(Neo)Adjuvant Chemotherapy and biological Agents (essentials in HER2 and TN early breast cancer)

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1 (Neo)Adjuvant Chemotherapy and biological Agents (essentials in HER2 and TN early breast cancer) Giuseppe Curigliano MD, PhD Breast Cancer Program Division of Experimental Therapeutics

2 Outline Neoadjuvant therapy in HER2 positive disease Picking the optimal treatment for adjuvant therapy of HER2 positive EBC Neoadjuvant treatment in triple negative EBC Picking optimal adjuvant chemotherapy for TN early breast cancer

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

4 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

5 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

6 FDA statement on pcr The absence of any residual invasive cancer on H&E evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypt0 ypn0 in the current AJCC staging system). This definition resumes the current understanding of major features of the intrinsic biology of early-stage breast cancer

7 Association of pcr and outcome by BC subtype: a FDA led meta-analysis (N=11,955) Cortazar et al, Lancet 2014

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

9 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 46 TH P H P 24 TP ER or PR positive ER and PR negative TH THP HP TP

10 Overview of dual blockade

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

12 pcr by Arm and Intrinsic Subtype % N=11 N=52 N=51 N=35 N=123 N=173 Carey L et al. J Clin Oncol 35 s, # 500

13 PIK3CA mut status and pcr pcr GBG studies ypt0/ypn0 NeoAltto ypt0/is P= CHERLOB ypt0/is, ypn0 P=0.007 P=0.06 N=173 N=91 N=240 N=112 N=124 N=119 N=~35 N=~35 N=~35 N=108 Loibl S et al. J Clin Oncol 2014; Majewski J Clin Oncol 2015; Guarneri V et al. ESMO 2014

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

15 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? Basedon NeoSphere, NeoAltto, Tryphaena

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

17 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) S U R G E R Y 70 THP HP HL+ET 12 HL+ET TBCRC 0023 Stage II/III HER2+ bc 12 weeks of HL +/-ET 24 weeks of 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

18 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 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.

19 ADAPT Trial Characteristic T-DM1 (n = 119) T-DM1 + ET (n = 127) Trastuzumab + ET (n = 129) Median age, yrs (range) 50.0 (21-78) 51.0 (27-76) 51.5 (23-77) ct, % 1 2 cn, % 0 1 PgR, % Negative Positive ER, % Negative Positive Central grading 3, % Median Ki67 (range) 40 (10-90) 40 (15-80) 35 (10-85)

20 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. Low cellularity (< 500 tumor cells) or Ki67 decline 30%in 3-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)

21 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.

22 Adjuvant therapy in HER2 positive EBC Optimal Adjuvant Therapy in 2016 for the average patient with HER2-positive breast cancer

23 The Adjuvant Setting: Present Situation Trastuzumab given concurrently with Taxanes after Anthracycline-based chemotherapy is the most common practice in Europe N = 465 medicaloncologists answering a questionnaire Trastuzumab with Tax, after A-CTH Trastuzumab seq, after A-CTH TCH Trastuzumab not available Zardavas D et al - Ann Oncol Aug;25(8):

24 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

25 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 SlamonD, 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 observation HR (95% CI)

26 Timing of Distant Recurrences in relation to Adjuvant Trastuzumab Romond EH, N Engl J Med 2005; 353: NSABP B-31 and NCCTG N9831

27 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)

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

29 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 Slamon D et al, SABCS 2-13, abstract #S1-03

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

31 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 physician 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

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

33 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)

34 ExteNET Endpoint Estimated event-free survival rate at 2 years, %* Neratinib (N=1420) Placebo (N=1420) Intention-to-treat population * Event-free rates for all endpoints, except for CNS recurrence for which cumulative incidence is reported. Stratified Cox proportional hazards model. Stratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray s method was used. CNS = central nervous system. Hazard ratio (95% CI) P Value Invasive disease-free survival (0 50, 0 91) Disease-free survival including ductal carcinoma in situ (0 46, 0 84) Distant disease-free survival (0 53, 1 04) Time to distant recurrence (0 50, 1 00) CNS recurrence Chan et al. Lancet Oncol 2016

35 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

36 ExteNET Hormone receptor-positive Hormone receptor-negative % % % 95.4% 91.2% 4.2% % 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

37 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

38 APHINITY S U R G E R Y Central Confirmation of HER2 status N=4806 R A N D O M I Z A T I O N 52 weeks Trastuzumab Pertuzumab Trastuzumab Placebo

39 Katherine Neoadjuvant CT + trastuzumab Residual invasive cancer R T-DM1 Trastuzumab Primary endpoint : IDFS 900/1400 patients recruited as of today

40 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! 40

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

42 Tolaney S, NEJM 2015 De-Escalation

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

44 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!)?

45 (Neo)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 targeting in neoadjuvant setting increase pcr 4. Dual HER2 blockade with the incorporation of lapatinib will not be applied in clinical practice the strategy assessing the addition of pertuzumab is ongoing (2016?). 5. We still lack a validated biomarker beyond HER2 for improved treatment tailoring. We need to: 1. Identify patients with disease resistant to HER2 blockade. 2. Identify patients not needing intensified regimens. 3. Identify patients candidate for chemotherapy-free regimens.

46 (Neo)Adjuvant therapy in TN EBC Who needs more treatment? Addition of carboplatin Nabpaclitaxel ready for prime time? Tumor infiltrating lymphocytes Postneoadjuvant setting

47 Carboplatin in TN Randomized phase IIb study in 51 German centers Pts with centrally confirmed TNBC* or HER2+ BC with ct2 - T4a-d or ct1 with N+ disease (N = 588) PMCb Carboplatin AUC 2 Q1W + Paclitaxel 80 mg/m² Q1W + Nonpegylated liposomal doxorubicin 20 mg/m² Q1W + (n = 295) PM Paclitaxel 80 mg/m² Q1W + Nonpegylated liposomal doxorubicin 20 mg/m² Q1W + (n = 293) Surgery Primary endpoint: pcr Secondary endpoints: RFS, DFS, OS *TNBC pts also received bevacizumab 15 mg/kg IV Q3W. HER2+ BC pts also received trastuzumab 8 mg/kg IV (initial dose), then 6 mg/kg IV Q3D (subsequent doses) and lapatinib 750 mg QD. Dose reduced to AUC 1.5 after 330 pts enrolled. von Minckwitz G, et al. SABCS Abstract S2-04.

48 Carboplatin in TN pcr, % PMCb PM Odds Ratio P Value All pts (n = 588) * HER2+ BC (n = 273) TNBC (n = 315) gbrca wild type (n = 241) gbrca mutant (n = 50) *Level for significance = 0.2 Test for interaction, P = von Minckwitz G, et al. SABCS Abstract S2-04. von Minckwitz G, et al. Lancet Oncol. 2014;15: von Minckwitz G, et al. ASCO Abstract 1005.

49 Carboplatin in TN N =60 (HER2 positive) N =1200 Core biopsy* (before study entry) R* Core biopsy* (after anti-her2 treatment / before study entry) Arm A R* Arm B 12 weeks 12 weeks Surgery If HER2 positive: trastuzumab acc. to AGO Guidelines Core biopsy 6 weeks Paclitaxel 80 mg/ m 2 weekly *Centrally confirmed: - Subtypes HER 2/ HR - Ki67 - SPARC nab-paclitaxel 125 mg/ m 2 weekly * Randomizations carried out simultaneously Epirubicin 90 mg/m 2 Cyclophosphamide 600 mg/m 2 Core biopsy optional Core biopsy optional If HER2 positive: Trastuzumab 8 mg/kg (loading dose) followed by 6 mg/kg Pertuzumab (absolute dose per application) 840 mg (loading dose) followed by 420 mg 1. Untch M, et al. Lancet Oncol Epub ahead of print. 2. von Minckwitz G, et al. Poster at SABCS 2015 [Abstract P ].

50 Carboplatin in TN 60% 50% 29% P= % 40% 30% 20% 10% 0% Paclitaxel Nab-paclitaxel 1. Untch M, et al. Lancet Oncol Epub ahead of print. 2. von Minckwitz G, et al. Poster at SABCS 2015 [Abstract P ].

51 TILs TNBC HER2+ Denkert C et al. J Clin Oncol Dec 2014; epub ahead of print

52 TILs in residual disease: DFS

53 TILs in residual disease: DFS

54 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

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

56 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

57 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

58 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.

59 Triple negative BRCA mutated Figure 1. OlympiA study design Screening Randomization (1:1) Olaparib 300 mg bid (12 months duration) Matched placebo (12 months duration) Invasive disease-free survival assessment (mammogram/breast MRI 6 months from randomization) Follow-up for local and distant recurrence and survival status Assessments

60 Subsets of triple-negative breast cancer 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, Lehman BD, et al. J ClinInvest 2011;121: higher LRF; PI3Kmut

61 Adjuvant therapy in TN Based on direct comparisons, subset analyses and considerations of toxicity/tolerability sequential anthracycline, cyclophosphamide and taxane-based therapy arguably ddac à paclitaxel Alternative regimens Preferred regimen without anthracyclines: TC Preferred regimen without taxanes: AC or CMF Neoadjuvant regimens = adjuvant regimens pcr surrogate of OS

62 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 Simple T1b Moderate to high Simple T1c High Simple or selectively sequential approach

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