Any News in EBC? Ann H. Partridge, MD, MPH Dana-Farber Cancer Institute November 11, 2016

Transcription

1 Any News in EBC? Ann H. Partridge, MD, MPH Dana-Farber Cancer Institute November 11, 2016

2 Yes! Age disparities vary by tumor subtype Genomic risk prediction data in young women Adjuvant systemic therapy considerations for young women

3 Hazard Ratio Young Women Are More Likely to Die in NCCN All Tumors Luminal A Luminal B Triple Negative N=17,575 N=7738 N=5149 N=2886 Adjusted for race/ethnicity, insurance, employment, center, education, treatment, stage at diagnosis, grade, year of diagnosis, and detection method (symptomatic or Screen) Partridge et al, JCO 2016

4 Breast Cancer Subtypes by Increasing Age HER2+ HR+/HER2+ * TNBC HR+/HER2- * Keegan et al, BCR, 2012

5 Hazard Ratio Young Women Are More Likely to Die 3,50 3,00 2,50 2,00 1,50 1,00 0,50 0,00 HER2 type N= from Luminal A Tumors Luminal A N=7738 1,7 1 Luminal B N=5149 1,2 1 1 Triple Negative N=2886 Adjusted for race/ethnicity, insurance, employment, center, education, treatment, stage at diagnosis, grade, year of diagnosis, and detection method (symptomatic or screen) 1,3 1 Partridge et al, JCO 2016

6 TAILORx RS < 10 Sparano et al, NEJM, 2015

7 MINDACT Cardoso et al, NEJM, 2016

8 HER2+: BCIRG-006 Disease Free Survival Final Analysis(10.3yrs) % alive and disease-free 1 0,9 0,8 0,7 0,6 0,5 0,4 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 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

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

10 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 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 1:1 randomization Neratinib x 1 year 240mg/day Placebo x 1 year Part A Part B Part C 2-year follow-up for idfs 5-year follow-up for idfs 5 + year survival Chan et al, ASCO 2015

11 ExteNet Primary Endpoint: Invasive DFS (ITT) Disease-free survival (%) P-value = HR (95% CI) = 0.67 ( ) 97.8% 95.6% Months after randomization Neratinib Placebo 93.9% 91.6% 2.5% absolute differenc e 40% grade 3 diarrhea Chan et al, ASCO 2015

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

13 AC-TH TCH HER2+: Standard Regimens for Moderate to High Risk Disease Role of adjuvant pertuzumab? Based on results in preoperative setting without any DFS or OS data Included in NCCN guidelines as a footnote Not ready for routine use outside of selected patients as neoadjuvant therapy I don t think regimen choice here should vary by age

14 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 Preoperative THP best reserved for patients at high risk of recurrence who need downstaging (e.g. stage IIB and III disease)

15 HER2+ ER+ or ER- Node Negative < 3 cm Accrual N=406 Less than 20% had T1a 50% had T1c or T2 APT Trial Study Design Enroll P T P T P T P T P T P T PACLITAXEL 80 mg/m 2 + TRASTUZUMAB 2 mg/kg x 12 T T T T T T T T T T T T T FOLLOWED BY 13 EVERY 3 WEEK DOSES P T P T P T 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 P T P T P T Tolaney et al, NEJM 2015

16 All patients APT Disease-Free Survival Disease-Free Survival (Probability) year DFS Time (Months) 95% Conf. Interval 98.7% 97.6% to 99.8% Poisson p-value: < events; only 2 distant and 4 local-regional recurrences Number at risk Tolaney et al, NEJM 2015

17 Cardiac Safety of Trastuzumab without Anthracycline: APT Trial Majority had stable LVEF during treatment 3.2%: asymptomatic drop in LVEF requiring trastuzumab hold 0.5%: grade 3 LV dysfunction, all had risk factors for cardiac dysfunction Dang et al, JAMA Oncol 2016

18 Stage I HER2+* ER+ or ER- PS 0-1 Adequate organ fx N=500 ATEMPT Trial Schema R Trastuzumab-DM1 q3weeks X17 *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. 3 1 N=375 Paclitaxel + Trastuzumab x12 Trastuzumab q3weeks x13 N=125 PI: Sara Tolaney, MD, MPH

19 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 Swain SM et al. N Engl J Med 2010;362: POSSIBLE REGIMENS AC-paclitaxel (dose dense) AC-weekly paclitaxel AC-docetaxel (every 3 weeks) FEC-docetaxel

20 2016 Is Anthracycline Necessary for TNBC? ABC Trials (TC/TAC, B-46I, B-49) Node+ or High Risk Node-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 Arm 1 Options Per Study USOR A only NSABP B-46I/USOR A only C AC q 2 wk PTX q 1 wk NSABP B-49 - investigator choice 1A-1D Endocrine therapy for ER+ or PgR+ patients for minimum of 5 years AC q 2 wk D PTX q 2 wk Designed to prove non-inferiority of non-anthracycline arm Blum et al, ASCO

21 Alive and Inv. Disease-free (%) ABC Trials: Invasive Disease Free Survival yr Treatment N Events IDFS TC % TaxAC % HR=1.23, 95% CI ( ) P= Years from Randomization Δ=2.5% Observed HR on initial 334 events Exceeded pre-specified threshold for futility (> 1.18) > not non-inferior Blum et al, ASCO 2016

22 2016 ABC Trials: IDFS by Hormone and Nodal Status Exploratory Analysis Pts Events 4 yr IDFS 4 yr IDFS HR (95% CI) TaxAC TC TaxAC TC TaxAC TC Delta 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+ Blum et al, ASCO

23 Eligibility: HER2- with residual disease after A- and T- containing NAC DFS Adjuvant Capecitabine? OS Dose: 2,500 mg/m2/day, D1-14, x 8 cycles (24 wks) Toi et al, SABCS 2015

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

25 Sikov et al. SABCS 2015; von Minckwitz et al. SABCS 2015 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

26 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?

27 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

28 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 N = 170; approximately 60 enrolled Multicenter study AC x 4 Cis x 4 Designed to show 20% improvement in pcr with cisplatin over AC Principal Investigators: Nadine Tung and Judy Garber S U R G E R Y Or Biopsy B Additional Chemo

29 Do We Have Sufficient Data To Incorporate Platinum in Early Treatment of BRCA Associated TNBC? May never have large, definitive trial Mounting evidence in neoadjuvant and metastatic settings Biology is consistent with clinical observations Probably ready or close to it ideally would like to see results of neoadjuvant INFORM trial How do we do it? Add to standard? Substitute for one or more agents?

30 Ovarian Suppression through chemotherapy: POEMS/S0230 Standard cyclophosphamide containing (neo)adjuvant chemotherapy Premenopausal Stage I, II, IIIA ER-/PR- Breast Cancer Under Age 50 Stratified by age and chemotherapy regimen Randomization Standard cyclophosphamide containing (neo)adjuvant chemotherapy + goserelin Moore et al, ASCO 2014, NEJM 2015

31 POEMS/S0203 Moore et al, ASCO 2014, NEJM 2015

32 POEMS Ovarian Failure Standard Chemotherapy Chemotherapy + Goserelin Ovarian failure at 2 years 15/69 = 22% 5/66 = 8% Logistic Regression Results: Analysis Odds Ratio 95% CI p-value One-sided Two-sided Univariate p=.01 p=.03 Stratified* p=.02 p=.04 Multivariate * p=.04 p=.08 *Accounting for age and regimen through stratification ( Stratified ) or covariate ( Multivariate ) adjustment, respectively Courtesy of H. Moore

33 POEMS Pregnancy Standard Chemotherapy n=113 Chemotherapy + Goserelin n=105 Adjusted OR Adjusted P-value Attempted pregnancy 18 (16%) 25 (24%) p=.12 Achieved pregnancy 12 (11%) 22 (21%) 2.45 p=.03 Patients with > 1 delivery Delivery or ongoing pregnancy Total number of babies Ongoing pregnancies Total adverse events Miscarriages Elective termination Delivery complication 8 (7%) 10 (9%) (15%) 19 (18%) p=.05 p=.04 Courtesy of H. Moore

34 Ovarian Suppression Through Treatment: RCTs Investigator Bawady Sverrisdottir Del M astro Leonard Gerber Munster Elgindy SWOG 0230 Year , update NEJM Patients (n) Study type Phase II RCT Substudy from combined analysis of 4 RCTs using core protocol Phase III RCT Phase III RCT (abstract only) Phase II RCT Phase III RCT Phase II RCT Phase III RCT Treatment CT + goserelin vs TAM^ +/-CT CT + triptorelin vs. CT + goserelin vs. CT + goserelin vs. CT + triptorelin vs. Delayed CT : CT + goserelin vs. arms CT Goserelin +/-CT CT CT CT CT CT + triptorelin vs. CT Goserelin/TAM +/-CT TAM +/-CT CT Early CT : CT + triptorelin + cetrorelix β vs. CT Median age [range] 30 [26-33] 45 [29-55] 39 [24-45] NR 37 [26-47] 39 [21-43] 33 [18-40] 38 [25-49] Premenopausal Regular LMP <6 months Actively Regular menses in Regular Regular Regular menstruation LMP < 6 weeks definition menstruation prior to study menstruation during 12 months menstruation menstruation ( 3 ( 3 consecutive pre-randomisation FSH <10 IU/L entry, including 6 weeks pre-ct preceding surgery FSH <15 in periods in 6 months, periods within or FSH & E2 in irregular cycles follicular phase lasting 2 days, days apart days) premenopausal range FSH <40 IU/L %ER+ NR 45% 81% NR 0% 73% 0% 0% Marker of fertility preservation Resumption of menstruation or spontaneous ovulation Resumption of menstruation Resumption of menstruation Resumption of menstruation Resumption of menstruation Resumption of menstruation Resumption of menstruation Resumption of menstruation, postmenopausal FSH, pregnancy Primary Rate of POF (no Recovery of Rate of CIA (no Rate of Rate of normal Uninterrupted or Rate of regular Rate of ovarian endpoint menstruation/ menstruation menstruation and amenorrhea 12 ovarian function at restored menstruation at 12 failure spontaneous post-menopausal months after start 6 months post-ct menstruation during months after (amenorrhea) at 2 ovulation) 3 months post-ct FSH/E2 levels) for 12 months post-ct of CT f/u of at least 2 years post CT completion of CT years, FSH Median f/u [range] NR [3-8 months] NR 12 months post-ct NR 6, 12, 24, 48 months post-ct 18 months [5-43 months] after CT NR All patients followed for at least 12 months Planned f/u at 1,2 and 5 years Rate of 90% (goserelin) At 6 months post 91.1% (triptorelin) NR 70% (goserelin) 88.5% (triptorelin) At 12 months post-ct 8% (goserelin) vs. recovery of vs. 33% ET cessation : vs. 74.1% (control) No statistically vs. 56.7% vs. 90.5% (control) Delayed CT: 22% (control) menstruation: (control), p< % (goserelin) vs. 10% (control), p<0.001 significant difference between (control) Trial stopped early for futility 72% (triptorelin) vs. 52% (control), p=0.15 Trial stopped prior 13% (TAM), 7% goserelin + TAM), treatment arms (further details not Early CT: 60% (triptorelin + to full accrual due to funding issues p= published) cetrorelix) vs 48% (control), p=0.39 Pregnancies No data on No data on 3 pregnancies in No data on 1 pregnancy in 2 pregnancies in 3 pregnancies, one in 21% vs. 11% pregnancies pregnancies triptorelin arm, 1 in pregnancies control arm each group control arm early CT + triptorelin + cetrorelix arm, 1 in early CT control arm pregnancy favouring goserelin Adapted from N. Turner et al., Ann Oncol 2013

35 Ovarian Suppression Through Treatment: 9 RCTs Investigator Bawady Sverrisdottir Del M astro Leonard Gerber Munster Elgindy SWOG 0230 Year , update NEJM Patients (n) Study type Phase II RCT Substudy from combined analysis of 4 RCTs using core protocol Phase III RCT Phase III RCT (abstract only) Phase II RCT Phase III RCT Phase II RCT Phase III RCT Treatment CT + goserelin vs TAM^ +/-CT CT + triptorelin vs. CT + goserelin vs. CT + goserelin vs. CT + triptorelin vs. Delayed CT : CT + goserelin vs. arms CT Goserelin +/-CT CT CT CT CT CT + triptorelin vs. CT Goserelin/TAM +/-CT TAM +/-CT CT Early CT : CT + triptorelin + cetrorelix β vs. CT Median age [range] 30 [26-33] 45 [29-55] 39 [24-45] NR 37 [26-47] 39 [21-43] 33 [18-40] 38 [25-49] Premenopausal Regular LMP <6 months Actively Regular menses in Regular Regular Regular menstruation LMP < 6 weeks definition 12 months menstruation menstruation ( 3 ( 3 consecutive pre-randomisation FSH Meta-analysis <10 IU/L entry, including 6 weeks ongoing pre-ct preceding surgery FSH <15 in periods in 6 months, periods within or FSH & E2 in irregular cycles follicular phase lasting 2 days, days apart FSH <40 IU/L days) premenopausal range %ER+ NR 45% 81% NR 0% 73% 0% 0% Marker of Resumption No of hint Resumption of of a Resumption safety of problem Resumption of Resumption of Resumption of Resumption of Resumption of fertility preservation menstruation or spontaneous ovulation menstruation menstruation menstruation menstruation menstruation menstruation menstruation, postmenopausal FSH, pregnancy Primary Rate of POF (no Recovery of Rate of CIA (no Rate of Rate of normal Uninterrupted or Rate of regular Rate of ovarian endpoint failure spontaneous Reasonable post-menopausal to consider months after start as 6 months an post-ct additional menstruation during months option after for (amenorrhea) at 2 ovulation) 3 FSH/E2 levels) for of CT f/u of at least 2 completion of CT years, FSH months preservation post-ct 12 months of post-ct menstrual functioning years post CT and fertility Median f/u NR [3-8 months] NR 12 months post-ct NR 6, 12, 24, months [5-43 NR Planned f/u at 1,2 [range] months post-ct months] after CT All patients followed for at least 12 months and 5 years Rate of 90% (goserelin) At 6 months post 91.1% (triptorelin) NR 70% (goserelin) 88.5% (triptorelin) At 12 months post-ct 8% (goserelin) vs. recovery of vs. 33% ET cessation : vs. 74.1% (control) No statistically vs. 56.7% vs. 90.5% (control) Delayed CT: 22% (control) menstruation: (control), p< % (goserelin) vs. 10% (control), p<0.001 significant difference between (control) Trial stopped early for futility 72% (triptorelin) vs. 52% (control), p=0.15 Trial stopped prior 13% (TAM), 7% goserelin + TAM), treatment arms (further details not Early CT: 60% (triptorelin + to full accrual due to funding issues p= published) cetrorelix) vs 48% (control), p=0.39 Pregnancies No data on No data on 3 pregnancies in No data on 1 pregnancy in 2 pregnancies in 3 pregnancies, one in 21% vs. 11% pregnancies pregnancies triptorelin arm, 1 in pregnancies control arm each group control arm early CT + triptorelin + cetrorelix arm, 1 in early CT control arm pregnancy favouring goserelin Adapted from N. Turner et al., Ann Oncol 2013

36 THANK YOU!