 91.8% 90.4% HR (95% CI) = 0.95 ( ) Two-sided P = % 89.3% 88.9% 88.8% 50 Neratinib 50 Neratinib Placebo Placebo No. at risk Months after randomization No. at risk Months after randomization Neratinib Neratinib Placebo Placebo Intention-to-treat population. Cut-off date: March 1, 2017 Martin M, et al. Presentation at European Society of Medical Oncology (ESMO) Annual Meeting, Sept Oral Presentation 149O

61 *A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed Von Minckwitz, G, et al. N Eng J Med. 2017;377: APHINITY S U R G E R Y Central confirmation of HER2 status (N = 4805) R Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo F O L L O W - U P 10 Y E A R S Randomization and treatment within 8 weeks of surgery 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

62 APHINITY 63% N+ 36% HR Number needed to treat: % A-based CT Von Minckwitz, G, et al. N Eng J Med. 2017;377:

63 Katherine Neoadjuvant CT + trastuzumab Residual invasive cancer R T-DM1 Trastuzumab Primary endpoint : IDFS 9 / 4 patie ts re ruited as of today

64 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 Worrysome : taxane + trastuzumab = T-DM1 = T-DM1 + pertuzumab in the first line metastatic MARIANNE trial! 63

65 Escalation attempts : preliminary conclusions Failed Succeeded V V V Trastuzumab x 2y Trastuzumab + bevacizumab Trastuzumab + lapatinib Trastuzumab followed by neratinib Trastuzumab + pertuzumab V V? T-DM1 after neoadj CT + trast?

66 Tolaney S, NEJM 2015 De-Escalation

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

68 De-Escalation attempts : preliminary conclusions Failed Succeeded V(so far Shorten trastuzumab duration Eliminate the anthracycline component? Use T-DM1 + pertuzumab instead of taxane + trastuzumab + pertuzumab V (in selected pts!)?

69 Adjuvant therapy in HER2 + EBC Stage Terapia medica De-escalation Escalation ER negative & HER2-positive pt1a pn0 No therapy No therapy pt1 b,c pn0 Higher T and N stage Chemotherapy plus trastuzumab Neoadjuvant therapy for stage II or III is the preferred initial treatment approach. Anthracycline/taxane with concurrent trastuzumab continued to 12 months Consider trastuzumab and paclitaxel plus one year trastuzumab without anthracyclines Pertuzumab/trastuzumab? Dual anti-her2 therapy with pertuzumab and trastuzumab with chemotherapy as the preferred option in the neoadjuvant setting Data with dual blockade in the adjuvant setting are pending ER positive & HER2-positive As above plus endocrine therapy appropriate to menopausal status as below Extended adjuvant therapy with neratinib after one year of trastuzumab 68

70 Adjuvant therapy in HER2+ EBC 1. Adjuvant trastuzumab treatment for 1 year is the standard of care. 2. Longer or shorter durations of adjuvant trastuzumab treatment are not justified by currently available data. 3. Dual HER2 blockade with the incorporation of pertuzumab is standard of are i high risk patie ts applied in clinical practice 4. We still la k a validated io arker eyo d HER for i proved treatment tailoring. We need to: 1. Identify patients with disease resistant to HER2 blockade. 2. Identify patients not needing intensified regimens. 3. Ide tify patie ts a didate for he otherapy-free regi e s.

71 Where we are Targeted therapy Chemo Targeted therapy Ch Chirurgia RT Endocrine therapy Duration of treatment : from 1 day to > 10 years! 70

72 Escalation More Patients Treated Longer Drug Exposure More Drugs Therapeutic Escalation 71

73 De-Escalation: Surgery Mastectomy and axillary dissection QUAD and axillary dissection only if SN + Sentinel node up to 2 SN+ 2016???? No surgery on the axilla 72

74 De-Escalation: Radiotherapy Duration in Days Standard RT AWBI APBI IORT No RT 73

75 Clinical research in the future $ $ $ Drug treatment de-escalation - Governments - EU - [Charities] $ $ $ $ $ $ $ $ $ $ $ Drug treatment escalation - Pharma 74

76 Thank you