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 Disclosure Consultant Tessaro, Leap, Genentech 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 16 Years Since Approval of Trastuzumab: Pivotal trial of Chemo versus Trastuzumab + Chemo in HER2+ MBC Chemo Chemo + T p value Response 32% 50% <.0001 TTP 4.6 mo 7.4 mo <.0001 Med. Survival 20.3 mo 25.1 mo year Survival 68% 79%.008 Results achieved despite: - many patients had HER2- disease by today s criteria - 65% in control arm ultimately crossed over to T Slamon et al, NEJM 2001
4 HER2 Remains a Relevant Target After Progression on Trastuzumab: Capecitabine +/- Trastuzumab TTP X : 5.6 ( ) mos XH : 8.2 ( ) mos P< HR=0.69 (two-sided p=0.034) von Minckwitz. JCO 2009 Median Follow-Up: 15.6 months ORR 48% vs 27%, p=0.0011
5 Lapatinib vs Lapatinib + Trastuzumab: PFS Cumulative % Alive without Progression Subjects At Risk L 148 L+T % % L N = 145 L+T N = 146 Progressed or Died, n Median, wks Hazard ratio (95% CI) 0.73 (0.57, 0.93) P value Mo PFS ORR 6.9% vs 11.3%, NS Time from Randomization (wks) Significant improvement in overall survival also seen Blackwell et al, JCO 2010
6 HER2-Directed Therapy In Combination With Hormonal Therapy? 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 Kaufman, B. et al. JCO, 2009; Johnston et al, JCO 2009
7 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
8 Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and Have Synergistic Activity HER2 receptor Trastuzumab Pertuzumab Subdomain IV of HER2 Trastuzumab continually suppresses HER2 activity Flags cells for destruction by the immune system Dimerisation domain of HER2 Pertuzumab inhibits HER2 forming dimer pairs Suppresses multiple HER signaling pathways Flags cells for destruction by the immune system
9 First-Line Setting: CLEOPATRA: Phase III Trial of Docetaxel + Trastuzumab vs Docetaxel + Trastuzumab + Pertuzumab HER2-positive MBC (53% no prior chemo 10% prior trastuzumab) N=800 1:1 Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab End points PFS and OS quality of life biomarker analysis
10 CLEOPATRA: Final OS Analysis Median follow-up 50 months (range 0 70 months) OS (%) n at risk HR % CI = 0.56, 0.84 p = months Time (months) Δ 15.7 months Ptz + T + D Pla + T + D 56.5 months The 56.5-month median OS is unprecedented in this indication and confirms the Ptz + T + D pertuzumab regimen as first-line standard of care for patients with Pla + T + D HER2-positive MBC Swain et al, ESMO 2014 and NEJM
11 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
12 TDM1 as Second Line Therapy: EMILIA Trial HER2+ (central) LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally qd PD PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Blackwell et al, ASCO 2012 Verma et al, NEJM 2012
13 EMILIA: Progression-Free Survival 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, ASCO 2012
14 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
15 Treatment Approach For Patient Presenting With HER2+ MBC in 2016 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 Important Exception: Some patients with ER+/PR+ disease can be treated up front with hormonal therapy +/- anti-her2 therapy
16 Incidence of CNS Metastases in Trastuzumab-Treated Patients Case Series Patient Population # Overall % Bendell et al, 2003 Trastuzumab-treated Clayton et al, 2004 Trastuzumab-treated Lai et al, 2004 Trastuzumab-treated Lower et al, 2003 Trastuzumab-treated Non-trastuzumab-treated Pinder et al, 2007 Trastuzumab-treated first-line Non-trastuzumab-treated Shmueli et al, 2004 Trastuzumab-treated Stemmler et al, 2006 Trastuzumab-treated Yardley et al, 2007 HER2-positive MBC Yau et al, 2006 Trastuzumab-treated Leyland-Jones B. J Clin Oncol. 2009;27(31):
17 Lapatinib + Capecitabine is an Active Regimen in Refractory CNS Disease Study Lin 2009 n=237 Lin 2009 n=50* Metro 2011 N=30 Sutherland 2010 n=33 Lin 2011 N=13 Regimen Lapatinib Lapatinib + capecitabine 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) Single agent lapatinib RR 6% Other drugs in pipeline for CNS disease: neratinib, ONT/ARRY 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 Case report of CNS response after treatment with T-DM1 Pre-T-DM1 Post-T-DM1 J Neurooncol (2014) 116:
19 First-Generation Adjuvant Trastuzumab Trials
20 % Survival B-31/N9831 Overall Survival ER and/or PR Positive AC P AC P+H AC P N Deaths AC P+H 86% 77.1% P= < P= < ER and PR Negative AC P AC P+H AC P AC P+H N Deaths % 73% HR: 0.61 (95%CI: ) HR: 0.64 (95%CI: ) No. at risk Years from Randomization Perez et al, JCO 2014
21 BCIRG-006 Disease Free Survival Final Analysis(10.3yrs) AC-T AC-TH TCH Patients Events HR (95% C.I.) P (reference) ( ) < ( ) % alive and disease-free Trastuzumab-containing regimens remain superior at 10y follow-up No formal comparison of anthracycline containing vs not G3/4 CHF: 21 vs 4 Despite benefits of trastuzumab, 25% of patients still recur by 10 years still room for improvement! 74.6% 73.0% 67.9% Time (months) Slamon et al, SABCS 2015
22 ALTTO Trial: DFS Analysis No added benefit from Lapatinib MFU = 4.5 yrs * ** * 97.5% CI **p-value required for statistical significance Piccart et al, NEJM 2016
23 Can We Improve in the Adjuvant HER2+ Setting? ExteNet: Study Design Part A Part B Part C HER2+ breast cancer (local) Prior adjuvant trastuzumab & chemotherapy Lymph node /+ or residual invasive disease after neoadjuvant therapy ER/PR + or 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 25% of patients may still recur despite HER2 therapy. 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 Chan et al, ASCO 2015
24 ExteNet Primary Endpoint: Invasive DFS (ITT) % 95.6% 93.9% 91.6% Disease-free survival (%) P-value = HR (95% CI) = 0.67 ( ) 2.5% absolute difference 40% grade 3 diarrhea 50 Neratinib Placebo Months after randomization Chan et al, ASCO 2015
25 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 starts with taxane
26 AC-TH Standard Regimens for Moderate to High Risk Disease TCH Role of adjuvant pertuzumab? Await results from Aphinity at ASCO Role of neratinib Await FDA decision
27 What About Stage I HER2+ Tumors?
28 Risk in < 1cm Node-Negative HER2+ Tumors HER2: About 15% risk of relapse in small node-negative tumors in most worrisome dataset Increased risk in T1b/T1c HER2+ cancers Given lower risk, and significant benefits of trastuzumab, a less intensive chemotherapy regimen may be most appropriate Gonzalez-Angulo, JCO 2009 * endocrine therapy permitted
29 APT Trial 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 Accrual N=406 Less than 20% had T1a 50% had T1c or T2 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)* *Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks ** Radiation and hormonal therapy was initiated after completion of paclitaxel Tolaney et al, NEJM 2015
30 APT Disease-Free Survival Disease-Free Surviv year DFS 95% Conf. Interval 98.7% 97.6% to 99.8% Poisson p-value: < events; only 2 distant and 4 local-regional recurrences Time (Months) Number at risk All patients Tolaney et al, NEJM 2015
31 APT Trial: Probabilities of Disease-free Survival 5 year DFS = 96.6% Only 3 distant recurrences Tolaney, Guo et al, personal communicatio
32 ATEMPT Trial Schema Stage I HER2+* ER+ or ER- PS 0-1 Adequate organ fx N=500 R 3 1 Trastuzumab-DM1 q3weeks X17 N=375 Paclitaxel + Trastuzumab x12 Trastuzumab q3weeks x13 N=125 *HER2-positive defined as IHC 3+ or FISH 2.0; will be confirmed by central HER2 testing prior to study enrollment 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
33 Neoadjuvant Therapy for HER2+ Disease
34 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
35 NeoSphere: PFS and DFS for PTD vs TD PFS, % TD PTD TD PTD n=107 n=107 5-year PFS, % (95% CI) 81 (71 87) 86 (77 91) HR (95% CI) 0.69 ( ) DFS, % TD PTD n=107 n=107 5-year DFS, % (95% CI) 81 (72 88) 84 (72 91) HR (95% CI) 0.60 ( ) Months Months Trial is underpowered for this analysis but results are suggestive of a benefit from the addition of pertuzumab to docetaxel + trastuzumab Gianni L, ASCO 2015
36 Preoperative Use of Pertuzumab FDA accelerated approval to pertuzumab in neoadjuvant setting 11/2013 as THP -> FEC or AC, or TCHP Approval based on NEOSPERE data, metastatic survival advantage, and completion of adjuvant trial NEOSPERE underpowered to determine if PFS predicts DFS/OS; await APHINITY Not inappropriate to use any standard adjuvant regimen as neoadjuvant therapy No advantage for stage I disease
37 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 Two equivocal results do not IHC 3+ equal one positive result! HER2 gene copy number > 6 Oncotype Dx should not be used to assess HER2 Requires close collaboration with pathology and selective retesting
38 THE CHALLENGE OF TRIPLE NEGATIVE BREAST CANCER
39 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
40 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
41 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
42 42 Chemotherapy Options per NCCN
43 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
44 100 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
45 % 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 17/18 0 Tutt et al, SABCS / Months from randomisation Interaction Term for treatment & BRCA 1/2 status p =
46 PARP Inhibition: Synthetic Lethality Inhibition of Poly(Adenosine Disphosphate [ADP]-Ribose) Polymerase 1 (PARP1) + Cells that have lost BRCA1 or BRCA2 function (i.e. deficient homologous recomb) = SELECTIVE CELL DEATH Iglehart and Silver, NEJM 2009
47 Phase II trial of the oral PARP inhibitor olaparib in BRCAdeficient advanced breast cancer ITT cohort Overall Response Rate, n (%) Complete Response, n (%) Partial Response, n (%) Stable Disease n (%) Olaparib 400 mg bid (n=27) 11 (41) 1 (4) 10 (37) 12 (44) Olaparib 100 mg bid (n=27) 6 (22) 0 6 (22) 12 (44) Adverse Events: Fatigue grade 1 or 2, 56% grade 3, 15% Nausea grade 1 or 2, 26%, grade 3 11% Median of 3 prior lines of chemotherapy. Tutt, Lancet 2010
48 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
49 Single Agent PARP Inhibition: Ongoing Trials evaluating Chemotherapy vs PARPi in Patients with BRCA Mutations gbrca1/brca2 Carriers Advanced anthracycline+taxane resistant breast cancer Olaparib OLYMPIAD NCT (Open in Boston all 3 DFHCC sites) Niraparib BRAVO NCT BMN673 EMBRACA NCT R PARP inhibitor at MTD as continuous exposure Physician Choice within SOC options Capecitabine or Vinorelbine or Eribulin or Gemcitabine Primary endpoint PFS
50 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
51 Early Success in Checkpoint Blockade Have Been Biased Towards Tumors with High Rates of Somatic Mutation Lawrence et al, Nature 2013
52 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
53 Phase 1 of PDL1 Inhibitor Atezolizumab (MPDL3280A) in TNBC RR 19% in pretreated disease, 75% of responses maintained Emens et al, AACR 2015
54 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
55 Phase 1 IMMU132: Antibody Drug Conjugate TNBC Best Response (N = 49 assessable patients) Best Response (% change in target lesion from baseline) Objective response = 14/49 = 29% Disease control = 37/49 = 76% Clinical benefit ratio [CR+PR+(SD 4 mo)] = 63%* *29/46; 3 pts with SD <4 mo are continuing treatment AE-neutropenia, Anemia, N/V/diarrhea/fatigue 9 pts with PD because of progression of nontarget lesion or new lesion are not shown in graph CR = 2 PR = 12 SD = 23 PD = pts continuing Assessable: 8 mg/kg (N = 13), 10 mg/kg (N = 34), 12 mg/kg (N = 2) Bardia ASCO 2015
56 Gene expression profile analysis from 587 TNBC samples 6 TNBC subgroups were identified with unique profiles Heterogeneity of TNBC Lehmann et al, JCI 2011
57 Phase II Trial of Enzalutamide Monotherapy in AR+ TNBC PFS 14.7 weeks Traina, ASCO 2015
58 WHAT IS OPTIMAL THERAPY FOR EARLY TNBC?
59 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:
60 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
61 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
62 Should Stage Affect the Choice of of a Treatment Regimen? What is the optimal treatment for small, node negative TNBC tumors?
63 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:
64 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
65 Is There a Role for Platinum Chemotherapy in the Neo/Adjuvant Management of Triple Negative Breast Cancer?
66 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
67 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
68 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?
69 Preoperative Cisplatin As Preoperative Therapy in Patients With BRCA1 Mutations 107 patients with BRCA1 mutations Stage I-III disease Treatment: Preoperative Cisplatin 75 mg/m 2 q 3 weeks x 4 Mastectomy Path CR defined as no invasive tumor in breast/nodes Pathologic complete response = 61% Byrski et al. Breast Cancer Research and Treatment 2014 and Arun et al, JCO 2011
70 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
71 In general, neoadjuvant therapy is preferred approach for stage II/III disease
72 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
73 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
74 FUTURE DIRECTIONS IN TNBC
75 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 development continues for BRCA1/2-associated cancers 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
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