Neoadjuvant Therapy for Breast Cancer

Transcription

1 Neoadjuvant Therapy for Breast Cancer Sandra M. Swain, MD Medical Director, Washington Cancer Institute Washington Hospital Center Professor of Medicine Georgetown University Washington DC

2 Drug development has occured at a snail s pace Large trials are cumbersome, slow, use high amount of resources both human and financial Even if active takes years to get to a patient Loses lives

3 Innovative Ideas for Breast Cancer Drug Approval The Neoadjuvant Model

4 Inflammatory Breast Cancer Standard Treatment Primary Chemotherapy* Surgery RT Hormonal Therapy *Trastuzumab for HER2 positive tumors

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7 IBC Survival: NCI MB Non-Inflammatory (42%) Inflammatory (20%) Years from On-Study Date Low et al, J Clin Oncol 2004;22:4067

8 Breast Cancer Intrinsic Subtypes Luminal B Claudin Low Basal-like HER2 Luminal A Claudin 3 Claudin 4 Claudin 7 E-Cadherin Perou C M The Oncologist 2010;15:39-48

9 Relapse-free Survival Breast Cancer Subtypes and Outcomes Prat A, et al. Breast Cancer Res. 2010;12(5):R68.

10 All molecular subtypes are present in IBC IBC (298 probe sets) Non-IBC (251 probe sets) Van Laere SJ et al. Clin Cancer Res. 2013;19:

11 Subtypes of TNBC and targeted therapy selection Basal1 Basal2 Immune Module Mesenchymal Mesenchymal Stem Cell Cell cycle, DNA damage GFR, glycolysis, p63 B/TCR, cytokines, JAK/STAT ECM receptors TGF-b Rho Wnt/b-Cat EMT Stem cell markers Luminal Androgen Receptor Lehmann BD et. al. J Clin Invest (7): 2750 Luminal CK s AR FOXA1 XBP1 No TNBC subtyping approach is yet of clinical utility

12 Correlation of Breast Cancer Axillary Metastases with Stem Cell Mutations N=30 9/10 4/20 Donovan, et al JAMA Surg epub July 2013

13 Personalizing Breast Cancer Treatment: Current State of Affairs Intrinsic Subtypes (Luminal, etc) Receptor Status (HR, HER2) Molecular Profiling (Recurrence Score,etc) Despite acceptance of expression-based subtyping, receptor status remains cornerstone of personalizing treatment in clinic. Narod SA. Lancet 2012;380:

14 Molecular Profiling Assays Developed to identify patients for treatment Need treatment Will benefit from a specific treatment Will not benefit from treatment

15 Large Randomized Neoadjuvant Trials in Breast Cancer

16 % Alive NSABP B-18: Preop vs. Postop AC: Overall Survival Update N Ev HR P Post Pre Years Rastogi et al. J Clin Oncol 2008

17 NSABP B-27 Schema Operable Breast Cancer (2411 pts) Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Docetaxel x 4 Surgery Surgery Docetaxel x 4

18 NSABP B-27: Pathologic Response in Breast and Axillary Nodes pcr in Breast Positive Nodes No Tumor Non- Invasive 80 P < % P < % 3.9% AC (1,492 pts) 25.6% AC 18.7% 6.9% Docetaxel (718 pts) % AC 41 AC Docetaxel Bear H, et al: J Clin Oncol, 2003

19 % Disease-free NSABP B-27: Disease-Free Survival TRT N Events AC AC T S HR=0.86 p=0.10 AC S T HR=0.91 p= Years after Surgery Bear H et al: SABCS 2004

20 % Disease-Free NSABP B-27 pcr as a Surrogate for Clinical Endpoints 100 pcr Hypothesis: Mixed with good prognosis patients who did not benefit Why is from the curve chemotherapy? for nopcr who not benefited steeper? but did not (or achieve a pcr)? No-pCR Years after Surgery

21 Probability of Survival NSABP B-27 Gene Expression and Survival Outcome Low-risk (n=163) High-risk (n=163) Time (months) Paik S: Unpublished data

22 Low-Risk Patients Have Good Outcome Regardless of pcr Probability of Survival pcr low-risk (16) No-pCR low-risk (147) Time (months) Paik S: Unpublished data

23 Combination of Prognostic Genes and pcr Defines Residual Risk after Chemotherapy Probability of Survival High-Risk & pcr (34) High-risk & no-pcr (125) Candidates for post-neoadjuvant chemo trials for targeted therapy Time (months) Paik S: Unpublished data

24 In Vivo Chemosensitivity-Adapted Neoadjuvant Chemotherapy: the GEPAR-TRIO Trial Sonography N=2072 NC R NX TACx6 Core biopsy: uni/bilateral ct2-4a-d cn0-3 size 2 cm* Conventional arms TACx6 Responseguided arms CR/ PR R *low risk patients were excluded (T2 + ER/PR pos. + cno + G1/2 + > 35 yrs) TACx8 Von Minckwitz G et al J Clin Oncol 2013:31;

25 Short Term Efficacy (pcr = ypt0 ypn0) 30% Responders N=1344 P=0.27 Non-Responders N=604 P= % 10% TACx6 TACx8 5.3 TACx6 6.0 TAC-NX Von Minckwitz G et al J Clin Oncol 2013:31;

26 pcr Rates by Subtype pcr (%) Luminal A (N=572) Luminal B (HER2-) (N=211) Luminal B (HER2+) (N=281) HER2+ (non-luminal) (N=178) Triple-negative N=362) HR+, HER2-, G1/2 HR+, HER2-, G3 HR+, HER2+ HR-, HER2+ HR-, HER2- Von Minckwitz G et al, SABCS 2011

27 DFS in Luminal A Tumors by pcr by Treatment Von Minckwitz G et al, SABCS 2011

28 DFS in Triple Negative Tumors by pcr by Treatment Von Minckwitz G et al, SABCS 2011

29 Surgery Subtype Specific Targeted Therapy N=595 centrally confirmed TNBC or R Her2-positive breast cancer PM PMCb Non-pegylated liposomal Paclitaxel 80 mg/m² q1w doxorubicin 20 mg/m² q1w Carboplatin AUC 1.5* q1w Her2-pos: Trastuzumab 6(8) mg/kg q3w (for 1 year) + Lapatinib 750 mg/d 18 wks TNBC: Bevacizumab 15 mg/kg q3w *reduced from AUC 2 at amendment 1 after enrolment of 330 patients Presented at the 2013 ASCO Annual Meeting. Presented data is the property of GBG and AGO-B.

30 Primary Endpoint: pcr 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 37.2% 46.7% PM ypt0 ypn0 P<0.2* PMCb N=293 N=295 * Level for significance = 0.2 Presented at the 2013 ASCO Annual Meeting. Presented data is the property of GBG and AGO-B.

31 pcr Rates by Subtype TNBC ypt0 ypn0 HER2-positive 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 37.9% 58.7% PM P<0.05 PMCb 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 36.3% 33.1% PM n.s. PMCb N=157 N=158 N=136 N=137 Presented at the 2013 ASCO Annual Meeting. Presented data is the property of GBG and AGO-B.

32 Neoadjuvant Studies Summary No improvement in survival overall with nonspecific treatment Pts with pcr have improved survival Triple negative disease has highest pcr with chemotherapy Carboplatin increases pcr Luminal A disease outcome not related to pcr

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34 CTNeoBC Selected Trials 12 neoadjuvant randomized controlled trials pcr clearly defined with all necessary data collected Long-term follow-up EFS and OS data collected TRIALS Patients (n) GBG/AGO: NSABP: EORTC/BIG: ITA: Total # patients Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 34

35 pcr Rates by Tumor Subtypes Grade 1-2 Grade 3 No Tras Yes Tras No Tras Yes Tras HR+ HER2+ HR+ HER2+ HR- TRIPLE NEG Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 35

36 EFS Definition ADJUVANT SYSTEMIC THERAPY SURGERY Time of DFS * randomization Time of randomization NEOADJUVANT SYSTEMIC SURGERY EFS * THERAPY *loco-regional or distant recurrence or deaths from any cause Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 36

37 Association of pcr on EFS and OS HR=0.48, P* < HR=0.36, P* < Individual patients who attain a pcr have a more favorable long-term outcome pcr=ypt0/is ypn0 * Nominal p-value Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 37

38 Association of pcr with EFS in HR+ HER2-Subtype HR=0.49, P* < HR=0.63, P* = 0.07 HR=0.27, P* < pcr=ypt0/is ypn0 * Nominal p-value Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 38

39 Association of pcr with EFS in Her2+ Subtype HR=0.39, P* < HR=0.58, P* = HR=0.25, P* < pcr=ypt0/is ypn0 * Nominal p-value Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 39

40 Association of pcr with EFS in Triple Negative Subtype HR=0.24, P* < pcr=ypt0/is ypn0 * Nominal p-value Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 40

41 Trial level correlation between pcr and EFS A perfect scenario example (simulated-data) R 2 ~ 1 Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 41

42 The magnitude of improvement in pcr rate did not predict EFS and OS effect R 2 =0.01 R 2 =0.18 Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 42

43 A Hypothetical Example Limitations of Responder Analysis Patient level Trial level pcr 5-yr EFS rate Δ = 2% Non-pCR HR=0.98 (95% CI: 0.84, 1.15) Exp Although patients with pcr have better EFS irrespective of treatment. There is no difference on EFS between the two randomized treatment arms. Ctrl pcr 21% 10% No pcr 79% 90%

44 Summary 1. pcr association with long term outcomes (EFS and OS): Individual patients who attain a pcr have a more favorable long-term outcome. 2. Association of pcr with EFS by breast cancer subtype: Larger Association in patients with aggressive breast cancer tumor subtypes Smaller Association in patients with less aggressive tumors Cortazar NEOADJUVANT BREAST CANCER WORKSHOP CTNeoBC 44

45 Innovative approaches to Drug Development Use of pcr as surrogate endpoint in breast cancer Smaller trials use less resources and are quicker Saves lives Molecular era discovers better targets Transformative

46 Draft Guidance for Industry: Pathological Complete Response in Neoadjuvant Treatment of Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval High risk early breast cancer RCT powered for EFS and OS Superiority design Add-on design to Standard tx Pathologists blinded to therapy Standard operating procedures for collection, handling and interpretation of pathology specimens Standard postop therapy should be the same in both arms Neoadjuvant Approval ODAC September

47 HER 2: A model target

48 Milestones of HER2/anti-HER2 therapies in BC EGFR discovery Cohen neu oncogene discovery Weinberg Her2 cloned Ullrich and Coussens FDA approves single agent trastuzumab for 2nd line and in combination with paclitaxel for 1st line MBC Amplification of Her2/neu correlates with shorter survival Slamon FDA approves lapatinib + capecitabine for MBC FDA approves pertuzumab + trastuzumab + docetaxel for MBC EGFR MoAb inhibited growth Mendelsohn MBC : metastatic breast cancer MoAb SM : monoclonal SWAIN antibody Her2 amplification in breast cancer Aaronson FDA approves trastuzumab in adjuvant setting FDA approves TDM1 for MBC FDA approves Pertuzumab + Trastuzumab neoadjuvant

49 Oncology Drugs Advisory Committee Meeting September 12, 2013

50 sbla submission for Pertuzumab PERJETA is a HER2/neu receptor antagonist indicated for: Neoadjuvant treatment of breast cancer, in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (>2 cm in diameter) as part of a complete early breast cancer regimen containing either fluorouracil, epirubicin and cyclophosphamide (FEC) or carboplatin

51 HER2-positive Population Has a High Risk NOAH Trial: 5 yr EFS/OS Gianni: ASCO 2013 ODAC September

52 NeoSphere: Study design and objectives Patients with operable or locally advanced /inflammatory* HER2-positive BC 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) S U R G Phase II design Primary endpoint: Comparison of pcr rates TH vs THP TH vs HP THP vs TP Chemo-naïve & primary tumors >2cm (N=417) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) E R Y Secondary endpoints: Clinical response DFS Breast conservation rate Biomarker evaluation Study dosing: q3w x 4

53 NeoSphere: Primary endpoint pathologic complete response (breast only) (ITT population) pcr, % 95% CI p= p= p= H, trastuzumab; P, pertuzumab; T, docetaxel p values from Cochran-Mantel-Haenszel test and adjusted for multiplicity TH THP HP TP Gianni L, et al. Lancet Oncol 2011 DOI: /S (11)

54 Pathologic complete response (%) NeoSphere Higher pcr rates with P+H+T Δ pcr % Arm A vs B Breast pcr 16.8 Total pcr H T P H T P H P T Arm: A B C D

55 Pathologic complete response (%) NEOSPHERE: pcr and hormone receptors status NEOSPHERE Hormone receptor status tpcr rates higher with P+H+T Δ tpcr % Arm A vs B 80 Hormone receptor neg Hormone receptor pos H T P H T P H P T Arm: A B C D

56 TRYPHAENA: Study Design Locally advanced, inflammatory, or operable HER2+ EBC, & primary tumors >2cm A (n=73) B (n=75) Pertuzumab(P) + Trastuzumab(H) x6 FEC x3 FEC x3 docetaxel x3 P + H x3 docetaxel x3 S U R G E Trastuzumab to complete 1 year (N=225) Randomized C (n=77) P + H x6 docetaxel x6 carboplatin x6 R Y Primary endpoint: cardiac safety Key secondary endpoint: breast pcr

57 Pathologic complete response (%) TRYPHAENA: Total pcr rates by hormone receptor status hormone receptor negative hormone receptor positive P+H+FEC P+H+T (n = 73) FEC P+H+T (n = 75) TCH+P x6 (n = 77) Arm: A B C

58 TRYPHAENA: Cardiac Safety (%) LVEF Decline LVSD Grade > 3 Ongoing LVEF < 50% ARM A ARM B ARM C LVEF decline > 10% and < 50%

59 Overall survival (%) CLEOPATRA confirmatory overall survival analysis 1 year % 89% 2 years 81% 69% 3 years 66% HR= % CI p= % Ptz + T + D: 113 events; median not reached Pla + T + D: 154 events; median 37.6 months n at risk Ptz + T + D Pla + T + D Time (months) Stopping boundary for concluding statistical significance at this second interim analysis was p D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Swain SM et al. Lancet Oncology

60 APHINITY: Study Schema S U R G E R Y N=3,806 Central confirmation of HER2 status R A N D O M I Z A T I O N Chemotherapy plus trastuzumab and pertuzumab Chemotherapy plus trastuzumab and placebo F O L L O W U P 10 Y E A R S Accrual: 11/11 8/13 Randomisation within 7 weeks HR: of surgery.75 Start treatment within 1 week Anti HER2 therapy for a total of 1 year (52 weeks) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

61 Neoadjuvant Anthracycline Study Design BERENICE Locally advanced, inflammatory, or operable HER2+ EBC, and primary tumors >2cm (N~240) AC, dose dense P + H P + H paclitaxel, weekly S U R G E R P+H to complete 1 year Parallel cohorts FEC docetaxel Y Primary endpoint: cardiac safety Key secondary endpoint: total pcr AC= doxorubicin + cyclophosphamide. P+H= Perjeta + Herceptin.

62 Will pcr Improvement With AntiHer2 Therapies Be Associated With Improved Long-term Outcome? NEOADJUVANT ADJUVANT METASTATIC TRIALS pcr Δ Abs TRIALS DFS HR TRIALS PFS Δ Mo (HR) OS Δ Mo (HR) Trastuzumab NOAH Trial 19%* 4 Trials ** Slamon 2.7 (0.53) 4.8 (0.80) Pertuzumab NEOSPHERE Trial 18% APHINITY Ongoing CLEOPATRA 6.1 (0.62) NR (0.66) * EFS HR: 0.59 p= Gianni: Lancet 2010 ** NSABP B-31/ NCCTG 9831, BCIRG 006, HERA NR= not reached ODAC September

63 ODAC September 12, 2013 Has Perjeta demonstrated a favorable benefit to risk evaluation for the neoadjuvant treatment of early breast cancer? Vote: 13 yes, 1 abstention Reasons for yes Totality of evidence CLEOPATRA survival benefit APHINITY already accrued Robust clinical development by company: N of 1 Safety reasonable

64 Pertuzumab accelerated approval September 27, 2013 Neoadjuvant indication for Perjeta is for use prior to surgery in combination with Herceptin and docetaxel chemotherapy in people with HER2-positive, locally advanced, inflammatory, or early stage (tumor is greater than two centimeters in diameter or node positive) breast cancer. Perjeta should be used as part of a complete treatment regimen for early stage breast cancer.

65 Molecular Profiling Assays Developed to identify patients for treatment Need treatment Will benefit from a specific treatment Will not benefit from treatment

66 I-SPY 2 TRIAL Schema Paclitaxel * (12 weekly cycles) AC (4 cycles) S Screening MRI Biopsy Blood Draw MUGA/ECHO CT/PET R A N D O M I Z E O N S T U D Y Paclitaxel* + Investigational Agent A (12 weekly cycles) Paclitaxel* + Investigational Agent B (12 weekly cycles) MRI Biopsy Blood Draw MRI Blood Draw AC (4 cycles) AC (4 cycles) MRI Blood Draw U R G E R Y Consent #2 Treatment Consent * HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab. Tissue

67 Frequency and Combination of Mutated Cancer Genes 40 Mutated Cancer Genes 100 Breast Cancers 7 mutated in >10% of cases 58% of driving genetic events 33 mutated in <10% of cases 42% of driving genetic events 73 different combinations of mutated cancer genes: most tumors differed from all others Substantial variation in numbers and types of mutations between tumors (base substitutions, indels) Stephens PJ, et al. Nature. 2012;486:

68 Lessons Learned Breast cancer complex and diverse Multiple distinct mutational processes Driver mutations operative in many genes Many infrequent mutations collectively contribute to driving events Stephens PJ, et al. Nature. 2012;486:

69 Gene and Transcript Analysis Reveals 10 Breast Cancer Subgroups Analysis of copy number and gene expression in 997 primary breast tumors revealed 10 integrative clusters, validated in 995 tumors Integrative clusters split intrinsic subtypes 10 Integrative Clusters PAM50 Intrinsic Subtype Curtis C, et al. Nature. 2012;486:

70 10 Clusters Associated With Distinct Clinical Outcomes Cluster 3 associated with a lower risk of death Future studies may identify patients in this cluster who can forgo chemotherapy Curtis. Nature. 2012;486:346; Narod. Lancet 2012;380:1212.

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72 Multidisciplinary Tumor Boards Required to Implement Cancer Genomics Genomics Pathology Bioethics Bioinformatics Clinical Genetics Clinical Oncology

73 Incorporating Genomic Information Into Clinical Decision Making Tran et al, JCO 2012; 30:655

74 US Food and Drug Administration Approvals in Metastatic Breast Cancer Adapted from Cortazar, et al. J Clin Oncol 2012: 30;

75 MAHALO!