Treatment of HER2+ and Triple Negative Breast Cancer. Eric P. Winer, MD Dana-Farber Cancer Institute Boston, USA

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1 Treatment of HER2+ and Triple Negative Breast Cancer Eric P. Winer, MD Dana-Farber Cancer Institute Boston, USA

2 Disclosure I have nothing to disclose. Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

3 Which of the following statements about triple negative breast cancer (TNBC) is true? 1. A preferred approach for a high-risk TNBC is to add platinum chemotherapy to an anthracycline- and taxane-based adjuvant regimen 2. Anti-PD-1 monotherapy is a highly active therapy for pretreated metastatic TNBC 3. For metastatic TNBC, carboplatin chemotherapy is superior to docetaxel if there is an associated BRCA mutation 4. Neoadjuvant carboplatin or cisplatin reduces risk of distant recurrence for TNBC. 5. The PARP inhibitor, olaparib, improves survival in stage IV, TNBC with BRCA mutations

4 45 yo with 1.6 cm high grade HER2 3+, ER+, PR- cancer with 0/3 sentinel nodes What would you recommend for adjuvant therapy? AC-TH TCH TCHP TH Hormonal therapy + trastuzumab

5 Chemotherapy versus Trastuzumab + Chemotherapy in HER2+ MBC Chemotherapy (AC/paclitaxel) Chemotherapy plus trastuzumab P value Response Rate 32% 50% <0.001 PFS 4.6 months 7.4 months <0.001 OS 20.3 months 25.4 months Slamon et al, NEJM 2001

6 Why Has anti-her2 Therapy Been Better Than Expected? Limitations in initial pivotal trial Inadequate screening test High rate of cardiac toxicity Recognition of the importance of HER2 suppression after progression oncogene addiction Development of additional anti-her2 agents

7 Proposed Mechanism of Pertuzumab/Trastuzumab Synergy HER2 HER2 HER2 HER 3 II II II II Trastuzuma b Pertuzumab

8 First-Line Setting: CLEOPATRA: Phase III Trial of Docetaxel + Trastuzumab + Placebo vs Pertuzumab HER2-positive MBC (53% no prior chemo 10% prior trastuzumab) 1:1 N=800 End points PFS and OS quality of life biomarker analysis Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab Only 10% had prior trastuzumab in adjuvant setting

9 HR % CI = 0.56, 0.84 p = OS (%) n at risk Ptz + T + D Pla + T + D CLEOPATRA: Final OS Analysis Median follow-up 50 months (range 0 70 months) months Time (months) Δ 15.7 months Ptz + T + D Pla + T + D 56.5 months Swain et al, ESMO 2014 and NEJM 2015 The 56.5-month median OS was unprecedented and established the role of pertuzumab in the first-line metastatic. Improvement in OS is larger than the PFS benefit.

10 T-DM1 Selectively Delivers DM1 to HER2-Positive Tumor Cells HER2 T-DM1 binds to the HER2 protein on cancer cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell

11 EMILIA: T-DM1 vs Capecitabine/Lapatinib in Second Line Setting Proportion progression-free Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Second interim analysis confirmed a statistically significant benefit in overall survival with T-DM Time (mos) Blackwell et al, NEJM 2012

12 Survival Advantage T-DM1 vs. Physician Choice Krop et al, Lancet Oncology 2017

13 MARIANNE Progression-Free Survival HT T-DM1 T-DM1+P Median PFS (mo.) Events (no.) Stratified HR vs HT 0.91 ( ) P= ( ) P=0.14 Progression-Free Survival (%) HT T-DM1 T-DM1+P Stratified HR vs T-DM ( ) No significant difference among the arms CLEOPATRA PFS 18 mo No. at Risk HT T-DM1 T-DM1+P Time (mo.) Ellis et al, ASCO 2015

14 HER2-Directed Therapy with Trastuzumab +/- Pertuzumab in Combination with Hormonal Therapy? Progression Free Survival Analysis TAnDEM (Anastrozole vs Anast/Trastuzumab) N=207, improved PFS, not OS PFS EGF30008 (Letrozole vs Let/Lapatinib) N=219 HER2+, improved PFS, not OS TTP OS Rimawi, SABCS 2016

15 Treatment Approach For Patient Presenting With HER2+ MBC in 2017 First Line: Taxane + Trastuzumab + Pertuzumab Second Line: TDM-1 Third, Fourth.Line Capecitabine + Lap Capecitabine + Trast Vinorelbine + Trast Lapatinib + Trast Other chemo + Trast Endocrine Therapy + Trast +/- Pertuzumab Exception: Patients with ER+/PR+ disease can be treated up front with hormonal therapy generally with anti-her2 therapy

16 CNS Relapse in HERA 1 Year Trastuzumab Observation Overall Number of Patients CNS as 1 st Event 37 (2%) 32 (2%) 69 (2%) Other Site as 1 st Event 326 (19%) 421 (25%) 747 (22%) Patients For Whom Questionnaires Were Returned (of 481) Number of Patients Died with CNS Relapse 98 (47%) 98 (57%) 196 (53%) Pestalozzi et al, Lancet Oncol 2013

17 Lapatinib + Capecitabine is an Active Regimen in Refractory CNS Disease Study Lin 2009 n=237 Single agent lapatinib RR 6% Lin 2009 n=50* Metro 2011 N=30 Sutherland 2010 n=33 Regimen Lapatinib Lapatinib + capecitabine Other drugs in pipeline for CNS disease: neratinib, ONT/ARRY-380 Lin 2011 N=13 Method Volumetric Volumetric WHO RECIST Volumetric* CNS ORR, n (%) 15 (6) 10 (20) 7 (32) 7 (21) 5 (38) CNS SD, n (%) 88 (37) 6 (27) 19 (58) PD, n (%) 108 (46) 9 (41) 6 (18) PFS/TTP, mo (range) 2.4 (2 3) 3.7 (1 8) 5.1 (4 7) 5.5 (4 5) OS, mo (range) 6.4 (5 8) 11 (4 18) 1. Lin NU, et al. Clin Cancer Res 2009;15: ; 2. Metro M, et al. Annal of Oncol 2011;22: ; 3. Sutherland S, et al. Br J Cancer 2010;102: ; 4. Lin NU, et al. J Neurooncol 2011.

18 CNS Response to T-DM1 Pre-T-DM1 Post-T-DM1 Now multiple reports of CNS regression J Neurooncol (2014) 116:

19 Therapy for Stage I-III HER+ Disease

20 Overall Survival Joint Analysis of AC-T +/- Trastuzumab Perez et al, JCO 2014

21 Disease Events in Joint Analysis (with extended follow-up) AC-T (n=2018) AC-TH (n=2028) First Event Local Recurrence Distant Recurrence Contralateral Other malignancy Death w/o disease Perez et al, JCO 2014

22 % alive and disease-free BCIRG-006 DFS Final Analysis (10.3yrs) AC-T AC-TH TCH Patients Events HR (95% C.I.) P (reference) ( ) < ( ) Trastuzumab-containing regimens remain superior at 10y follow-up No formal comparison of anthracycline containing vs not Despite benefits of trastuzumab, 25% of patients have events before 10 years still room for improvement 74.6% 73.0% 67.9% Time (months) Slamon et al, SABCS 2015

23 ALTTO Trial: DFS Analysis No statistically significant benefit from Lapatinib MFU = 4.5 yrs * ** * 97.5% CI **p-value required for statistical significance Piccart et al, JCO 2016

24 Can We Improve in the Adjuvant HER2+ Setting? ExteNet: Study Design HER2+ breast cancer (local) Prior adjuvant trastuzumab & chemotherapy Lymph node /+ or residual invasive disease after neoadjuvant therapy ER/PR + or N=2880 1:1 randomization Neratinib x 1 year 240mg/day Placebo x 1 year 2-year follow-up for idfs 5-year follow-up for idfs 5 + year survival A sizeable minority still experience recurrences in spite of chemotherapy plus trastuzumab. HERA did not support longer duration Trastuzumab. Primary endpoint: invasive disease-free survival (idfs) at 2 years (4 years after treatment completion) Complicated study with many amendments

25 Adjuvant Extended Neratinib: Improvement in DFS with Greater Effect in HR+ than HR- Chan et al, Lancet Oncology 2016

26 APHINITY Schema S U R G E R Y N=4800 Central confirmation of HER2 status ACT or TCH trastuzumab + pertuzumab* x 1 year ACT or TCH trastuzumab + placebo* x 1 year Population: Node + or high risk node negative *antibody therapy started with taxane

27 APHINITY Invasive Disease Free Survival Analysis (Primary Endpoint) von Minckwitz et al NEJM 2017

28 APHINITY: By Nodal Subgroups +3.2% -0.5% Node Positive Node Negative Also greater impact in ER- than ER+

29 Pertuzumab For All? Node negative...no Node positive...generally yes (about 3% benefit) ER+...Maybe not if only 1-3 nodes ER-...Generally yes, unless node neg

30 The Standard Approach for Moderate to High Risk will Change in Spite of Recent Findings More biologic agents will be incorporated into early stage disease Probably less chemotherapy Greater individualization of treatment approach Can the clinical trials keep pace with scientific discovery? Will we be prevented from moving forward in the clinic because of older trials which may not be relevant?

31 Risk in Node Negative HER2+ Tumors Shown Below Risk in Patients with T1a and T1b HER2: Gonzalez-Angulo, JCO 2009 About 15% risk of relapse in small node-negative tumors in most worrisome dataset * endocrine therapy permitted Other series of T1a/b less worrisome Clearly, increased risk in T1c HER2+ cancers Given lower risk, and significant benefits of trastuzumab, a less intensive chemotherapy regimen may be most appropriate

32 APT: Study Design HER2+ ER+ or ER- Node Negative < 3 cm Enroll P P P P P P P P P P P P T T T T T T T T T T T T PACLITAXEL 80 mg/m 2 + TRASTUZUMAB 2 mg/kg x 12 N=410 T T T T T T T T T T T T T FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)* Tolaney et al, NEJM 2015

33 Disease-Free Survival Events with Median Followup of 7 Years DFS Event N (%) Time to event [months; mean(range)] Any recurrence or death 23 (5.7) Local/Regional Recurrence* Ipsilateral axilla (HER2+) Ipsilateral breast (HER2+) New Contralateral Primary Breast Cancer HER2+ HER2- Unknown 5 (1.2) (1.5) (12-54) 51 (37-65) (12-59) 87 (84-90) Distant Recurrence 4 (1.0) 49 (27-63) Death Non-breast cancer related 8 (2.0) 58 (13-71) Tolaney et al, ASCO 2017

34 APT: Updated Recurrence Free Interval RFI Events Invasive Local/Regional Recurrence Distant Recurrence Point Est. 95% Conf. Interval No. of events 3-yr RFI 99.2% 98.4% to >99.9% 3 5-yr RFI 98.1% 96.8% to 99.5% 7 7-yr RFI 97.5% 95.9% to 99.1% 9 Death from Breast Cancer Tolaney et al, ASCO 2017

35 ATEMPT Trial Schema Stage I HER2+* ER+ or ER- R 3 Trastuzumab-DM1 q3weeks X17 N=375 PS 0-1 Adequate organ fx 1 Paclitaxel + Trastuzumab x12 Trastuzumab q3weeks x13 N=500 ACCRUAL COMPLETED 2016 N=125 All HER2 testing centrally confirmed Adjuvant endocrine therapy can be initiated after completion of 12 weeks of therapy Adjuvant radiation therapy can be administered concurrently with study treatment. PI: Sara Tolaney, MD, MPH

36 Neoadjuvant Therapy for HER2+ Disease Neoadjuvant therapy should never be given unless decision already made that some form of systemic therapy should be administered in general not a question with HER2+ disease Leads to less extensive breast and axillary surgery Any of of the standard adjuvant regimens can be given outside of trial Appropriate for most patients with stage II/III disease

37 Standard Neoadjuvant Approaches THP Surgery AC THP AC Surgery TCHP Surgery There may be some situations where one does not need pertuzumab.( i.e. 3.5 cm ER+, clinically node negative)

38 Activity of Preoperative Dual HER2 Blockade: Pathologic Response Rates In NEOSPHERE TH TP THP HP ITT (Overall) 29% 24% 46% 17% ER- 37% 30% 63% 27% ER+ 20% 17% 26% 6% Gianni et al, Lancet 2012

39 A Design to Decrease Treatment, Assess Resistance, and Test New Therapies Target Population Highly Active Targeted Therapy pcr No pcr Limited therapy and follow Sample size will depend on confidence intervals for phase II study of CR patients and phase III of high risk patients (almost certainly < 2000) Comprehensive Tissue/Blood Collection and Analysis Standard Treatment Experimental Treatment

40 The Challenge of HER2 Testing Relatively straightforward most of the time, however confusion can arise from: Testing variability (pre/post testing) Biologic heterogeneity (probably the major issue) Clinical HER2 positivity FISH > 2.0 IHC 3+ HER2 gene copy number > 6 Two equivocal results do not equal one positive result! Oncotype Dx should not be used to assess HER2 Requires close collaboration with pathology and selective retesting

41 THE CHALLENGE OF TRIPLE NEGATIVE BREAST CANCER

42 Timing of TNBC Recurrence is Early Rates of distant recurrence following surgery in triple-negative vs other breast ca Dent et al, Clin Cancer Res 2007

43 Site of 1 st TNBC Recurrence in NCCN Triple Negative vs Luminal HER2+ vs Luminal Site OR (95% CI)** p OR (95% CI) p Distant vs Locoregional 1.33 (1.00, 1.78) (0.84, 1.56) 0.39 Lung vs Other 2.27 (1.50, 3.43) < (1.05, 2.60) 0.03 Brain vs Other 5.32 (2.85, 9.91) < (2.93, 10.43) <0.001 Bone vs Other 0.23 (0.16, 0.33) < (0.28, 0.53) <0.001 Liver vs Other 1.06 (0.69, 1.62) (1.12, 2.52) 0.01 *Analysis based on cohort of 1,235 patients with documented recurrence (TN, n=408; HER2+, n=341; Luminal, n=486). Luminal cohort used as the referent group for all analyses. **OR=odds ratio; CI=confidence interval; Other refers to any/all other distant/locoregional site Lin et al, ASCO 2009

44 The Challenge of Advanced TNBC In patients with TNBC, recurrences: tend to occur early commonly involve lung and CNS are associated with poor survival Better therapeutic options are desperately needed Strategies to consider: new chemotherapy approaches targeted options

45 45 Chemotherapy Options per NCCN

46 Is there a Selective Advantage for Platinum in TNBC? Sledge (JCO 1988) reported 47% response rate in first line metastatic disease Abandoned for many years because of concerns about toxicity largely replaced by taxanes Renewed interest in patients with TNBC due to DNA crosslinking mechanism of action Data from neoadjuvant studies supports activity in TNBC, with pcr rates 20-70% Greatest activity seen in BRCA carriers Sledge et al, JCO 2008; Silver et al JCO 2010; Gronwold et al, ASCO 2009

47 100 TNT Trial: 1 st Line Carboplatin vs Docetaxel in Metastatic TNBC % patients progression free Median PFS: Carboplatin: 3.1 mths (95% CI = 2.5 to 4.2) Docetaxel: 4.5 mths (95% CI = 4.1 to 5.2) Restricted mean survival to 15 mths: Carboplatin: 4.8 mths Docetaxel: 5.2 mths Absolute difference: -0.4 (95% CI -1.1 to 0.3) p = 0.29 Carboplatin = 181 /188 Docetaxel = /188 Months from randomisation Tutt et al, SABCS 2014, Nature Medicine in press 47

48 % patients progression free 100 TNT Trial: Docetaxel vs Carboplatin in TNBC: Influence of BRCA Mutation Status Carboplatin + BRCA1/2 mutated Carboplatin + BRCA1/2 not mutated Docetaxel + BRCA1/2 mutated Docetaxel + BRCA1/2 not mutated 10 17/ / Months from randomisation Interaction Term for treatment & BRCA 1/2 status p = 0.03 Tutt et al, SABCS 2014, Nature Medicine in press 48

49 PARP Inhibition: Synthetic Lethality Iglehart and Silver, NEJM 2009 Inhibition of Poly(Adenosine Disphosphate [ADP]-Ribose) Polymerase 1 (PARP1) in setting of loss of BRCA1 or BRCA2 function (i.e. deficient homologous recomb) leads to cell death

50

51 Primary endpoint: progression-free survival by BICR

52 Objective response by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting

53 Study Design: EMBRACA Patients with locally advanced or metastatic HER2-negative breast cancer and a germline BRCA1 or BRCA2 mutation* Stratification factors: Number of prior chemo regimens (0 or 1) TNBC or hormone receptor positive (HR+) History of CNS mets or no CNS mets Phase 3, international, open-label study randomized 431 patients in 16 countries and 145 sites Primary endpoint Progression-free survival by RECIST by blinded central review Key secondary efficacy endpoints Overall survival (OS) ORR by investigator Safety Exploratory endpoints Duration of response (DOR) for objective responders Quality of life (QoL; EORTC QLQ-C30, QLQ-BR23) Abbreviations: CNS, central nervous system; EORTC, European Organisation for Research and Treatment of Cancer; HER2, human epidermal growth factor receptor 2; mets, metastases; PO, orally (per os); QLQ-BR23, Quality of Life Questionnaire breast cancer module; QLQ-C30, Quality of Life Questionnaire Core 30; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1; TNBC, triple-negative breast cancer. *Additional inclusion criteria included: no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease; prior treatment with a taxane and/or anthracycline unless medically contraindicated. HER2-positive disease is excluded. Physician's choice of therapy must be determined prior to randomization. (NCT ) R 2:1 Talazoparib 1 mg PO daily Treatment (21-day cycles) continues until progression or unacceptable toxicity Physician's choice of therapy (PCT) : capecitabine, eribulin, gemcitabine, or vinorelbine Litton et al, SABCS 2017

54 Primary Endpoint: PFS by Blinded Central Review TALA Overall PCT TALA (n = 287) Overall PCT (n = 144) Events, no. (%) 186 (65%) 83 (58%) Median, mo (95% CI) 8.6 (7.2, 9.3) 5.6 (4.2, 6.7) Hazard ratio, 0.54, 95% CI, 0.41, 0.71 P <.0001 Median follow-up time: 11.2 months Litton et al, SABCS 2017

55 Interim OS Analysis: Secondary Endpoint TALA Overall PCT TALA (n = 287) Overall PCT (n = 144) Events, no. (%) 108 (38%) 55 (38%) Median, mo (95% CI) 22.3 (18.1, 26.2) 19.5 (16.3, 22.4) Hazard ratio, 0.76, 95% CI, 0.54, 1.06 P =.105 Survival Probability at: TALA (n = 287) Overall PCT (n = 144) Month 24, % (95% CI) 45% ( ) 37% ( ) Month 36, % (95% CI) 34% ( ) 0%

56 PARP Inhibition in BRCA1+ and Sporadic TNBC 100 Randomized phase II olaparib in sporadic TNBC and known BRCA mutation carriers: % change from baseline TNBC BRCA TNBC non-brca Non-TNBC BRCA Gelmon K, Lancet Oncology 2011 Clinical data to date: Small trials of olaparib, veliparib encouraging in BRCAassociated, not encouraging in sporadic TNBC TNBC alone does not select for BRCA1 dysfunction

57 IMMU-132 Target: Trop2 (EGP-1) Pan-epithelial cancer antigen (related to EpCAM) 80% of patients have moderate to strong expression of Trop-2 by immunohistology; therefore, this is not used for patient selection Prognostic marker in several cancer types Linker: ph sensitive linker (CL2A) Cytotoxic: SN-38 (Irinotecan active metabolite) 7.6 drug molecules/igg Dose schedule: 10 mg/kg days 1 and 8 of 21-day cycles 57

58 Bardia et al, SABCS 2015

59 Other Antibody Drug Conjugates in Development for TNBC CDX-011 (glembatumumab vedotin) Target: GPNMB, Cytotoxic- monomethyl-aurostatin E (MMAE) EMERGE study Ph2 CDX-011 vs Investigator Choice In TNBC with high GPNMB (16 total): ORR 33% SGN-LIV1A Target: LIV-1, transmembrane protein in 65% TNBC Ph1 in breast ca ongoing PF Target: EFNA4 59 Yardley, SABCS 2012

60 20% express PD-L1 Immunotherapy for TNBC: Why Target PD-L1 in TNBC? Robust presence of tumor infiltrating lymphocytes (TILs) High TILs are an independent predictor for pcr/response to chemotherapy High TILs are associated with increased PD-1 expression in TNBC May suggest sensitivity to immune directed therapies Higher mutational load than other breast cancer subtypes Ibrahim E et al, Br Ca Res Treat, 2014; Denkert C et al, JCO, 2010, 2014, 2015

61 Early Success in Checkpoint Blockade Have Been Biased Towards Tumors with High Rates of Somatic Mutation Lawrence et al, Nature 2013

62 Anti PD-1 Ab Pembrolizumab in TNBC: KEYNOTE-012: Waterfall Plot of Response ORR: 18.5%, Median response range weeks 3/5 responders 11 months -Heavily pretreated TNBC -Required tumors to be PD-L1 positive (58% of all screened were PD-L1 +) -Most common toxicities: arthralgia, fatigue, mylagia, nausea (all G1-2) Nanda, SABCS 2014, JCO 2016

63 Ph 1b Atezolizumab + nab-paclitaxel in TNBC Enrolled 24 patients, atezolizumab 800 mg q 2 weeks, nab-paclitaxel 125 mg/m2 weekly 3/1 schedule Responses see in both PD-L1 positive and negative tumors Adams et al, SABCS 2015

64 WHAT IS OPTIMAL THERAPY FOR EARLY TNBC?

65 A Sequential Antracycline-Taxane Combination is the Standard of Care for Moderate-Risk TNBC NSABP-B30 AC-T x 8 vs AT x 4 vs TAC x 6 POSSIBLE REGIMENS AC-paclitaxel (dose dense) AC-weekly paclitaxel AC-docetaxel (every 3 weeks) FEC-docetaxel Swain SM et al. N Engl J Med 2010;362:

66 Pooled Analysis of Dose Dense vs Not Recurrence by ER status ER Negative ER Positive This AACR-SABCS 2017 presentation is the intellectual property of the authors/presenters. Contact for permission to reprint and/or distribute. Grey et al, SABCS 2017 For EBCTCG

67 ABC Trials Schema (nee TC/TAC, B-46I, B-49) Node+ or High Risk Node-Negative Stratification Variables Number of + Nodes (0, 1-3, 4-9, 10+); Hormone Receptor (ER or PgR+, Both Negative) ARM 1 (TaxAC Options) ARM 2 (TC) A TAC q 3 wk TC q 3 wk B AC q 3 wk PTX q 1 wk C AC q 2 wk PTX q 1 wk Arm 1 Options Per Study USOR A only NSABP B-46I/USOR A only NSABP B-49 - investigator choice 1A-1D D AC q 2 wk PTX q 2 wk Endocrine therapy for ER+ or PgR+ patients for minimum of 5 years Designed to prove non-inferiority of non-anthracycline arm Blum et al, ASCO 2016

68 ABC Trials: Invasive Disease Free Survival 100 Alive and Inv. Disease-free (%) yr Treatment N Events IDFS TC % Δ=2.5% TaxAC % HR=1.23, 95% CI ( ) P= Years from Randomization Observed HR on initial 334 events Exceeded pre-specified threshold for futility (> 1.18) > not non-inferior

69 ABC Trials: IDFS by Hormone and Nodal Status Exploratory Analysis Pts TaxAC TC Events TaxAC TC 4 yr IDFS TaxAC TC 4 yr IDFS Delta HR (95% CI) ER/PgR (-) N % 1.31 ( ) 1-3 N % 1.58 ( ) 4+ N % 1.34 ( ) ER or PgR (+) N % 0.69 ( ) 1-3 N % 1.14 ( ) 4+ N % 1.46 ( ) Suggests all groups aside from ER+ N0 benefit from A-containing regimens, especially ER- N+ Presented by: Joanne L. Blum, MD,

70 Should Stage Affect the Choice of of a Treatment Regimen? What is the optimal treatment for small, node negative TNBC tumors?

71 Outcome in National Comprehensive Cancer Network Distant Relapse Free Survival HR-HER2- No chemotherapy Chemotherapy T1a = 74 T1b = 94 T1a = 25 T1b = 170 T1a 5- year estimate : 93% (84-97) T1b 5-year estimate : 90% (81-95) T1a 5- year estimate : 100% T1b 5-year estimate : 96% (90-98) Vaz-Luis et al. JCO 2014;32:

72 Options for Stage 1 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

73 Is There a Role for Platinum Chemotherapy in the Neo/Adjuvant Management of Triple Negative Breast Cancer?

74 Randomized Trials of Preoperative Platinum Chemotherapy for TNBC GeparSixto Schema GerparSixto pcr: platinum vs not CALGB Schema CALGB pcr: platinum vs not Sikov et al. JCO 2015;33:13-21; von Minckwitz et al. Lancet Oncology, May 2014

75 Does Addition of Preoperative Platinum Improve Survival Outcomes for TNBC? GeparSixto 3Y DFS: Improved with Carbo CALGB Y EVS: Not Improved with Carbo Mixed results on survival benefits from preop platinum in TNBC Achieving pcr is a good surrogate for long-term outcomes on a patient level No evidence that pcr rates can be used as a surrogate for survival on a trial level to compare regimens in TNBC Sikov et al. SABCS 2015; von Minckwitz et al. SABCS 2015

76 Is Carboplatin Ready for Primetime in Unselected TNBC in the Adjuvant or Neoadjuvant Setting? NO Need definitive study showing improvement in DFS and/or OS If platinum is ultimately used, should it be added to standard therapy or substituted for one or more drugs? Are there triple negative subtypes that are particularly sensitive to platinum, ie biomarker driven?

77 INFORM: preop cisplatin vs AC for BRCA 1/2 carriers Schema: Randomized Phase 2: 166 patients Stage II/III BC with BRCA1 or 2 mutation AC x 4 Cis x 4 N = 170; approximately 60 enrolled S U R G E R Y Or Biopsy Additional Chemo Multicenter study Designed to show 20% improvement in pcr with cisplatin over AC B Principal Investigators: Nadine Tung and Judy Garber

78 In general, neoadjuvant therapy is preferred approach for stage II/III disease

79 Create-X: Trial Design Capecitabine for Residual Disease Eligibility: HER2- with residual disease after A- and T-containing NAC Dose: 2,500 mg/m2/day, D1-14, x 8 cycles (24 wks) DFS OS Toi et al, SABCS 2015 Masuda et al NEJM 2017

80 PI: Ingrid Mayer EA1131 Stage II/III TNBC At least 1 cm residual disease in breast after neoadjuvant Rx R A N D O M I Z E Capecitabine 1000 mg/m 2 D1-14 q3 weeks x 6 Cisplatin 75 mg/m 2 q3 weeks x 4 OR Carboplatin AUC 6 q3 weeks x 4 Stratified by PAM50 basal vs. non-basal Observation arm removed in Spring 2016

81 TNBC: Summary A disease defined by negatives is not one disease! Andrew Tutt, MD mtnbc is sensitive to a variety of standard chemotherapies, with many reasonable options Platinum chemotherapy may have a role for some mtnbc May be more active in BRCA carriers, but no evidence of superiority in sporadic Not ready for routine use in early disease PARP is a reasonable option for BRCA1/2-associated cancers with MBC Significant scientific effort has identified many new potential therapeutic targets in TNBC, and there is the promise of immunotherapy Given the limited benefit of standard cytotoxics, clinical trial participation should always be considered