Treatment of metastatic breast cancer with positive hormonal receptors (HR+) Prof. Jean Marc NABHOLTZ Director, Cancer Research and Consultant, Division of Onco-Hematology King Saud University Medical City, Riyadh, Saudi Arabia Professor of Medicine and Former Director, Cancer Therapy Development Program and Solid Tumor Program, University of California at Los Angeles (UCLA), CA, USA Founder and Past Chairman, Breast Cancer International Research Group (BCIRG)

Breast Cancer Worldwide : Worldwide :  > 1,400,000 new cases/year  > 450,000 deaths/year  Doubling incidence within 15 years (countries in transition) Early disease: Curable Early disease: Curable  Cure rates Stable from 1930 until 1990 Stable from 1930 until 1990 Improvement in the 1990’s (Screening, Adjuvant therapy) Improvement in the 1990’s (Screening, Adjuvant therapy) Ageing population in Europe: Absolute No of deaths still rising (2004: 130,000 / 2006: 132,000)Ageing population in Europe: Absolute No of deaths still rising (2004: 130,000 / 2006: 132,000) Metastatic disease: Non Curable Metastatic disease: Non Curable Concept of chronic diseaseConcept of chronic disease

Breast Cancer Subtypes ER/PR+ ER/PR– HER „Triple negative“ Breast Cancer

Intrinsic Classification of Breast Cancer: ER + Tumors Luminal A Luminal B 60% Breast Cancers 20% Breast Cancers High expression ER Lower expression ER High expression of genes regulated byER (Gata-3, FOX A1...) Lower expression of genes regulated byER (Gata-3, FOX A1...) Low proliferation High proliferation Mutated P53: 13% Mutated P53: 66%

5 HER2+ Breast Cancer Subtypes 5 Breakdown of the 21% HER2+ Bauer K., Cancer. 2010;10:228. ER+/PR+/HER2+ ER+/PR-/HER2+ ER-/PR+/HER2+ ER-/PR-/HER % 7.1% 3.3% 0.5% N=114,786 ~21% HER2+ ~79% HER2-

T.O. Nielsen et al., Clinical Cancer Research 10, (2004). Luminal A= ER+, PR+, HER2-, KI67 low (<15%) Luminal B= ER+,PR+/-, HER2-, KI67 high (>15%) HER2+ = ER- and HER2+ (IHC 3+ or FISH+) Triple Negative: Basal-like = ER-, HER2-, CK5/6+ and/or EGFR+ Unclassified = negative for all 4 markers IHC intrinsic subtype surrogates., ).

Sorlie, T et al: PNAS 2001; 98: Breast Cancer is an Heterogeneous Group of Diseases OS DFS

Predictive Factors Chemotherapy Trastuzumab Chemotherapy Trastuzumab Chimiothérapie Chemotherapy RH+ RH- HER2+++ HER2- Hormonetherapy

Management of MBC Diagnosis of MBC Determination of site and extent of disease Assessment of hormonal receptor status, disease-free interval, age and menopausal status No life-threatening disease Hormone-responsive /Her 2- 1st-line hormonal therapy Response 2nd-line hormonal therapy Progression Progression 3rd-line hormonal therapy Response No Response Hormone-unresponsive Her2-, Her2+ or Life-threatening disease 1st-line chemotherapy (+AntiHER2 if Her2+) + bevacizumab 2nd-line CT (+AntiHER2 if Her2+) Progression Progression 3rd-line CT... 3rd-line CT... Supportive care

Visceral Crisis Severe organ dysfunction based on: –Signs (eg, jaundice) and symptoms –Laboratory studies –Rapid progression of disease It is not the mere presence of visceral metastases; presence implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly because another treatment option at progression will probably not be possible (time issue)

Development of endocrine therapy Oophorectomy Stilboestrol Tamoxifen Ameg Receptor blockade Modern AIs Adrenalectomy Estrogen deprivation Fulvestrant 2004 Beatson

Efficacy of Endocrine Agents in Women With Advanced Breast Cancer AblativeOophorectomy33 Adrenalectomy, Hypophysectomy32 Radiation therapy32 AdditiveEstrogens26 Progestins29 Androgens21 Glucocorticoids25 CompetitiveTamoxifen32 InhibitiveAminoglutethimide + HC31 Therapy Response Rate (%) Response data from comprehensive reviews Rose C, et al. Acta Oncol 1998; 27: 721-8

Tamoxifenwas Gold Standard in early breast cancer.

Aromatase Inhibitors Nonselective Nonselective  Aminoglutethimide (competitive) Selective: Discovery Late 80’s Selective: Discovery Late 80’s  Competitive– Noncompetitive (nonsteroidal)(steroidal) Anastrozole ExemestaneAnastrozole Exemestane Letrozole FormestaneLetrozole Formestane VorozoleVorozole FadrozoleFadrozole

Kaplan-Meier Curve for TTP Among the Combined Patients from Trials 0030 and 0027 Known to be Receptor-positive Percentage not progressed ‘Arimidex’ (n=305) Tamoxifen (n=306) Median TTP:‘Arimidex’ 10.7 months Tamoxifen 6.4 months HR= 0.78 p= Time to progression (months) Nabholtz et al, J Clin Oncol.,2000.

Comparison of FIRST with Phase III studies of first-line endocrine monotherapy for ABC: PFS Nabholtz et al. J Clin Oncol 2000 (n=611) Mouridsen et al. J Clin Oncol 2001 (n=916) Paridaens et al. J Clin Oncol 2008 (n=371) AnaLetExe Median TTP (months) Tam ABC, advanced breast cancer; Ana, anastrozole; Exe, exemestane; F500, fulvestrant 500 mg; Let, letrozole; Tam, tamoxifen

Efficacy of Endocrine Agents in Women With Advanced Breast Cancer AblativeOophorectomy33 Adrenalectomy, Hypophysectomy32 Radiation therapy32 AdditiveEstrogens26 Progestins29 Androgens21 Glucocorticoids25 CompetitiveTamoxifen32 InhibitiveAminoglutethimide + HC31 AI 3 rd generation Therapy Response Rate (%) Response data from comprehensive reviews Nabholtz et al. SABCS 2003

Are we heading to further improvements in Hormonetherapy?

FASLODEX Offers a Different Way to Overcome Disease Resistance Unlike tamoxifen or the aromatase inhibitors, FASLODEX completely inhibits ER signalling 1-3 This distinct and different mechanism of action (MOA) may delay the development of resistance and so increase the likelihood of lasting disease control FASLODEX binds, blocks and unlike other therapies, accelerates degradation and loss of the ER As a result, there is less chance of the ER being activated by alternative pathways (e.g. growth factor mediated mechanisms) that are believed to cause resistance 1. Nicholson RI & Johnston SR et al. Breast Cancer Res Treat 2005; 93: S3-S10; 2. Ring A & D Dowsett M. Endocrine-Related Cancer 2004; 11: ; 3. Moy B & Goss PE. Clin Cancer Res 2006; 12:

-238. Fulvestrant vs anastrozole after SERMs Trials 0020/0021

p= Mean ± 1SEM p= p=0.026 Placebo (n=29) (*n=19) 50mg Faslodex (n=31) 125mg Faslodex (n=32) 250mg Faslodex (n=32) 18mg SA s/c (*n=12) J Robertson et al, Cancer Research 2001 DeFriend DJ, et al. Cancer Res. 1994;54: Post-treatment Mean ER H-scores 1ng/ml 2.5ng/ml 5ng/ml 23ng/ml Conc. after:- 2 weeks 2 weeks 1 week 1 week 6mg SA s/c (*n=6) 7ng/ml 500mg LA = 14ng/ml

FIRST Trial. Fulvestrant vs anastrozole in endocrine-naïve breast cancer Robertson J F et al. JCO 2009;27: st line MBCAnastrozole Fulvestrant 500

This presentation is the intellectual property of John F. R. Robertson. Contact at for permission to reprint and/or distribute San Antonio Breast Cancer Symposium, December 9-13, 2014 Fulvestrant 500 mg n=102 Anastrozole 1 mg n=103 Dead, n (%)63 (61.8)74 (71.8) Median OS (months) FIRST: overall survival analysis Proportion of patients alive Time (months) Fulvestrant 500 mg Anastrozole 1 mg HR= % CI (0.50, 0.98) p= Months Fulvestrant 500 mg Anastrozole 1 mg Number of patients at risk: Patients not known to have died were right-censored at the last time they were known to be alive

This presentation is the intellectual property of John F. R. Robertson. Contact at for permission to reprint and/or distribute San Antonio Breast Cancer Symposium, December 9-13, 2014 Ongoing Phase III study: FALCON Progression Fulvestrant 500 mg + placebo Survival Postmenopausal women presenting with ER+ and / or PgR+ LA / MBC not previously treated with any hormonal therapy Progression Survival Anastrozole + placebo PFS analysis at 306 progression events OS analysis at 50% Randomization 1:1 (n=450) 25 FALCON, Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer ClinicalTrials.gov identifier: NCT LA / MBC, locally advanced / metastatic breast cancer

Efficacy of Endocrine Agents in Women With Advanced Breast Cancer AblativeOophorectomy33 Adrenalectomy, Hypophysectomy32 Radiation therapy32 AdditiveEstrogens26 Progestins29 Androgens21 Glucocorticoids25 CompetitiveTamoxifen32 InhibitiveAminoglutethimide + HC31 AI 3 rd generation ER Down regFulvestrant 500 mg Therapy Response Rate (%) Response data from comprehensive reviews Nabholtz et al. SABCS 2010

Combination of Hormonotherapy with biologic modifiers

Luminal HER2+

TAnDEM RH+ surexpression d’HER2 (n=208) R anastrozole 1 mg / day + trastuzumab 4 mg/kg D1 then 2 mg/kg / week until progression anastrozole 1 mg / day until progression (cross over allowed) Primary endpoint : PFS Secondary endpoints : RR, Clinical benefit, Time to progression, Duration of response, OS + toxicités Kaufman B, et al. J Clin Oncol 2009 Sep 28 [Epub ahead of print]

PFS TAnDEM A + T A % CI 3.7, , 4.6 p value Median PFS 4.8 months 2.4 months Events temps en mois Kaufman B, et al. J Clin Oncol 2009

Study EGF30008 RH+ HER2 – ou +++ (n=1286) pour HER2+++ : n=219 R letrozole 2,5 mg /day + lapatinib 1500 mg/ day until progression letrozole 2,5 mg / day + placebo until progression (No cross over) Primary endpoint: PFS in HER2+++ Secondary endpoints: PFS (ITT),RR? Clinical benefit, OS + toxicity Johnston S, et al. J Clin Oncol 2009

Study EGF30008 (L vs L+L) HR (95% CI) 0.71 ( ) p value Median PFS 8.2 months 3.0 months Events PFS patients HER2+++

Cortés J, et al. Nat Rev Clin Oncol. 2011;8: Lower ORR When Endocrine Therapy Was Added to Anti- HER2 Therapy in HER2+/HR+ Patients 33

Luminal HER2-

Estrogen Receptor Transcription Factor Classic Nucleus ER Cytoplasm membrane-bound ER X Activated by Estrogen Activated by tamoxifen And Estrogen Cross talk with Growth factors signals Genomic effects Non-Genomic effects Blocked by Tamoxifen Adapted from Dowsett

Cross-talk between signal transduction and endocrine pathways Adapted from Johnston 2005 ERE ER Basal transcription machinery p160 ER target gene transcription CBP P P Cytoplasm Nucleus Plasma membrane Oestrogen  Proliferation

Cross-talk between signal transduction and endocrine pathways Adapted from Johnston 2005 Basal transcription machinery p160 EREER target gene transcription ER CBP P P P P ER Cytoplasm Nucleus Plasma membrane Growth factor Oestrogen P P IGFR1/EGFR / HER2 Akt P PI3-K mTOR Growth factor  Proliferation Inspite of hormonal treatment i.e. Hormone resistance AIs Tamoxifen X

BOLERO-2. Progression-free Survival Exemestane ± everolimus after prior AI P = Baselga J et al. N Engl J Med 2012;366:

BOLERO-2 (39-Month) Final OS Analysis One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS®. CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System; PBO, placebo. Piccart M, et al. Presented at EBCC-9; March 2014; Glasgow, Scotland. Abstract 1LBA. 4.4-month difference

The PI3K/Akt/mTOR pathway and Breast Cancer Ras 4EBP1 Raf Erk Rsk PI3K TORC1 S6K Rheb S6 PIP 3 Tuberin PTEN TORC2 MEK Akt PDK1 HER2/HER3

FERGI Study Design – Faslodex +/- PI3K Inhibitor GDC-0941 ER+, HER2-, postmenopausal women with advanced or MBC Prior aromatase inhibitor in adjuvant (PD<6mo) or metastatic setting ECOG PS 0, 1 No diabetic patients 0-1 chemotherapy or <2 prior endocrine therapies Fulvestrant 500mg 1 + pictilisib (GDC-0941) 340 mg QD R Treat to PD 2 N = 168 Stratification factors1° objective PIK3CA-MT and PTEN loss 3 Measurable disease 1 o vs. 2 o resistance 4 PFS in the ITT PFS in PIK3CA-MT pts Safety pictilisib + fulvestrant Cross Over 1:1 1 Administered on D1 of each 28 day cycle and C1D15; 2 Tumor assessments performed every 8 weeks; 3 Exons 9 and 20 in the codons encoding amino acids E542, E545, and H1047 were detected by RT-PCR; 4 Disease relapse during or within 6 months of completing AI treatment in the adjuvant setting, or disease progression within 6 months of starting AI treatment in the metastatic setting. 5 Data presented is an additional year of follow up per-protocol primary analysis Fulvestrant 500 mg 1 + placebo QD

FERGI: Progression-Free Survival in the ITT Population 43 Dose Reductions for Skin/GI toxicity

FERGI: Progression-Free Survival in Patients with ER and PR Positive Disease Progesterone-Receptor Positive Population

BELLE-2: Study Design Primary endpoints: PFS in overall population, pts with known PI3K activation status (activated or not), and PI3K-activated only group Secondary endpoints: OS, ORR, CBR, safety, PK, QoL Exploratory endpoint: PFS by PIK3CA mutation status Buparlisib 100 mg/day + Fulvestrant 500 mg (n = 576) Placebo + Fulvestrant 500 mg (n = 571) Baselga J, et al. SABCS Abstract S6-01. Stratified by PI3K pathway activation (yes vs no vs unknown), visceral disease status Postmenopausal women with HR+/HER2- inoperable locally advanced or metastatic BC, with progression on/after AI therapy (N = 1147)

BELLE-2: PFS Baselga J, et al. SABCS Abstract S6-01. Median PFS, Mos (95% CI) Buparlisib + Fulvestrant (n = 576) Placebo + Fulvestrant (n = 571) HR (95% CI) P Value Overall population6.9 ( )5.0 ( ) 0.78 ( ) <.001 *N = 372; n = 188 buparlisib + fulvestrant; n = 184 pl + fulvest † Not statistically significant based on a threshold of P =.01 in the trial design for this subpopulation. PI3K-activated pts*6.8 ( )4.0 ( ) 0.76 ( ).014 †

PIK3CA mutation analysis in ctDNA by BEAMing method (N = 587 pts) Buparlisib + fulvestrant extended survival in pts with PIK3CA mutations vs fulvestrant alone ORR higher with buparlisib + fulvestrant in pts with PIK3CA mutations vs fulvestrant alone (18.4 % vs 3.5%) but similar in pts with nonmutant PIK3CA (11.6% vs 10.6%) BELLE-2: Efficacy by PIK3CA Mutation in ctDNA Baselga J, et al. SABCS Abstract S6-01. *n = 87 buparlisib + fulvestrant; n = 113 placebo + fulvestrant. † n = 199 buparlisib + fulvestrant; n = 188 placebo + fulvestrant. Median PFS, Mos (95% CI) Buparlisib + Fulvestrant Placebo + Fulvestrant HR (95% CI) P Value ctDNA PIK3CA mutant (n = 200)* 7.0 ( )3.2 ( )0.56 ( )<.001 ctDNA PIK3CA non mutant (n = 387) † 6.8 ( )6.8 ( )1.05 ( ).642

Targeting the cell cycle

49 Paloma 1 / Phase 2 Study Design ER+, HER2– Locally Recurrent or Metastatic Breast Cancer N=66 1:1 Part 1 Post- menopausal ER+, HER2– BC status No prior treatment for advanced disease RANDOMIZATION Palbociclib 125 mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Part 2 N=99 1:1 Post- menopausal ER+, HER2– BC with CCND1 amplification and/or loss of p16 No prior treatment for advanced disease RANDOMIZATION Palbociclib 125 mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Stratification Factors Disease Site (Visceral vs Bone only vs Other) Disease-Free Interval (>12 vs ≤12 mo from end of adjuvant to recurrence or de novo advanced disease) a Schedule 3/1 Key Eligibility Criteria Measurable disease (RECIST 1.0) or bone-only disease ECOG PS of 0 or 1 Adequate blood counts and organ function No prior/current brain metastases

50 Paloma 1: Progression-Free Survival (ITT) PAL + LET (N=84) LET (N=81) Number of Events (%)41 (49)59 (73) Median PFS, months (95% CI) 20.2 (13.8, 27.5) 10.2 (5.7, 12.6) Hazard Ratio (95% CI) (0.319, 0.748) p-value0.0004

PALOMA-1/TRIO-18: Overall Survival (ITT) at Time of Final PFS Analysis Number of patients at risk PAL+LET LET PAL+LET (n=84) LET (n=81) Number of events (%)30 (36)31 (38) Median OS, months (95% CI) 37.5 (28.4-NR) 33.3 (26.4-NR) Hazard ratio (95% CI)0.813 ( ) P value.2105 Abbreviations: CI, confidence interval; ITT, intent to treat; LET, letrozole; NR, not reached; OS, overall survival; PAL, palbociclib; PFS, progression-free survival. Reprinted from Finn RS, et al. AACR 2014, Abst CT101 [oral presentation]. 51

PALOMA 3: Study Design a All received goserelin. b Must have progressed on prior endocrine therapy (pre-/perimenopausal) or aromatase inhibitor therapy (postmenopausal). c Patients randomized. d Administered on Days 1 and 15 of Cycle 1, then every 28 d. Phase 3, double-blind study involving 144 centers in 17 countries (NCT ) Placebo (3 wks on/1 wk off) + Fulvestrant d (500 mg IM q4w) Palbociclib (125 mg QD; 3 wks on/1 wk off) + Fulvestrant d (500 mg IM q4w) Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs post-menopausal 2:1 Randomization N=521 c Stratification: HR+, HER2– ABC Pre-/peri- a or postmenopausal b Progressed on prior endocrine therapy: –On or within 12 mo adjuvant –On therapy for ABC ≤1 prior chemotherapy regimen for advanced cancer n=347 n=174 Turner NC, et al. N Engl J Med. 2015;373: Turner NC, et al. ASCO 2015 (Abstract LBA502)

53 PALOMA 3: Primary Endpoint of Investigator- Assessed PFS (ITT Population) Turner NC, et al. N Engl J Med. 2015;373: Turner NC, et al. ASCO 2015 (Abstract LBA502) CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival Palbociclib + fulvestrant n=347 Placebo + fulvestran t n=174 Median PFS, months (95% CI) 9.2 (7.5, NE) 3.8 (3.5, 5.5) HR (95% CI)0.42 (0.32, 0.56) 2-sided P value <0.001 Palbociclib plus letrozole Letrozole

Antiangiogenics

LEA Study design Phase III study MBC N = 380 patients Breast cancer Locally advanced or metastatic HR+/HER2- Letrozole (2,5 mg/day or Fulvestrant 250 mg i.m.q. 28 days Letrozole (2,5 mg/d) or Fulvestrant 250 mg i.m. q. 28 days + Bevacizumab (15 mg/kg q. 3 weeks R Stratification : AI adjuvant (Yes/no) Number of lesions (one/several) measurable lesions (yes/no) Country (Spain/Germany) Until progression HT HT-B Martin M. et al. SABCS 2012

18,4 mois 13,8 mois BrasHT HT + Bev LEA Martin M. et al. SABCS 2012 Progression-Free Survival Bra s HTHT + Bev Overall Survival

Study Design - CALGB (Alliance) Multicenter Randomized Phase III Trial of 1st-line Letrozole +/- Bev N=352 (planned) Postmenopausal ER and/or PR+ HER2 any No prior endocrine therapy for unresectable LABC or MBC Letrozole 2.5mg orally/day Letrozole + Bevacizumab (Bev) 15 mg/kg IV q3 wks Until progression of disease Cycle = 21 days R 1:1 Stratification factors: 1.Measurable disease (Yes/No) 2.Disease-free interval (≤ 24 mos./ > 24 mos) Primary endpoint: Progress-free survival between treatment arms Secondary endpoints: Overall Survival, Response rate, Clinical benefit rate (CR+PR+SD ≥ 6 mos), Treatment-related toxicity and Correlative endpoints Concurrent Phase II: Tamoxifen +/- Bev (not included in this presentation)

Median PFS (mos) # Events/ # Treated Letrozole + Bev / 173 Letrozole alone / 170 Stratified HR = 0.75 (95% CI, 0.59 – 0.96) 1-sided p-value PFS: Interval from study entry until first disease progression or death from any cause Progression-Free Survival CALGB (Alliance) Median follow-up of progression-free pts: 39 mos (range mos)

Overall Survival CALGB (Alliance) Median OS (mos) # Events/ # Treated Letrozole + Bev4781 / 173 Letrozole alone4490 / 170 Stratified HR = 0.87 (95% CI, 0.65 – 1.18) 1-sided p-value 0.188

E AVADO 2,3 RIBBON-1 1 HR Median, months HR Median, months HR CapecitabineTax/anthra Median, months HR Median, months Pac Bev + pac Pla + doc Bev + doc Pla + cape Bev + cape Pla + t/aBev + t/a Overall a n=722n=488n=615n= Visceral mets b n=482n=386n=423n= Adjuvant taxane b n=142n=77n=245n= Triple negative b n=232n=111n=137n= a Stratified analyses; b Unstratified analyses Overview of Bevacizumab PFS in MBC in Clinically Relevant Subgroups of Patients Hormone receptor positive b n=459n=376n=458n= O’Shaughnessy et al. SABCS 2009; 2 Miles et al. SABCS Roche data on file 2009

Management of MBC Diagnosis of MBC Determination of site and extent of disease Assessment of hormonal receptor status, disease-free interval, age and menopausal status No life-threatening disease Hormone-responsive /Her 2- 1st-line hormonal therapy Response 2nd-line hormonal therapy Progression Progression 3rd-line hormonal therapy Response No Response Hormone-unresponsive Her2-, Her2+ or Life-threatening disease 1st-line chemotherapy (+AntiHER2 if Her2+) + bevacizumab 2nd-line CT (+AntiHER2 if Her2+) Progression Progression 3rd-line CT... 3rd-line CT... Supportive care

Chimiothérapies 1ère ligne Cancer du Sein Vogel CL, Nabholtz Oncologist 1999; 4: Nabholtz et al. Exp. Opin Pharmacother 2000; 1:

Shifting Landscape for Therapy for ER+ Metastatic Breast Cancer DecadeAdjuvantMetastatic 1980sNoneOA, tamoxifen 1990sTamoxifenAIs 2000sAI, tamoxifen[AIs, tamoxifen], fulvestrant 2010sAI, tamoxifen[AI, tamoxifen], fulvestrant, Bevacizumab, mTOR and CDK4/6 inhibition

Conclusions Metastatic Luminal A/B:Hormonetherapy except in case of visceral crisis:  Combination with Biologics (mTOR, CDK 4/6, PI3K Inhibitors, Bevacizumab….)  Chemotherapy after exhaustion of hormonesensitivity. Metastatic HER Luminal  Hormonetherapy: adjunct treatment…