Fulvestrant: cuándo y dónde usarlo? Dra. S. López-Tarruella

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Ernest Cain
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1 Fulvestrant: cuándo y dónde usarlo? Dra. S. López-Tarruella

2 FULVESTRANT mechanism of action Carlson et al Clin Breast Cancer 2005; Howell Crit Rev Oncol Hematol 2016; Robertson et al Cancer Res 2001; De Friend et la Cancer Res 1994

FULVESTRANT monotherapy evidence (early steps) Progression to TAMOXIFEN in the 1 st line FULVESTRANT vs ANASTROZOLE Study Treat. N ER+ (%) TTP (m) Osborne et al (2002) USA Howell et al (2002) Intl.

3 FULVESTRANT monotherapy evidence (early steps) Progression to TAMOXIFEN in the 1 st line FULVESTRANT vs ANASTROZOLE Study Treat. N ER+ (%) TTP (m) Osborne et al (2002) USA Howell et al (2002) Intl. FULV 250 ANA FULV 250 ANA (HR 0.92, p=0.43) (HR 0.98, p=0.84) CB (%) (p=0.26) (p=0.85) ORR (%) (OR 1.38, p=0.20) Combined analysis of trial 0020 and trial 0021 Howell et al JCO 2002 ; Osborne et al JCO 2002; Howell et al Cancer 2005

and SoFEA (monotherapy data) 4.8 mo 3.4 mo 31.6% 26.9% 6.

4 FULVESTRANT monotherapy evidence (early steps) Progression to AIs in the 1 st Line FULVESTRANT vs EXEMESTANE EFFECT and SoFEA (monotherapy data) 4.8 mo 3.4 mo 31.6% 26.9% 6.9% 3.6% Chia et al JCO 2008; Johnston et al Lancet Oncol 2013

5 FULVESTRANT finding the optimal dose (consolidation) - Progression to AIs/AEs in 1 st Line (de novo MBC OR relapse >12mo Adj_HT) - Relapse on OR <12mo from completion AIs/AEs Adj_HT FULVESTRANT at different doses Eligibility (N = 736) Postmenopausal women ER+, advanced disease Recurred or progressed following endocrine therapy R 1:1 Fulvestrant 250 mg* + placebo* (n = 374) Fulvestrant 500 mg (n = 362) * 1 injection IM; 2 injections (250 mg each) IM PRIMARY ENDPOINT: PFS Secondary Endpoints: OOR, CBR, DoCB, OS and QoL Di Leo et al JCO 2010 & JNCI2013

6 FULVESTRANT finding the optimal dose (consolidation) 34% vs 25% Median PFS 6.5 vs 5.5 mo 16% vs 11% N CR PR SD>24wk ORR (%) CBR (%) FULV 500 mg (1.1%) 29 (8%) 132 (36.5%) 33 (9.1%) 165 (45.6%) FULV 250 mg (0.3%) 37 (9.9%) 110 (29.4%) 38 (10.2%) 148 (39.6%) OR (p) (p=0.795) 1.28 (p=0.100) Di Leo et al JCO 2010 & JNCI2013

7 FULVESTRANT finding the optimal dose (consolidation) OS (final deaths) OS retrospectively adjusted HR= 0.79 (P=0.007) Median OS 26.4 vs 22.3 mo 19% reduction in risk of death & 4.1-mo difference in median OS Di Leo et al JCO 2010 & JNCI2013

FULVESTRANT 500 approaches the 1L LA/MBC therapy Design Treat. (N) FU (mo) TTP (mo) CB (%) OS (mo) Ph II, randomized, multicentric, openlabel [100% HR+] FUL500 (102) vs ANA (103) 16.5 23.4 vs 13.1 (0.

8 FULVESTRANT 500 approaches the 1L LA/MBC therapy Design Treat. (N) FU (mo) TTP (mo) CB (%) OS (mo) Ph II, randomized, multicentric, openlabel [100% HR+] FUL500 (102) vs ANA (103) vs 13.1 (0.66, p=0.01*) 72.5 vs 67.0 (1.30, p=0.386) 54.1 vs 48.4* (0.70, p=0.041) No prior HT for LA/MBC (74.63% pts): ETnaïve subgroup (HR 0.63*) Adjuvant HT allowed if completed >12 mo before (24.88% pts): (HR 1.01) Robertson et al JCO 2009; Ellis et al JCO 2015

Advanced luminal BC algorithm evolution 1975-1990 By 2015 TAMOX Megestrol A.

9 Advanced luminal BC algorithm evolution By 2015 TAMOX Megestrol A. 1G/2G AI TAMOX 3G NSAI Megestrol A. 3G NSAI TAMOX/FULV/EXE Hart et al NRCO 20015

oncology data in France, Germany, Italy, Spain, and the UK Postmenopausal HR+ MBC stage

10 Patient database analysis of FUL500 in MBC: EU perspective OA is a fully syndicated, retrospective, longitudinal cancer treatment database collecting anonymized patient-level oncology data in France, Germany, Italy, Spain, and the UK Postmenopausal HR+ MBC stage III or IV ( ), N=27214 pts (6500 Spain) CT AI TAM FUL Marchettti et al The Breast 2017

11 Single-agent FUL in 1L endocrine-naïve: FALCON trial The objective of the FALCON study was to confirm the PFS (TTP) superiority of FUL over ANA in postmen HR+ LA/MBC who had not received prior ET Ellis et al ESMO 2016; Robertson et al Lancet Oncol 2016

12 Single-agent FUL in 1L endocrine-naïve: FALCON trial Most diagnosis <1 year (43% <2mo & 27% 2-12mo range) 1/3 prior CT Ellis et al ESMO 2016; Robertson et al Lancet Oncol 2016

13 Single-agent FUL in 1L endocrine-naïve: FALCON trial Ellis et al ESMO 2016; Robertson et al Lancet Oncol 2016;t Robertson et al SABCS 2016 (P )

14 Single-agent FUL in 1L endocrine-naïve: FALCON trial Ellis et al ESMO 2016; Robertson et al Lancet Oncol 2016

15 Single-agent FUL in 1L endocrine-naïve: FALCON trial Ellis et al ESMO 2016; Robertson et al Lancet Oncol 2016

evidence of a detriment with FUL vs ANA in time to deterioration for both Trial Outcome

16 Single-agent FUL in 1L endocrine-naïve: FALCON trial FALCON: Toxicity Profile Overall health-related quality of life (HRQoL) was maintained and similar for FUL and ANA No evidence of a detriment with FUL vs ANA in time to deterioration for both Trial Outcome Index and FACT-B total score Ellis et al ESMO 2016; Robertson et al Lancet Oncol 2016; ASCO 2017 Abst 1048

Real-world evidence to define prevalence of HT-naïve HR+ LA/MBC Cross-sectional

stage in the Optum ehr database during the study period had postmenopausal,

literature data 18-30% (all countries) Extrapolated HR+/HER2- LA/MBC HT-naïve

17 Real-world evidence to define prevalence of HT-naïve HR+ LA/MBC Cross-sectional obervational study retrospectively analysed data from ehr database ( ) covering BC diagnosed pts 11.5% of pts with BC and discernible postmenopausal status, HR status, and disease stage in the Optum ehr database during the study period had postmenopausal, HR+/HER2- (or unknown) LA/MBC and had not received prior HT vs previous literature data 18-30% (all countries) Extrapolated HR+/HER2- LA/MBC HT-naïve Proportion of postmenopausal HR+/HER2- (or UK) LA/MBC HT-naïve represents a substantial pt population in US Nunes et al SABCS 2016 (P )

FACT Fulvestrant-based Combination (Endocrine-Therapy) First line Tam sensitive First (naïve or or second-line pretreated 12-month post-ai NSAI adjuvant resistant ther) FACT Design Rx Arm (N) Ph III,

12 months or as first-line treatment for at least 6 months) SoFEA S0226 Ph III, randomized, open-label [40% prior HT; 39% de novo MBC; 33% prior adj CT] Crossover FUL250+ ANA (345) vs ANA (349)

18 FACT Fulvestrant-based Combination (Endocrine-Therapy) First line Tam sensitive First (naïve or or second-line pretreated 12-month post-ai NSAI adjuvant resistant ther) FACT Design Rx Arm (N) Ph III, randomized, open-label FUL250+ANA (258) [68% prior HT; 7% de novo MBC; 46% vs prior adj CT] ANA (256) 500 mg IM d1 250 mg D15 and 29 SWOG S0226 (progression on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months) SoFEA S0226 Ph III, randomized, open-label [40% prior HT; 39% de novo MBC; 33% prior adj CT] Crossover FUL250+ ANA (345) vs ANA (349) Combination ET may be offered to some pts with MBC without prior exposure to adjuvant ET [ESMO 2017] After loss of response to NSAIs maximum double endocrine treatment (FUL+ E deprivation) no better than either FULV or EXE Johnston et al Lancet Oncol 2013; Bergh et al JCO 2012; Mehta et al NEJM 2012

19 Fulvestrant-based Combination (Targeted-Therapy) FUL+ CDK 4/6 inhibitors Trial Phase (N) PALOMA-3 III (521) Palbociclib+ FUL vs Placebo + FUL Design Population 1º Endpoint MBC pre & postm PFS PEARL III (600) Palbociclib + FUL/EXE vs Capecitabine MONALEESA-3 III (660) Ribociclib+ FUL vs Placebo + FUL MBC postm MBC postm PFS PFS MONARCH-2 III (630) Abemaciclib + FUL vs Placebo + FUL MBC postm PFS FLIPPER: phase II FUL+Palbo/pbo 1L MBC PARSIFAL: phase II Palbo+ FUL/LET 1L MBC

20 Fulvestrant-based Combination (Targeted-Therapy) FUL+ CDK 4/6 inhibitors: PALOMA-3 vs MONARCH-2 2:1 Randomization HR+ HER2- ABC Pre/peri or post men Progressed on prior ET: on or within 12 mo adjuvant / on therapy for ABC < 1 prior CT regimen for ABC (Any # lines ET MBC) Palbociclib 125 mg QD (3/1 schedule) + Fulvestrant 500 mg IM q4w (N=347) Placebo (3/1 schedule) + Fulvestrant 500 mg IM q4w (n = 174) 2:1 Randomization HR+ HER2- ABC Pre/peri or post men ET resistant: relapsed on NA or on/within 12 mo adjuvant; progressed on 1L ET No CT for MBC ECOG <1 (1 lines ET MBC) N=521 N = 669 Abemaciclib 150mg BID (cont. schedule) + Fulvestrant 500 mg IM q4w (n = 446) Placebo BID (cont. schedule) + Fulvestrant 500 mg (n = 223) Primary endpoint: PFS by investigator Secondary endpoints: ORR, CBR, OS, safety, biomarkers, PROs Stratification: visceral mets, sensitivity prior HT; menopausal status Primary endpoint: PFS by investigator Secondary endpoints: OS, ORR, CBR, safety Stratification: metastatic site, ET resistance (primary vs secondary) Turner et al NEJM 2015; Cristofanilli et al Lancet Oncol 2016; Sledge et al ASCO 2017

Fulvestrant-based Combination (Targeted-Therapy) FUL+ CDK 4/6 inhibitors: PALOMA-3 vs MONARCH-2 ORR (%) CB (%) FUL/PALBO 19 67 FUL/pbo 9 40 Ratio (p) 2,47 (p=0.

21 Fulvestrant-based Combination (Targeted-Therapy) FUL+ CDK 4/6 inhibitors: PALOMA-3 vs MONARCH-2 ORR (%) CB (%) FUL/PALBO FUL/pbo 9 40 Ratio (p) 2,47 (p=0.0019) 3.05 (p<0.0001) (neo)adjuvant only but no previous systemic therapy for MBC Turner et al NEJM 2015; Cristofanilli et al Lancet Oncol 2016; Sledge et al ASCO 2017

3% Back pain 15.1% FULV (control): Fatigue 26.9% Nausea 22.9% Headache 15.2% Diarrhea 24,7% Hot flushes 9.

22 Fulvestrant-based Combination (Targeted-Therapy) FUL+ CDK 4/6 inhibitors: PALOMA-3 VS MONARCH-2 FULV (control): Fatigue 26.7% Nausea 26.2% Headache 17.4% Diarrhea 17.4% Hot flushes 16.3% Arthralgia 16.3% Back pain 15.1% FULV (control): Fatigue 26.9% Nausea 22.9% Headache 15.2% Diarrhea 24,7% Hot flushes 9.9% Arthralgia 14.3% Back pain 12.6% Turner et al NEJM 2015; Cristofanilli et al Lancet Oncol 2016; Sledge et al ASCO 2017

23 Fulvestrant-based Combination (Targeted-Therapy) FUL+ PI3K/AKT/mTOR inhibitor: PreCOG 0102 Kornblum et al SABCS 2016

24 Fulvestrant-based Combination (Targeted-Therapy) FUL+ PI3K/AKT/mTOR inhibitor: PreCOG 0102 Kornblum et al SABCS 2016

25 Fulvestrant-based Combination (Targeted-Therapy) FUL+ PI3K/AKT/mTOR inhibitor: BELLE-2 Baselga etl al Lancet Oncol 2017& SABCS 2015

26 Fulvestrant-based Combination (Targeted-Therapy) FUL+ PI3K/AKT/mTOR inhibitor: BELLE-2 Baselga etl al Lancet Oncol 2017& SABCS 2015

27 Fulvestrant-based Combination (Targeted-Therapy) FUL+ PI3K/AKT/mTOR inhibitor: BELLE-2 Baselga etl al Lancet Oncol 2017& SABCS 2015

28 Fulvestrant-based Combination (Targeted-Therapy) FUL+ alpha-specific PI3K inhibitor PALOMA-3 SANDPIPER SOLAR-1 DESIGN III III III Size 521 (2:1) 600 (2:1) 2 cohorts 560 (1:1) 2 cohorts Rx Arms FUL+palbo/pbo FUL+taselisib/pbo FUL+alpelisib/pbo POPULATION stratif factor Visceral disease ED_sensitivity Menopausal status Visceral disease ED_sensitivity Geograph region Liver/lung mets CDK4/6 inh Menopausal status Pre/PostM PostM PostM (men) Previous BL exposure CDK4/6 inh Previous HT exposure AI prog/recurr* AI prog/recurr AI prog/recurr Previous QT exposure ABC 1L_QT 1L_QT NO Clinical timeframe On/within 12 mo from Adj HT (no Tx ABC) On/within 1 mo AI progression 1L MBC *PreM (progression HT non AI) On/within 12 mo from Adj HT (no Tx ABC) On/within 1 mo AI progression 1L MBC On/within 12 mo from (N)Adj HT (no Tx ABC) >12 mo from (N)Adj HT (progressed 1L HT ABC) De novo MBC progressed 1L HT >12 mo from (N)Adj HT (no Tx ABC) 1º ENDPOINT PFS (invest) PFS (PIK3CA mut) PFS (PIK3CA mut)

Potential mechanisms that contribute to FUL resistance ESR1 mutations and FUL ESR1 ESR1 mut mutations targetable are with rare high in primary dose FUL BC but more prevalent in MBC (previously AI)

29 Potential mechanisms that contribute to FUL resistance ESR1 mutations and FUL ESR1 ESR1 mut mutations targetable are with rare high in primary dose FUL BC but more prevalent in MBC (previously AI) acquired Non-invasive liquid biopsies to detect ESR1 and other mutations in ctdna isolated from plasma samples under development A diversity of activating ESR1 mut exist, only some of which confer resistance to existing ER antagonists that might be overcome by next generation inhibitors Jeselsohn et al Curr Oncol Rep 2017; Toy et la Nat Gen 2013 & Cancer Discovery 2017

30 Potential mechanisms that contribute to FUL resistance ESR1 mutations and FUL ESR1 mut ESR1 wt SoFEA 39.1% ESR1 mut PALOMA % ESR1 mut Fribbens et a l JCO 2016

31 Advanced luminal BC algorithm transformation (US) Post-Menopausal Pre-Menopausal Fulvestrant Fulvestrant Rugo et al JCO 2016

32 Advanced HR positive BC changing landscape Delaying CT in the treatment of HR+HER2- advanced BC?? Johnston S. SABCS 2016; Brufsky A Clin Med Insights 2015

Fulvestrant es un fármaco potencialmente superior a los IA en el ámbito de la monoterapia endocrina a la dosis adecuada (500) en pacientes endocrino-naïve en 1L Fulvestrant en combinación con CDK4/6

33 Fulvestrant es un fármaco potencialmente superior a los IA en el ámbito de la monoterapia endocrina a la dosis adecuada (500) en pacientes endocrino-naïve en 1L Fulvestrant en combinación con CDK4/6 inhs ha demostrado eficacia en pacientes con HT previa, y es una HT de elección para su combinación con las nuevas terapias de diana en estudio (p.e. PI3K/At/mTOR inhs) Como elegir entre monoterapia vs terapia combinada se basa actualmente en criterios clínicos y de acceso pero el descubrimiento y validación de biomarcadores de endocrino-sensibilidad es clave para poder tomar decisiones fundamentadas en el trasfondo biológico de la enfermedad en cada momento de la historia de la paciente (los avances en diagnostico molecular incluida BIO líquida pueden ser herramientas de interés) Uno de los verdaderos desafíos actuales es definir la secuencia óptima en la que deben integrarse todas estas opciones para que las pacientes con CM luminal avanzado vivan más y mejor

34 Muchas Gracias!

Endocrine Therapy 2017: Is There a Better Single Agent and when Should we Use it?

Endocrine Therapy 2017: Is There a Better Single Agent and when Should we Use it? ET1 ET2 ET3 Targeted agent 1 Targeted agent 2 Hope S. Rugo, MD Director, Breast Oncology and Clinical Trials Education