Endocrine Therapy for Advanced Breast Cancer (ABC) Dr Yoon-Sim YAP Division of Medical Oncology, National Cancer Centre Singapore

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1 Endocrine Therapy for Advanced Breast Cancer (ABC) Dr Yoon-Sim YAP Division of Medical Oncology, National Cancer Centre Singapore

2 Outline Guidelines and Evolving Clinical Treatment Landscape for HR+ HER2- advanced breast cancer (ABC) Optimising endocrine therapy backbone Improving outcomes further with targeted therapy Sequencing of Treatments First Line setting vs Second-line setting & beyond Predictive Biomarkers Other Novel Therapeutic Strategies Conclusions 2

3 Treatment guidelines for HR+, HER2 advanced breast cancer ESMO 1 ABC 2 ASCO 3 NCCN 4 In HR +, HER2 disease, endocrine therapy is the treatment of first choice independent of metastatic site, unless rapid response is needed. Limited visceral metastases are not a contraindication for endocrine therapy Endocrine therapy is the preferred option for HR + disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response Endocrine therapy should be recommended as initial treatment for patients with HR+ metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy. Endocrine therapy recommended unless there is visceral crisis, or progression with no clinical benefit after 3 sequential endocrine therapy regimens. 1. Cardoso F et al. Ann Oncol 2012;23(Suppl 7):vii11-vii19 2. Cardoso F et al. Ann Oncol 2014;25(10): ASCO Available at 4. NCCN V Available at 3

4 Chemotherapy versus Endocrine Therapy Chemotherapy has higher response rate. Wilcken et al, Cochrane System Database Review

5 Chemotherapy versus Endocrine Therapy No significant differences in overall survival. Wilcken et al, Cochrane System Database Review

6 What are the Endocrine Therapy Options? What is the evidence for doing what we do? (ie if people are practising evidence-based medicine) 6

7 Endocrine Therapy Combination Therapy Breakthroughs in hormone receptor positive (HR+) breast cancer FDA approvals of new treatments 1977 Tamoxifen 1996 Goserelin 1997 Letrozole 1999 Exemestane 2012 Everolimus + Exemestane 2002 Fulvestrant 2015 Palbociclib + Letrozole 2016 Palbociclib + Fulvestrant Megestrol Acetate 1995 Anastrozole 2017 Ribociclib (with AI) 2017 Abemaciclib (single agent or with fulvestrant)

8 ASCO Guidelines Postmenopausal Premenopausal Rugo et al, JCO

9 Courtesy of Ian Smith from ESMO 2014

10

11 Mechanism of Action of Tamoxifen and Aromatase Inhibitors Johnston, Nature Reviews Cancer 2003

12 First-line Comparative Tamoxifen Trials in Advanced Breast Cancer (2004) Tamoxifen versus N=17 Progestogens 6 Estrogens 1 Androgens 1 Anti-Estrogens 2 Aminogluthetimide 3 Formestane 1 Fadrozole 2 Fulvestrant 1 Tamoxifen always better or at least as good. Schiavon and Smith, Haematol Oncol Clin North AM

13 Rationale for OS + Tamoxifen in Premenopausal MBC Randomised study: n=161 (original target 348) Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated,respectively; P =.11 [x2 test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). 5-year survival were 34.2% (95% confidence interval [CI] = 20.4% 48.0%), 14.9% (95% CI =3.9% 25.9%), and 18.4% (95% CI = 7.0% 29.8%), respectively. Klijn et al, JNCI

14 Use of 2 nd line AIs v megesterol acetate AIs: RR, TTP and overall survival only slightly better than megestrol acetate Smith NEJM 2003

15 Progestins Mechanism of action unclear. May inhibit aromatase activity or increase estrogen turnover, since estrogen levels fall during therapy. May also act through the glucocorticoid receptor, androgen receptor, or progesterone receptor. Activity appears to be maintained in patients who are refractory to SAIs. Side-effects: weight gain, fluid retention, thromboembolic complications, PV bleeding. Willemse, EJC 1990; Abrams, JCO 1999

16 What is the optimal 1 st -line endocrine therapy? PFS / TTP of AIs as 1 st -line endocrine therapy trials in HR+ MBC Trial AI (response rate, %) Tamoxifen (response rate, %) AI (PFS, mths) Tamoxifen (PFS, mths) Hazard Ratio Nabholtz et al, 2000 (n=353) Anastrozole vs tamoxifen Bonneterre et al, 2001 (n=668) Anastrozole vs tamoxifen Mouridsen et al, 2001 (n=907) Letrozole vs tamoxifen Paridaens et al, 2008 (n=371) Exemestane vs tamoxifen Range Meta-analysis: compared to tamoxifen, there was a statistically significant survival benefit (11 percent relative hazard reduction, 95% CI 1 to 19 percent) for first-line third generation SAIs, but not for aminoglutethimide or second generation SAIs. Mauri et al, JNCI 2006 Johnston, SABCS

17 AI + Ovarian Suppression in Premenopausal Is it better than tamoxifen + ovarian suppression?? No randomised trials with tamoxifen and OS for comparison in metastatic setting. 17

18 What are the endocrine options after AI? How good is tamoxifen after an AI? TAMRAD (Tamoxifen vs Tamoxifen + Everolimus after AI) (Bachelot et al, JCO 2012) Tamoxifen arm (26% received 1 line of palliative chemo): 6mth clinical benefit rate 42%; TTP 4.5 mths; response rate 13% How good is exemestane (monotx) after an AI? EFECT (Chia, JCO 2008): median TTP 3.7mths; response rate 6.7% SOFEA (Johnston, Lancet Oncol 2013): median PFS 3.4mths; response rate 2.8% BOLERO-2 (Baselga, NEJM 2012): median PFS 2.8mths, response rate 0.4%. How good are progestins after an AI? No prospective data How good is fulvestrant after an AI? See following. 18

19 Mode of Action of Estradiol, Tamoxifen and Fulvestrant Estradiol E Tamoxifen T Fulvestrant + ER E AF1 + E + AF1 AF1 + ER F ER F F AF1 Receptor dimerisation No dimerisation T AF1 T AF1 AF2 AF2 ACTIVE AF1 ACTIVE AF2 INACTIVE AF1 + AF2 INACTIVE ACCELERATED RECEPTOR DEGRADATION FULLY ACTIVATED TRANSCRIPTION (tumour cell division) PARTIALLY INACTIVATED TRANSCRIPTION (reduced rate of tumour cell division) NO TRANSCRIPTION (no tumour cell division) Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7:

20 Fulvestrant: Preclinical Activity Osborne et al, JNCI 1995 Osborne et al, Cancer Chemo and Pharm

21 Clinical Trials on Fulvestrant (250mg LD) Pretreated Pretreated Howell, JCO 2002 Osborne, JCO 2002 Treatment-naive Only just as good as tamoxifen or anastrozole Howell, JCO

22 Clinical Trials on Fulvestrant (250mg LD) Chia, JCO Only just as good as exemestane even after relapse/progresson on non-steroidal AI Caveat: 250mg dose was suboptimal Johnston, Lancet Oncol 2013

23 CONFIRM phase III Trial: Fulvestrant 250mg vs 500mg Median OS 26.4mths vs 22.3mths Di Leo et al, JNCI 2014

24 Clinical Trials on Fulvestrant (500mg HD) Primary Endpoint: CBR fulvestrant HD vs anastrozole 72.5% v 67.0% (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P.386). Robertson et al, JCO 2009 Caveat: OS not preplanned analysis; not all patients participated in OS followup. 24 Ellis et al, JCO 2015

25 FALCON: Phase III 1 st line study of Fulvestrant 500 vs AI in Endocrine Therapy Naïve MBC / LABC N=450 ER +ve, HER2 negative Locally advanced (not suitable for surgery) or metastatic disease Up to 1 line of chemotherapy At least 1 lesion that can be assessed Fulvestrant 500mg i.m. Anastrozole 1mg OD Note no prior endocrine therapy allowed Primary endpoint: PFS Secondary endpoint: OS Other secondary endpoints include ORR, CBR, duration of response, duration of clinical benefit, time to deterioration of HRQoL, Safety Ellis et al, LBA14 ESMO 2016

26 Proportion of patients alive and progression free FALCON: Fulvestrant 500 vs anastrozole in 1 st -line endocrine therapy naïve ER+ MBC Proportion of patients alive and progression-free Proportion of patients alive and progression-free Number of patients at risk: Fulvestrant Anastrozole Primary endpoint: PFS HR (95% CI 0.637, 0.999) p= Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months Time (months) Fulvestrant (n=230) Anastrozole (n=232) HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months PFS without visceral disease Fulvestrant (n=95) Anastrozole (n=113) HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months Time (months) PFS with visceral disease Time (months) Fulvestrant (n=135) Anastrozole (n=119) Ellis et al, LBA14 ESMO 2016; Robertson et al, Lancet 2016

27 What is the optimal 1 st -line endocrine therapy? PFS / TTP of AIs as 1 st -line endocrine therapy trials in HR+ MBC Trial Nabholtz et al Anastrozole vs tamoxifen Bonneterre et al Anastrozole vs tamoxifen Mouridsen et al Letrozole vs tamoxifen Chernozemsky et al Exemestane vs tamoxifen Paridaens et al Exemestane vs tamoxifen Mehta et al Anastrozole vs anastrozole + fulvestrant 250mg Bergh et al Anastrozole vs anastrozole + fulvestrant 250mg Ellis et al Anastrozole vs Fulvestrant 500mg Date AI (months) Tamoxifen (months) AI + fulvestrant 250mg (months) Fulvestrant 500mg (months) Hazard Ratio Is Fulvestrant the gold standard for 1 st -line treatment now? PFS benefit modest PFS benefit restricted to patients without visceral mets Only applies to endocrine naïve patients? Activity of other endocrine therapies post-fulvestrant unclear Await overall survival data.. Other more effective alternative options available now Range

28 ESR1 Mutations 28 Toy et al, Nature Genetics 2013

29 New generation SERDs (Selective Estrogen Receptor Degraders - oral) Limitations of fulvestrant Poor bioavailability Requires oil-based IM formulation; limitations with increasing dose intensity Variable ER down-regulation Van Kruchten et al, 2015 SERD Company Current status GDC-0810 Genentech Phase I/II GDC-0927 Genentech Phase I RAD1901 Radius Phase I AZD9496 Astra Zeneca Phase I LSZ-102 Novartis Phase I SAR Sanofi Phase I H3b-6545 (SERCA) H3 BioMedicine Phase I FDA Breakthrough Drug Designation

30 Definitions of Endocrine Resistance in ER+ MBC PRIMARY ENDOCRINE RESISTANCE Relapse while on the first 2 years of adjuvant ET, or PD within first 6 months of 1 st line ET for MBC, while on ET SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE Relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of completing adjuvant ET, or PD 6 months after initiating ET for MBC, while on ET Courtesy of Johnston, SABCS 2016; Cardoso, Annals Onc 2014

31 What can we add to endocrine therapy to overcome endocrine resistance? First-line setting CDK4/6 Inhibitor (Trials using Temsirolimus, Bevacizumab, EGFR Inhibitors negative or mixed results.) Second-line and beyond CDK4/6 Inhibitor vs mtor Inhibitor? PI3K inhibitor 31

32 Cyclin Dependent Kinase(CDK) 4/6 Inhibitors Lange and Yee, Endocrine Related Cancer 2011 Ma, ASCO

33 CDK4/6 Inhibitors O Leary et al, Nat Rev Clin Onc 2016

34 PALOMA-2 & MONALEESA-2: Design of Phase III Studies PALOMA-2 MONALEESA-2 Postmenopausal ER+ HER2 advanced breast cancer with no prior treatment for advanced disease. AI-resistant patients excluded N=666 R A N D O M I S E (2:1) Palbociclib (125 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) Placebo + letrozole (2.5 mg QD) Postmenopausal women with HR+/HER2 advanced breast cancer with no prior therapy for advanced disease N=668 R A N D O M I S E (1:1) Ribociclib (600 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) Placebo + letrozole (2.5 mg QD) Stratified by the presence/absence of liver and/or lung metastases Primary endpoint: PFS Secondary endpoints: Response, OS, safety, biomarkers, PROs Primary endpoint: PFS Secondary endpoints: OS (key), ORR, CBR, safety Courtesy of Johnston, SABCS 2016

35 PALOMA-2 & MONALEESA-2: PFS PALOMA-2 MONALEESA-2 mpfs (months) Palbociclib letrozole: 24.8 Placebo letrozole: 14.5 mpfs mpfs (months) Ribociclib letrozole: ribociclib letrozole: NR NR Placebo letrozole: placebo letrozole: Finn R, et al. NEJM. 2016;375(20): Hortobagyi G, et al. NEJM. 2016;375(18):

36 Rate (%) Rate (%) PALOMA-2 & MONALEESA-2: Secondary endpoints PALOMA-2 Measurable disease MONALEESA-2 Measurable disease Palbociclib + letrozole Placebo + letrozole OR (95% CI): 2.23 ( ) p< Ribociclib + letrozole Placebo + letrozole p= OR (95% CI): 1.55 ( ) p= p= Objective response rate Clinical benefit rate 0 Objective response rate Clinical benefit rate Finn R, et al. NEJM. 2016;375(20): Finn R, et al. Abstract 507, ASCO 2016 Hortobagyi G, et al. NEJM. 2016;375(18): Hortobagyi G, et al. LBA01, ESMO 2016

37 PALOMA-2 & MONALEESA-2: Toxicity PALOMA-2 MONALEESA-2 Finn R, et al. NEJM. 2016;375(20): Hortobagyi G, et al. NEJM. 2016;375(18): Other potential AEs: Transaminitis, prolonged QT

38 MONARCH-1: Abemaciclib (Inhibitor of CDK4>CDK6) Phase 2 single-agent trial in metastatic HR+HER2- mbc. No. of prior systemic regimens (any setting); 5 (2-11). 1-2 chemotherapy regimens in metastatic setting. 38 Dickler et al, ASCO 2016; CCR 2017

39 MONARCH-3 Goetz et al, JCO

40 MONARCH-3 Goetz et al, JCO

41 CDK 4/6 inhibitors for ER+ MBC New Gold Standard in 1 st -line treatment Adjuvant trials have also commenced. Unanswered Questions Does every patient need CDK4/6 inhibitor upfront?

42 Potential Predictors of CDK4/6 Inhibitor Activity In sensitive cell lines: Cyclin D1 (CCND1) Retinoblastoma (Rb) p16 PALOMA-1 ER+HER2- Unselected ER+HER2- Plus Amplification of CCND1 and/or Loss of p16 Finn RS, et al. Br Ca Research 2009 Finn RS, et al. Lancet Oncol 2015

43 Predictive Biomarkers? PALOMA-2: No subgroup of ER+ patients was found that did not benefit from the addition of palbociclib to letrozole. 43 Finn RS, et al. ESMO Abstract LBA15 [oral].

44 Predictive Biomarkers? Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), HER2- negative (HER2 ) advanced breast cancer (ABC): efficacy by baseline tumor markers 44 Andre et al, AACR 2017

45 Subgroup Analyses MONALEESA-2 PALOMA-2 Hortobagyi et al, NEJM 2016 Finn et al, NEJM

46 MONARCH-3 Patients with bone-only disease Patients without bone-only disease Goetz et al, JCO

47 Not all patients reach the next line of ABC therapy After failure of first-line therapy, a proportion of patients cannot undergo second line therapy due to rapid disease progression In general, response to further lines of therapy is worse About one third of patients stop their treatment with each new line of therapy These results are concordant with large retrospective cohort studies Study 2 nd line 3 rd line 4 th line 5 th line Dufresne et al % 56% 25% 11% Tacca et al % 68% 43% 23% Bernardo et al % 82% 36% 11% Planchat et al % 76% 56% 37% Current study; Jackisch et al ,6 100% 70% 46% 27% 1. Dufresne A et al. Breast Cancer Res Treat 2008;107: Tacca O et al. Cancer Invest 2009;27: Bernardo G et al. Cancer Res 2010;70(Suppl 24):446s,P Planchat E et al. Breast 2011;20: Jackisch C et al. BMC Cancer 2014;14: Jackisch et al. P , SABCS 2016 Courtesy of Harbeck, ESMO Asia

48 Considerations in choosing 1 st -line therapy in ER+ MBC Tumour Biology ER & PR levels Luminal Subtype / Proliferation Clinical Features Prior Endocrine Rx / DFI / Pace of Disease Visceral vs non-visceral mets / Symptoms / Tumor Burden Patient Factors Age / Co-morbidities / Geographical Logistics Patient Preference / Availability of Rx / Quality of Life Partly adapted from Johnston, SABCS 2016

49 CDK 4/6 inhibitors for ER+ MBC New Gold Standard in 1 st -line treatment Adjuvant trials have also commenced. Unanswered Questions Does every patient need CDK4/6 inhibitor upfront? Will there be improvement in Overall Survival?

50 PALOMA-1 OS data (not powered) Finn et al, ASCO

51 MONALEESA-2 Update (OS data still immature) Hortobagyi et al, ASCO

52 CDK 4/6 inhibitors for ER+ MBC New Gold Standard in 1 st -line treatment. Adjuvant trials have also commenced. Unanswered Questions Does every patient need CDK4/6 inhibitor upfront? Will there be improvement in Overall Survival? What is the optimal treatment after CDK4/6 Inhibition? What is the optimal sequence of treatment?

53 Second-Line and Beyond BOLERO-2 & PALOMA-3: Design of Phase III studies BOLERO-2 PALOMA-3 Postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrozole R A N D O M I S E (2:1) Everolimus 10 mg daily + exemestane 25 mg daily (n=485) Placebo + exemestane 25 mg daily (n=239) HR+, HER2- ABC Pre/peri or postmenopausal Progressed on prior ET on or within 12 months of adjuvant therapy and/or on therapy for advanced breast cancer 1 or more prior chemotherapy regimen for advanced cancer R A N D O M I S E (2:1) Palbociclib (125 mg QD; 3 weeks on, 1 week off) + fulvestrant (500 mg IM Q4W) (n=347) Placebo (3 weeks on, 1 week off) + fulvestrant (500 mg IM Q4W) (n=174) Primary endpoint: PFS Secondary endpoints: OS, ORR, Safety, QoL, CBR Primary endpoint: PFS Secondary endpoints: OS, OR, CBR, Safety, QoL

54 BOLERO-2 & PALOMA-3: PFS BOLERO-2 PALOMA-3 Baselga J, et al. N Engl J Med 2012;366:520-9 Turner N, et al. N Engl J Med 2015;373:209-19

55 MONARCH-2 55 Patients were required to have disease that progressed while receiving neoadjuvant or adjuvant ET, # 12 months after adjuvant ET, or while receiving ET for ABC. Patients must not have received more than one ET or any prior chemotherapy for ABC. Sledge et al, ASCO 2017; JCO 2017

56 BOLERO-2: Overall Survival Results Why? Not statistically powered to detect 4.4mth OS benefit. Imbalance in poststudy salvage chemo use? Higher rate of discontinuation of EVE due to AE: 26% vs 5% Paradoxical activation of AKT via negative feedback loop? Need predictive biomarkers? 56 Piccart et al, Ann Onc 2014

57 BOLERO-2 Correlative Genomic Analysis Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, mtor somatic mutations may be associated with greater benefit from mtor inhibition. Somatic FGFR mutations associated with poor prognosis. High chromosomal instability associated with less everolimus benefit and worst outcome. Hortobagyi et al, JCO

58 PI3K/AKT/mTOR Pathway 58 Rodon et al, Nature Reviews Clin Onc 2013

59 PI3K Inhibitors still promising? Efficacy limited in unselected patients. Significant toxicities with Pan-PI3K Inhibitors. FERGI (n=168): fulvestrant + pictilisib vs fulvestrant + placebo: negative BELLE2 (n=1147): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; benefit mainly with PIK3CA mutated (cdna) BELLE3 (n=432)(post-mtor inhibitor): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; ; benefit mainly with PIK3CA mutated (tumour or cdna) Alpha-specific PI3K Inhibitors Better tolerated? Ongoing phase 3 trials Taselisib + fulvestrant vs placebo + fulvestrant (SANDPIPER) Alpelisib + fulvestrant vs placebo + fulvestrant (SOLAR) Potential activity after progression on CDK4/6 Inhibitors? 59

60 Other Novel Therapeutics HDAC Inhibitors? Immunotherapy? Etc etc Novel SERD Epigenetic Modulators? Immunotherapy, Bone-modifying agents RTK Inhibitor Still a role for chemotherapy Endocrine Resistance Inhibitors of MDM2?BCL2? Inhibitors of PI3K/MEK pathway CDK Inhibitor Inhibitors of NOTCH?WNT? Ma et al, Nature Rev Ca 2015

61 Pink Ribbon Walk, October 2016 Thank you for your attention! 61