Endocrine Therapy of Advanced Breast Cancer School of Breast Oncology November 2012

Transcription

1 Endocrine Therapy of Advanced Breast Cancer School of Breast Oncology November 2012 Ruth M. O Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University, Chief of Hematology and Medical Oncology, Georgia Cancer Center for Excellence, Grady Memorial Hospital

2 Outline General principles Endocrine agents Fulvestrant dosing Combinational targeting of ER Endocrine-resistance HER2-positive Role of ER signaling in HER2-positive breast cancers

3 The Lancet July 11, 1895 ON THE TREATMENT OF INOPERABLE CASES OF CARCINOMA OF THE MAMMA: SUGGESTIONS FOR A NEW METHOD OF TREATMENT, WITH ILLUSTRA- TIVE CASES. 1 BY GEORGE THOMAS BEATSON, M.D. EDIN., SURGEON TO THE GLASGOW CANCER HOSPITAL; ASSISTANT SURGEON, GLASGOW WESTERN INFIRMARY: AND EXAMINER IN SURGERY TO THE UNIVERSITY OF EDINBURG Apsley-place, May 6th, 1895 Dear Dr. Beatson,-The bearer is, and has been, suffering, I fear, from a malignant breast. She has been in the Royal Infirmary before she came to me. My own opinion is that nothing can be done for her, but as she is a woman of great courage you might have a look at it for my sake, and perhaps you can order her something in the way of dressing. Even this little will be accepted by her as a great deal. With kindest regards, yours very truly, James W. Wallace.

4 Major Goals of Endocrine Therapy in Metastatic Disease Palliative treatment Improve progression free and overall survival Increase time to chemotherapy Improve quality of life

5 Principle 1: Likelihood of benefit from endocrine therapy can be predicted by Disease Free Interval DFI Age Menopausal Status # Organ Sites ECOG PS Well differentiated Low S phase, diploid Primary/Previous Rx Median Survival

6 and by ER/PR status 80 Percent Response to Endocrine Therapy ER-/PgR- ER+/PgR- ER-/PgR+ ER+/PgR+ Receptor Status

7 ER-positive cancers are heterogeneous at diagnosis (and at recurrence too) ER+ ER+ Copyright 2003 by the National Academy of Sciences Sorlie et al PNAS 2003

8 and luminal A cancers may not be luminal A at recurrence Receptor discordance in primary and metastatic breast cancers relatively common resulting in treatment changes in up to 15% of patients Changes in receptors impact prognosis Most common change is in hormone receptors especially PgR going from positive to negative (represents a change from luminal A to luminal B?) Changes in HER2 less common Recurrent cancer should be biopsied at least once Amir et al, Locatelli et al, Karlsson et al PASCO 2010

9 Principle 2: Patients achieving stable disease do just as well as patients that respond 100 Clinical Benefit = CR + PR + Stable 24 wks Survival (%) At 2-Year Risk Deaths Estimate CR or PR % Stable 24 wk % Other % Years From Randomization Robertson JF, et al. Breast Cancer Res Treat. 1999;58:

10 Principle 3: If it works the first-time. 40% 30% 25% 15% 1 st Line 2 nd Line 3 rd Line 4 th Line R E S I S T A N C E

11 Bottom-line Endocrine therapy works and should be given to all patients with hormone-responsive MBC Chemotherapy only indicated for: life-threatening visceral mets or when endocrine therapy options fail and/or exhausted

12 Endocrine Agents for Breast Cancer SERMs Tamoxifen Toremifene Raloxifene Estrogens Estradiol DES, EE 2 ER-Down Regulator Fulvestrant Aromatase Inhibitors Anastrozole Letrozole Exemestane Progestins Megestrol Acetate MPA Androgens Fluoxymesterone

13 Quick summary of older trials Tamoxifen effective regardless of menopausal status and only agent approved for premenopausal patient (combination ovarian ablation + tamoxifen > tamoxifen alone) All aromatase inhibitors > tamoxifen in first-line setting (9 to 11 months PFS AI vs 6 months TAM) Non-steroidal AIs are cross-resistant Steroidal and non-steroidal are not crossresistant and can be used sequential

14 Fulvestrant Equivalent to anastrozole in patients with metastatic breast cancer previously treated with tamoxifen (FDA approved for antiestrogen treated MBC) Equivalent to tamoxifen in first-line treatment of ER-positive MBC Equivalent to exemestane in patients with MBC previously treated with non-steroidal AIs Dose and schedule may have been sub-optimal in earlier trials Howell et al JCO 2004, Gradishar JCO 2008

15 Evaluation of Fulvestrant and Exemestane Clinical Trial EFECT Postmenopausal ER+ and/or /PgR+ in ABC EXEM 25mg PO Fulvestrant 500mg IM D1, 250mg D14, 250mg D28 And q 4 weeks Endpoint: TTP Endpoint: TTP Patients had received previous treatment with a non-steroidal AI

16 Proportion of patients progressionfree Time to progression (ITT) Median (months) Fulvestrant 3.7 Exemestane 3.7 HR = 0.963, 95% CI (0.819, 1.133), p= Cox analysis, p= Fulvestrant Exemestane At risk: Fulvestrant Exemestane 0.0 Gradishar et al JCO Months

17 CONFIRM Phase III Trial: Fulvestrant at 250 mg vs. 500 mg in ER-Positive Advanced Breast Cancer Eligibility criteria: ER + advanced disease Postmenopausal Primary endpoints: TTP R A N D O M I Z E Fulvestrant 250 mg, days 1, 14, 28, then q 28 days Placebo, days 1, 14, 28, then q 28 days (n = 374) Fulvestrant 500 mg days 1, 14, 28, then q 28 days (n = 362) Secondary endpoints: OS, ORR, CBR, duration of response, safety, QOL 57.5% of patients had received prior antiestrogens, and 42.5% had received prior AIs Approximately one third had demonstrated no response to prior hormonotherapy Di Leo et al. JCO 2010.

18 CONFIRM Phase III Trial of Fulvestrant in ER- Positive Advanced Breast Cancer: Efficacy Fulvestrant 500 mg (n = 362) Fulvestrant 250 mg (n = 374) HR/OR (95% CI) P Value Median TTP 6.5 months 5.5 months 0.80 ( ).006 ORR 9% 10% 0.94 ( ) NR CBR 46% 40% 1.28 ( ) NR Median Duration of Benefit 16.6 months 13.9 months NR NR Median OS 25.1 months 22.8 months 0.84 ( ).091 Di Leo et al. JCO2010

19 FIRST Study Design Randomization (1:1), open-label firstline ER+ postmenopausal patients with advanced breast cancer (target, n = 200; actual, n = 205) Fulvestrant 500 mg (500 mg IM on Days 0, 14, and 28, and every 28 days thereafter) Progression Anastrozole 1 mg (1 mg PO daily) Progression Endpoints at primary DCO Primary endpoint Clinical benefit rate Secondary endpoints Objective response rate Time to progression Duration of response Duration of clinical benefit Safety Exploratory endpoints Best response to subsequent therapy Follow-up Follow-up DCO = data cut-off Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3., JCO 2009

20 FIRST: Efficacy Outcomes at Follow-Up Analysis Median, months Outcome Fulvestrant (n = 102) Anastrozole (n = 103) Hazard ratio (95% CI) P value TTP ( ).01 TTF ( ).05 TTP (adjusted for predefined covariates) ( ).01 Median follow-up for TTP for fulvestrant was 18.8 months and for anastrozole was 12.9 months CI = confidence interval; TTF = time to treatment failure; TTP = time to progression Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3.

21 FIRST: TTP at Follow-Up Analysis Proportion of patients alive and progression-free Number of patients at risk: Fulvestrant 500 mg 102 Anastrozole 1 mg 103 Fulvestrant 500 mg Anastrozole 1 mg 0.2 HR = 0.66 (95% CI: ) 0.0 P = Time (months) CI = confidence interval; HR = hazard ratio; TTP = time to progression Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3.

22 SWOG S0226 Phase III Trial of Anastrozole + Fulvestrant 250 vs Anastrozole Alone N = 707 Post menopausal women with HR+ advanced breast cancer, untreated with HR for advanced disease FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO qday* ANASTROZOLE 1 mg PO qday* Primary PFS Secondary OS *Crossover to fulvestrant 500 mg allowed after progression FUL + ANA n = 355 ANA n = 352 HR P value Mehta et al NEJM PFS (mo) OS (mo) median

23 FACT: Phase III Study of Anastrozole + Fulvestrant 250 vs Anastrozole Alone N = 514 Pre/Post menopausal women with HR+ advanced breast cancer, untreated with HR for advanced disease FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO qday ANASTROZOLE 1 mg PO qday Primary TTP Secondary TTF, ORR, CBR, Safety, OS FUL + ANA n = 256 ANA n = 254 HR P value TTP (mo) OS (mo) median Bergh et al. J Clin Oncol. 2012;30(16):

24 Sequencing: which order is best? All we know from a series of phase 2 trials is that agents with different mechanisms of action can be sequencing successfully The exception is using non-steroidal aromatase inhibitors sequencing letrozole and anastrozole does not work Unclear which order is best EFECT trial suggests it does not matter AI or Fulvestrant probably good choices as 1 st line therapy

25 Mechanisms of hormone resistance VEGFR P P IGF1R P P PI3-K EGFR/HER2 P P SOS RAS RAF Increased upstream signaling through EGFR and/or IGF-IR and or VEGFR Akt MEK AI SERD T E2 ER p90 RSK MAPK Increased signaling through PI3-K pathway Cytoplasm P P P P ER ER p160 CBP Basal Transcription Machinery ERE ER Target Gene Transcription Plasma Membrane Nucleus Absence or undetectable target From Johnston CCR 2005

26 HER2-positive breast cancers are intrinsically resistant to endocrine therapy Transfection of ER-positive breast cancer cells with HER2 renders them resistant to tamoxifen Retrospective analyses of trials in the ERpositive metastatic setting show a worse outcome for cancers that co-express HER2, compared to those that do not Median progression free survival is less than 6 months for ER+ HER2+ MBC treated with aromatase inhibitors Benz BRCT BRCT 1992, De Laurentiis J Clin Oncol 2005, Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009

27 Outcome for patients with ER+ metastatic breast cancer based on HER2 status Progression free survival(months) HER2- LET LET ANAST LET HER2+/- ANAST Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009, Bonneterre Cancer 2001, Moridisen J Clin Oncol 2003, Nahta BRCT 2012

28 Progression-free survival in patients with HRpositive, HER2-positive MBC Probability Events Median PFS 4.8 months 2.4 months 95% CI 3.7, , 4.6 p value No. at risk A + H A Months CI, confidence interval PFS = time from randomisation to date of progressive disease or death Kaufman et al JCO 2009

29 Letrozole ± Lapatinib in HR-positive MBC ITT HER2+ HER2- let let + lap let let + lap let let + lap (n=644) (n=642) (n=108) (n=111) (n=474) (n=478) PFS (months) ORR CBR OS (months) HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P = % 30% 15% 28% 32% 33% P =.262 P =.021 P = % 56% 29% 48% 56% 58% P =.096 P =.003 P =.761 NR NR NR NR NR HR 0.74; P =.113 NR Johnston et al., JCO 2009;27:

30 TAMRAD Study Design Randomized Phase II HR-positive MBC with prior exposure to aromatase inhibitors (AI) R A: Tamoxifen 20 mg/day (TAM) B: Tamoxifen 20 mg/day + RAD mg/day (TAM + RAD) Stratification: Primary or secondary hormone resistance Primary: Relapse during adjuvant AI; progression within 6 months of starting AI treatment in metastatic setting Secondary: Late relapse ( 6 months) or prior response and subsequent progression to metastatic AI treatment No crossover planned Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

31 Primary Endpoint: Clinical Benefit Rate CBR, % P =.045 (exploratory 61.1 analysis) 42.1 ( ) ( ) TAM TAM + RAD Median (range) follow-up: TAM: 22.6 ( ) months; TAM + RAD: 22.3 ( ) months CBR = clinical benefit rate; RAD = RAD001; TAM = tamoxifen Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

32 Probability of survival Patients at risk: TAM + RAD: n = TAM: n = Time to Progression TAM TAM + RAD 4.5 mo. 8.6 mo. Hazard Ratio (HR) = 0.53 (95% CI: ) Exploratory log-rank: P = Months CI = confidence interval; HR = hazard ratio; RAD = RAD001; TAM = tamoxifen Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

33 Probability of survival Patients at risk: TAM + RAD: n = TAM: n = Overall Survival (as of October 2010) TAM TAM + RAD Hazard Ratio (HR) = 0.32 (95% CI: ) Exploratory log-rank: P = Months CI = confidence interval; HR = hazard ratio; RAD = RAD001; TAM = tamoxifen Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

34 Time to Progression as Function of Intrinsic Hormone Primary hormone resistance (n = 54) TAM: 3.9 months TAM + RAD: 5.4 months HR = 0.74 ( ) Secondary hormone resistance (n = 56) TAM: 5.0 months TAM + RAD: 17.4 months HR = 0.38 ( ) HR = hazard ratio; RAD = RAD001; TAM = tamoxifen Resistance Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6. Probability of survival Probability of survival TAM TAM + RAD Months Months

35 BOLERO-2: Trial Design N = 724 Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole 2 1 Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) PFS OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over 35 ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 negative; PFS: progression-free survival; PK: pharmacokinetics Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

36 BOLERO-2: Addition of everolimus to exemestane improves PFS in HR+ MBC Probability of Event (%) Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) HR = 0.36 (95% CI: ) Log rank P value = 3.3 x EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months Time (weeks) Baselga et al ESMO 2011 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

37 ENCORE 301 Study Design Hypothesis: Entinostat re-sensitizes tumors to aromatase inhibitors (AI) Post-menopausal women with metastatic or locally advanced ER+ breast cancer progressing on a non-steroidal AI (anastrozole or letrozole) R A N D O M I Z E Exemestane + Entinostat (ENT) 5 mg po weekly N ~ 57 Exemestane + Placebo (PLA) 5 mg po weekly N ~ 57 Stratification Factors: AI disease progression (Adjuvant vs MBC setting) Bone only disease (yes / no) Geographic region (North America vs EU/Russia) Randomized, double-blind, placebo-controlled Endpoints include: 1⁰ PFS, 2⁰ ORR and CBR; Exploratory Endpoint - OS

38 ENCORE 301 Primary Endpoint PFS (ITT) 2 Endpoints EP EE ORR 4.6% 4.7% CBR 25.8% 26.6% Yardley et al ASCO Breast 2011

39 ENCORE 301 Survival Data Intent-to-treat population Yardley et al ASCO Breast 2011

40 A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients with Hormone Receptor-Positive Metastatic Breast Cancer Proposed Schema Eligible: Advanced breast cancer ER/PR+, HER2- N 600 Progression/no progression on prior non-steroidal AI R A N D O M I Z E Exemestane plus Entinostat Exemestane plus Placebo FES-PET and FDG-PET: baseline Blood sampling: baseline, 2 wks Treatment until Progression/Intolerance: Exemestane 25mg daily po AND Entinostat/Placebo 5mg po weekly.

41 HER2 trumps ER when both receptors are expressed.. But is this true for all ER+ HER+ breast cancers?

42 Pathologic complete response is consistently lower in ER+ HER2+ breast cancers compared to ER- HER2+ breast cancers Percent PCR T L T/LT L T/LT L T/LT L T P T/PT/P T/L P P -> FECFEC -> EC P -> D Reviewed in Nahta and O Regan BRCT 2012

43 DFS in HER2+ ER-negative breast cancers based on PCR von Mitchwitz et al SABCS 2011

44 DFS in ER+ breast cancers based on PCR ER-positive, HER2-negative ER-positive, HER2-positive von Mitchwitz et al SABCS 2011

45 Why is this important? We may (and probably are) over-treating a subgroup of ER+, HER2+ breast cancers in the adjuvant setting This subgroup of patients with ER+, HER2+ breast cancers may suffer late recurrences (similar to what we see with luminal A cancers)

46 Likelihood of PCR is inversely related to level of ER expression for HER2+ breast cancers HER2+/HR- Percent PCR HER2+/ER+ HER2+/ER+++ ER expression Bhargava Mod Path 2011, Nahta BRCT 2012

47 Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89) Knauer et al BJC 2010

48 Conclusions Although HER2 signaling is associated with intrinsic resistance to endocrine agents, a subset of HER2+, ER+ cancers appear to be driven, at least in part, by ER Identification of these cancers is crucial: They may require less aggressive treatment approaches with earlier institution of ER inhibition May behave like ER+ HER2- cancers with late relapses ER plays a role in resistance to HER2-directed agents

49 Possible schema for future clinical trials ER-positive, HER2-positive breast cancer Driven by ER (high ER and PgR) Driven by HER2 (Low ER and/or PgR) Endocrine therapy + HER2-directed agent Chemotherapy + HER2-directed agent ± endocrine therapy Nahta and O Regan BRCT 2012

50 We have made progress! Receptor negative Receptor positive Andre F, et al. J Clin Oncol 22: 3302, 2004