Ruth M. O Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University, Chief of

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1 Endocrine Therapy of Advanced Breast Cancer School of Breast Oncology November 9 th 2013 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 General principles Endocrine agents Fulvestrant dosing Outline Combinational targeting of ER Endocrine-resistance HER2-positive Role of ER signaling in HER2-positive breast cancers

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

4 Change in receptor status impacts outcome in the metastatic setting 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

5 Survival (%) Principle 2: Patients achieving stable disease do just as well as patients whose tumors respond 100 Clinical Benefit = CR + PR + Stable 24 wks 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:

6 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 Endocrine therapy

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

8 Use of 21-gene recurrence score in MBC Objective To determine whether the 21-gene Recurrence Score provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in TBCRC 013. Eligibility Metastatic breast cancer with intact primary* Tissue from primary tumor and metastatic lesion 110 pts (86%) with pre-treatment primary tumor samples suitable for 21-gene Recurrence Score analysis Included patients with ER-negative and HER2-positive disease * small number developed mets within 3-months of diagnosis King et al Proc ASCO 2013

9 % progression free Time to 1 st Progression by Risk Group RS<18 RS RS 31 months Median TTP, mos RS<18 RS18-30 RS 31 Log rank, p All pts (n=102) 32 (16-NR) 20 (15-NR) 15 (9-21) ER+ (n=86) 32 (16-NR) 20 (15-NR) 15 (9-25) ER+HER2- (n=70) 32 (16-NR) 20 (15-NR) 15 (9-26) 0.013

10 % alive with disease 2yr Overall Survival by Risk Group RS<18 RS RS 31 2 yr OS, % RS<18 RS18-30 RS 31 Log rank, p All pts (n=102) 100 (78-100) 100 (78-100) 80 (69-93) ER+ (n=86) 100 (78-100) 100 (78-100) 77 (64-94) ER+HER2- (n=70) 100 (78-100) 100 (75-100) 69 (51-93) 0.001

11 % progression free ER+ pts treated with 1st line endocrine tx high RS shorter TTP ER positive (IHC) ER pos Her 2 neg RS<18 RS RS 31 Median TTP, mos RS<18 RS18-30 RS 31 Log rank, p ER+ (n=50) NR (18-NR) 22 (13-NR) 15 (8-NR) ER+HER2- (n=49) NR (18-NR) 22 (13-NR) 15 (8-NR) 0.016

12 % progression free ER+ pts treated with 1st line chemotherapy No difference in TTP by RS ER positive ER pos Her 2 neg RS<18 RS RS 31 Median TTP, mos RS<18 RS18-30 RS 31 Log rank, p ER+ (n=36) 10.5 (4-NR) 20 (12-NR) 16 (9-NR) 0.54 ER+HER2- (n=21) 10.5 (4-NR) 18 (12-NR) 13 (9-NR) 0.56

13 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

14 Quick summary of older trials Tamoxifen effective regardless of menopausal status and only agent approved for premenopausal patients (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 sequentially

15 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 suboptimal in earlier trials Howell et al JCO 2004, Gradishar JCO 2008

16 EFECT: Time to progression (ITT) 1.0 Fulvestrant Exemestane Proportion of patients progressionfree Median (months) 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 *500mg D1 250mg D14, q28d

17 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 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. JCO2010

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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 Outcome Median, months Fulvestrant (n = 102) Anastrozole (n = 103) Hazard ratio (95% CI) P value TTP ( ).01 TTF ( ).05 TTP (adjusted for predefined covariates) ( ).01 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 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

22 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):

23 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 may not matter AI or Fulvestrant* probably good choices as 1 st line therapy * Fulvestrant not approved in 1 st line setting

24 Mechanisms of hormone resistance VEGFR P P P P IGF1R 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

25 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

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

27 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

28 Johnston et al., JCO 2009 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

29 Randomized Phase II TAMRAD Study Design 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.

30 Probability of survival TAMRAD: Time to Progression TAM 4.5 mo. TAM + RAD 8.6 mo. Hazard Ratio (HR) = 0.53 (95% CI: ) Exploratory log-rank: P = Months Primary endpoint: Clinical benefit rate improved from 42% with TAM to 61% with TAM + RAD (p=.045 exploratory analysis) Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

31 Effects of mtorc1 Activation Treilleux I. ASCO Abstract 510.

32 Treilleux I. ASCO Abstract 510. Markers of Treatment Response Everolimus Response in ER+ MBC TAM, tamoxifen; RAD, RAD-001 (everolimus)

33 Treilleux I. ASCO Abstract 510. Markers of Treatment Response Everolimus Response in ER+ MBC TAM, tamoxifen; RAD, RAD-001 (everolimus).

34 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 34 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.

35 Probability of Event (%) BOLERO-2: Addition of everolimus to exemestane improves PFS in HR+ MBC HR = 0.36 (95% CI: ) Log rank P value = 3.3 x EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 20 0 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) Time (weeks) Baselga et al ESMO 2011 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA.

36 Markers of Treatment Response Everolimus Response in BOLERO-2 EVE, everolimus; PBO, placebo. Hortobagyi G. ASCO Abstract 509.

37 Phase 2 Trial of CDK 4/6 inhibitor PD in first-line metastatic HR-positive breast cancer Part 1 Part 2 ER-positive Her2- negative MBC PD Letrozole N=66 Letrozole ER-positive Her2- negative MBC with CCDN1 amp and/or loss of p16 N=99 PD Letrozole Letrozole Primary Endpoint: PFS Stratification Disease site (visceral vs bone-only vs other) Disease-free interval (> 12 mths vs 12 mths from adjuvant to recurrence or de novo advanced disease Finn et al SABCS 2012

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39 Most Common AEs Adverse Event (n) PD Letrozole (n=83) Letrozole (n=77) Grade 1/ /2 3 4 Neutropenia Fatigue Anemia Nausea Hot flashes Alopecia Arthralgias Thrombocytopenia Stomatitis Finn et al SABCS 2012

40 Phase 3 trial of PD (Palbociclib) Finn RS. ASCO Abstract 652. Primary endpoint: PFS

41 Summary other targeted agents in HRpositive MBC Bevazicumab does not significantly improve TTP when added to letrozole in first-line setting (LEA trial) Inhibition of IGF1R does not enhance activity of aromatase inhibition Addition of HDAC inhibitor, Entinostat, to endocrine therapy improved overall survival (confirmatory ECOG trial planned) Martin et al SABCS 2012, Robertson et al Lancet Onc 2013, Yardley et al J Clin Oncol 2013

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

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

44 PCR is prognostic in ER- cancer but not ER+ cancers that co-express HER2 ER-negative, HER2-positive ER-positive, HER2-positive von Mitchwitz et al SABCS 2011

45 Why is this important? We may (and probably are) overtreating 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) Can we identify this subgroup?

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

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

48 C40601: HER2+ Subtypes by Hormone Receptor (HR) HR-negative HR-positive Carey et al Proc ASCO 2013

49 HER2 signaling decreases ER activation and inhibition of HER2 increases ER-regulated gene transcription TRAST HER2 HER1/2/3 HER2 HER1/2/3 Membrane x TKI Membrane PI3-K Ras PI3-K Ras AKT MEK AKT MEK FOXO3a Erk1/2 Cytoplasm Erk1/2 Cytoplasm Nucleus FOXO3a ER ER x ER-regulated gene transcription Nucleus FOXO3a ER ER ER-regulated gene transcription ERE ERE Xia PNAS 2006, Valabrega Oncogene 2005

50 Clinical relevance of this cross-talk Inhibition of HER2 without inhibition of ER may increase ER signaling allowing ER to act as an escape mechanism This could contribute to the lower PCR seen in ER+ HER2+ breast cancers and have potential implications in the metastatic setting There may be a subset of ER+ HER2+ breast cancers where ER inhibition is critical (more important than chemotherapy)

51 Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks) pcr (%) 60 pcr 40% % % All ER+ ER - pcr + npcr 5 3 % 5 6 % 4 8 % All ER+ ER- npcr = < 1cm residual cancer in the breast Rinawi CCR 2013

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