Brustzentrum der Universität München

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1 CAMPUS GROSSHADERN CAMPUS INNENSTADT KLINIK UND POLIKLINIK FÜR FRAUENHEILKUNDE UND GEBURTSHILFE DIREKTOR: PROF. DR. MED. SVEN MAHNER The new management of luminal ABC: Best sequence of available therapies Nadia Harbeck Breast Center, University of Munich (LMU), Germany Brustzentrum der Universität München Leitung: Prof. Nadia Harbeck

2 2 Luminal ABC Prof. Harbeck Potential conflicts of interest Honoraria for consulting: Lilly, Novartis, Pfizer Honoraria for lectures: Novartis, Pfizer KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

3 3 Luminal ABC Prof. Harbeck Luminal MBC: How to sequence endocrine + targeted agents Diagnosis & Staging Tumor -board Endocrine therapy Endocrine therapy + targeted agent Endocrine therapy + targeted agent Endocrine therapy KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Tumorboard Tumorboard Tumorboard Tumorboard Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

4 4 Luminal ABC Prof. Harbeck International Treatment Guidelines for HR+, HER2 ABC: Endorsing Endocrine Therapy 1. Cardoso F, et al. Ann Oncol. 2012;23(suppl 7):vii11-vii19; 2. Cardoso F, et al. Ann Oncol. 2014;25(10): ; 3. AGO Breast Committee. Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer. Recommendations Available at KLINIKUM DER UNIVERSITÄT MÜNCHEN ESMO treatment guidelines for HR+, HER2 ABC 1 In HR+, HER2 disease, ET is the treatment of first choice independent of metastatic site, unless rapid response is needed. Limited visceral metastases are not a contraindication for ET ABC2 treatment guidelines for HR+, HER2 ABC 2 ET 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 AGO treatment guidelines for HR+, HER2 ABC 3 Endocrine-based therapy represents the first choice for HR+ metastatic breast cancer except for acute, life-threatening disease ABC, advanced breast cancer; AGO, Association of Gynecological Oncology; AI, aromatase inhibitor; ESMO, European Society for Medical Oncology; ET, endocrine therapy; HR hormone receptor; HER2, human epidermal growth factor receptor 2. Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

5 Metastatic breast cancer 5 Luminal ABC Prof. Harbeck Endocrine therapy* in metastatic breast cancer (before the availability of novel targeted therapies) Adjuvant TAM 5 years AI FUL TAM Adjuvant AI 5 years TAM FUL AI * premenopausal: + GnRH Sequence Tam 2-3y. AI End of Insgesamt adjuvant 5 Jahre therapy TAM AI FUL AI TAM KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Extended adjuvant TAM 5y. AI TAM AI FUL AI TAM Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

6 HR+ HER2- metastatic breast cancer: Recent approvals provide more options 6 Luminal ABC Prof. Harbeck Tamoxifen (1977) Letrozole (1997) Toremifene (1997) Anastrozole (1995) Exemestane (1999) Fulvestrant (2002) Modified after Drugs@FDA. Accessed May 24, 2012 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Everolimus (2012) Palbociclib (2015) 2015 Ribociclib (2017) Abemaciclib (FDA 2017) Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

7 7 Luminal ABC Prof. Harbeck Luminal ABC: First line therapy Endocrine monotherapy or endocrine plus? KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

8 FULVESTRANT st line (FIRST): Overall survival 1 Proportion of patients alive Number of patients at risk: Time (months) Fulvestrant 500 mg Anastrozole 1 mg Patients not known to have died were right-censored at the last time they were known to be alive Fulvestrant 500 mg Anastrozole 1 mg Median OS: Fulvestrant 500 mg = 54.1 months Anastrozole 1 mg = 48.4 months Hazard ratio = 0.70; 95% CI: ; P=0.041 Median OS was significantly increased for fulvestrant 500 mg vs anastrozole 1 mg 1. Robertson JFR, et al. SABCS 9-13 December 2014; San Antonio, USA. Abstract S Harbeck, educational session

9 9 Luminal ABC Prof. Harbeck KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

10 Progression-Free Survival, % Progression-Free Survival Probability (%) PALOMA 2: PFS: Investigator-Assessed - (ITT Population) Time, months (Month) Number of patients at risk PAL+LET PCB+LET ITT=intent-to-treat; LET=letrozole; NR=not reached; PAL=palbociclib; PCB=placebo; PFS=progression-free survival. PAL+LET (N=444) PCB+LET (N=222) Number of Events, n (%) 194 (44) 137 (62) Median (95% CI) PFS 24.8 (22.1 NR) 14.5 ( ) HR (95% CI); 1-sided P value 0.58 ( ); P< Finn et al, ASCO 2016

11 PFS Subgroup Analysis (ITT, Investigator Assessment) All randomized patients Age Race Site of metastatic disease Prior hormonal therapy Disease-free interval Region ECOG performance status Bone-only disease at baseline Measurable disease Prior chemotherapy Most recent therapy Number of disease sites <65 y 65 y White Asian Visceral Nonvisceral Yes No De novo metastases 12 mo >12 mo North America Europe Asia/Pacific 0 1/2 Yes No Yes No Yes No Aromatase inhibitor Antiestrogen Yes No 666 (100) 404 (60.7) 262 (39.3) 516 (77.5) 95 (14.3) 324 (48.6) 342 (51.4) 375 (56.3) 291 (43.7) 248 (37.2) 147 (22.1) 271 (40.7) 267 (40.1) 307 (46.3) 92 (13.8) 359 (53.9) 307 (46.1) 151 (22.7) 515 (77.3) 509 (76.4) 157 (23.6) 322 (48.3) 344 (51.7) 135 (20.3) 229 (34.4) 204 (30.6) 462 (69.4) ECOG=Eastern Cooperative Oncology Group; ITT=intent-to-treat; LET=letrozole; PAL=palbociclib; PCB=placebo; PFS=progression-free survival ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) (0.439, 0.897) ( ) ( ) ( ) ( ) ( ) (0.270, 0.872) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Finn et al, ASCO 2016

12 MONALEESA-2: Analyses in patients with de novo ABC 1 Probability of PFS (%) Ribociclib + Letrozole Placebo + Letrozole n=114 n=113 Events, n (%) 22 (19.3) 42 (37.2) Hazard ratio (95% CI) ( ) PFS rate, % (95% CI) 6-month 88.8 ( ) 83.0 ( ) 12-month 81.6 ( ) 65.7 ( ) Time (Months) Ribociclib + letrozole treatment benefit was maintained in patients with de novo ABC; PFS was prolonged in patients with de novo* ABC in the ribociclib + letrozole vs placebo + letrozole arm (hazard ratio=0.448; 95% CI: ) In patients with de novo ABC, ribociclib + letrozole resulted in a similar safety profile to that observed in the full population AEs were the cause of ribociclib/placebo dose reductions in 48.2% vs 5.4% of patients in the ribociclib + letrozole vs placebo + letrozole arms Neutropenia and leukopenia were the most common Grade 3/4 AEs *Patients with de novo ABC were diagnosed with advanced/metastatic breast cancer up-front they had not relapsed from an earlier disease stage. ABC, advanced breast cancer; AE, adverse event; CI, confidence interval; PFS, progression-free survival. 1. O Shaughnessy J et al. SABCS 2016; abstr P (poster). Hortobagyi GN, et al. American Society of Clinical Oncology, June 2 6, 2017, Chicago, IL, USA. Poster De novo ABC (n=227) MONALEESA-2 CLEE011A2301 ClinicalTrials.gov Identifier: NCT Freigegeben zur Präsentation und Abgabe an Fachkreisangehörige

13 Change From Baseline in Global Health Patient-reported Outcomes, by Treatment Arm Global Health Status/QoL Scale Score of EORTC QLQ-C30 No. of patients assessed Ribociclib + Letrozole Placebo + Letrozole Data cut-off: January 4, The time profile provides the average estimates for the change from baseline for the interval from baseline up to the respective cycle as derived from the linear effects model. Positive changes from baseline are related to improvement in HRQoL. >5 point improvement from baseline in HRQoL score was defined as clinically meaningful. Only patients with baseline scores and at least one non-missing post-baseline assessment are included for change from baseline analysis which was performed using the linear effect model with treatment, stratification factor, and baseline score in the model. Abbreviations: C, Cycle; D, Day; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer s cancer questionnaire; EOT, end of treatment; HRQoL, health-related quality of life; LSM, least squares mean; QoL, quality of life; SEM, standard error of the mean. Verma S, et al. American Society of Clinical Oncology, June 2 6, 2017, Chicago, IL, USA. Poster Change From Baseline Baseline 0-10 LSM +/- SEM Threshold for clinically meaningful improvement from baseline C3D1 C7D1 C11D1 C15D1 C19D1 C25D1 EOT Time Point MONALEESA-2 CLEE011A2301 ClinicalTrials.gov Identifier: NCT Freigegeben zur Präsentation und Abgabe an Fachkreisangehörige Ribociclib + Letrozole Placebo + Letrozole

14 MONALEESA-2: PROGRESSION-FREE SURVIVAL BY BIOMARKER STATUS Freigegeben zur Präsentation und Abgabe an Fachkreisangehörige André et al AACR 2017 CT045

15 MONARCH-3: Primary Endpoint (PFS) Met at Interim Analysis Median PFS abemaciclib + NSAI: not reached placebo + NSAI: 14.7 months HR (95% CI): (0.409, 0.723) p = PFS benefit confirmed by blinded independent central review: HR (95% CI): (0.359, 0.723); p = Di Leo et al, ESMO 2017

16 Exploratory PFS Analysis: Treatment-free Interval (TFI) TFI <36 months Median PFS abemaciclib + NSAI: not reached placebo + NSAI: 9.0 months HR (95% CI): 0.48 (0.25, 0.91) Landmark PFS Rate Arm 6 months 12 months 18 months abemaciclib (n=42) 77.5% 64.8% 53.0% placebo (n=32) 58.6% 37.9% 30.3% TFI 36 months Median PFS abemaciclib + NSAI: not reached placebo + NSAI: not reached HR (95% CI): 0.83 (0.46, 1.52) Landmark PFS Rate Arm 6 months 12 months 18 months abemaciclib (n=94) 82.4% 73.7% 59.4% placebo (n=40) 83.5% 66.2% 53.9% Di Leo et al, ESMO 2017

17 First line efficacy of endocrine + targeted agents 17 Luminal ABC Prof. Harbeck Phase III trial PALOMA 2 (n=666) MONALEESA 2 (n=668) KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum MONARCH 3 Targeted agent Palbociclib Ribociclib Abemaciclib Endocrine agent Letrozole Letrozole Anastrozole / Letrozole PFS 24.8 vs months 25.3 vs months HR (PFS) Most frequent G3/4 side effects neutropenia, leukopenia, anemia, fatigue neutropenia, vomiting, back pain, fatigue Finn et al, NEJM 2016; Hortobagyi et al, ASCO 2017; Di Leo et al, ESMO 2017 n.r. vs months diarrhea, neutropenia, leukopenia, anemia Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

18 18 Luminal ABC Prof. Harbeck Options after failure of endocrine therapy Does CDK 4/6i work after endocrine pretreatment? Does the use of CDK 4/6i impact further therapies? KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

19 MONARCH2: Primary Endpoint: PFS (ITT) Median PFS abemaciclib + fulvestrant: 16.4 months placebo + fulvestrant: 9.3 months HR (95% CI):.553 (.449,.681) P < PFS benefit confirmed by blinded independent central review (HR:.460; 95% CI:.363,.584; P < ) Sledge et al, oral presentation; JCO 2017

20 MONARCH 1: Conclusions Abemaciclib, a CDK4 & 6 inhibitor, demonstrates single agent activity in heavily pretreated patients with HR+/HER2- MBC ORR of 19.7% (95% CI: 13.3, 27.5; 15% not excluded) Median DoR of 8.6 mos CBR of 42.4%, median PFS of 6.0 mos, median OS of 17.7 mos Safety and toxicity profile of twice daily continuous administration was consistent with previous experience Few patients (7.6%) discontinued treatment due to adverse events Phase III studies of abemaciclib in combination with endocrine therapies are ongoing MONARCH 2: abemaciclib plus fulvestrant in endocrine pre-treated MBC MONARCH 3: abemaciclib plus an NSAI as initial treatment for MBC Presented by: Maura N. Dickler, MD

21 21 Luminal ABC Prof. Harbeck PALOMA Turner et al, SABCS 2016 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

22 22 Luminal ABC Prof. Harbeck PALOMA Turner et al, SABCS 2016 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

23 23 Luminal ABC Prof. Harbeck PALOMA-3 PRO ANALYSIS: GLOBAL QOL RESULTS AT INTERIM ANALYSIS 1 A statistically significant difference was seen in overall change from baseline score for global QoL with palbociclib + fulvestrant compared with placebo + fulvestrant (66.1 [95% CI: ] vs [95% CI: ], respectively; P=0.0313) 1, Global QoL: Baseline and overall scores on treatment by arm 1 Higher global QOL Mean global QoL Score Baseline 66.1 * 63.0 Overall on treatment Palbociclib + fulvestrant Placebo + fulvestrant *P= vs. palbociclib + fulvestrant for overall on-treatment score Data cutoff December used for interim analysis; median follow-up 5.6 months KLINIKUM DER UNIVERSITÄT MÜNCHEN 1. Harbeck N, et al. Presented at the European Cancer Congress 2015; Brustzentrum Vienna, Austria (P004); 2. Harbeck N, et al. Ann Oncol 2016 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe [Published online March ; doi: /annonc/mdw139]

24 Luminal ABC Prof. Harbeck Time to Deterioration* in Pain Scores (QLQ-C30) Median: Palbociclib + Fulvestrant (8 mo) vs Placebo + Fulvestrant (2.8 mo) HR = 0.642: P<.001 Harbeck N, et al. ECC Abstract KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum *Deterioration defined as a 10-point increase from baseline. +Censored. Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

25 BOLERO-2: Final Analysis of Progression-free Survival by (A) Local and (B) Central Assessment HR, hazard ratio; CI, confidence interval; EVE, everolimus; EXE, exemestane; PBO, placebo; mo, months. KLINIKUM DER UNIVERSITÄT MÜNCHEN 25 Luminal ABC Prof. Harbeck Probability of Event, % A 100 B Censoring times EVE+EXE (n/n = 310/485) PBO+EXE (n/n = 200/239) Time, wk Patients at risk EVE + EXE PBO + EXE HR = 0.45 (95% CI, ) Log-rank P <.0001 Kaplan-Meier medians EVE+EXE: 7.8 mo PBO+EXE: 3.2 mo Probability of Event, % Yardley D et al. Adv Ther. 2013; 30(10): Censoring times EVE+EXE (n/n = 188/485) PBO+EXE (n/n = 132/239) Patients at risk EVE + EXE PBO + EXE Brustzentrum Time, wk HR = 0.38 (95% CI, ) Log-rank P <.0001 Kaplan-Meier medians EVE+EXE: 11.0 mo PBO+EXE: 4.1 mo Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

26 Second line (and beyond) efficacy of endocrine + targeted agents 26 Luminal ABC Prof. Harbeck Phase III trial PALOMA 3 (n=521) MONARCH 2 (n=669) KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum BOLERO 2 (n=724) Targeted agent Palbociclib Abemaciclib Everolimus Endocrine agent Fulvestrant Fulvestrant Exemestane PFS 11.2 vs. 4.6 months 16.4 vs. 9.3 months HR (PFS) Most frequent G3/4 side effects neutropenia, leukopenia, anaemia Turner et al. SABCS 2016; Christofanilli et al. 2016; Sledge et al. 2017; Baselga et al diarrhoea, neutropenia, leukopenia, anaemia, nausea, fatigue 10.6 vs. 4.1 months stomatitis, anaemia, dyspnea, hyperglycemia, fatigue, pneumonitis HR, hazard ratio; PFS, progression-free survival Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

27 27 Luminal ABC Prof. Harbeck How do we sequence? How do we decide? What do we need to take into consideration? KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

28 28 Luminal ABC Prof. Harbeck Benefit scales: INTERNATIONAL FRAMEWORKS KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

29 Luminal ABC: How to decide between endocrine monotherapy and combination therapy? 29 Luminal ABC Prof. Harbeck Importance of PFS prolongation Quality of life Side effects Convenience Drug availability Treatment costs KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

30 Survival, % TTD in HRQOL: Both Treatment Arms Combined Statistically significant delay in TTD in HRQOL as assessed by FACT-B and FACT-G total scores was observed in patients who had not progressed vs those who had progressed in ALL patients Time to Deterioration in FACT-B Total Score *Unstratified log-rank. PAL+LET/PBO +LET (n=329) PAL+LET/PBO +LET (n=328) Time to Deterioration in FACT-G Total Score PAL+LET/PBO+ LET (n=329) PAL+LET/PBO+ LET (n=328) Median (95% CI), mo 28.6 (26.3 NE) 19.4 ( ) Median (95% CI), mo 31.3 (24.9 NE) 18.4 ( ) Hazard ratio (95% CI) ( ) Hazard ratio (95% CI) ( ) 1-sided P value* < sided P value* < % 80% 60% 40% 20% 0% Patients at risk: PAL+LET/PBO+LET (Not Progressed) PAL+LET/PBO+LET (Progressed) Not Progressed Progressed 100% Not Progressed Progressed Time to Deterioration, mo Survival, % 80% 60% 40% 20% 0% Patients at risk: PAL+LET/PBO+LET (Not Progressed) PAL+LET/PBO+LET (Progressed) Time to Deterioration, mo Harbeck et al, ABC4 4 2

31 31 Luminal ABC Prof. Harbeck Endocrine monotherapy vs. CDK 4/6i: Which therapy is optimal in what setting? Endocrine therapy CDK4/6i + ET Efficacy (PFS) + ++ Efficacy (OS) + +/- Tolerability ++ + QoL 1 st line QoL > 1 st line + ++ Convenience ++ + Costs ++ + Access ++ + KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

32 Luminal ABC Prof. Harbeck 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. (2008) 1 100% 56% 25% 11% Tacca et al. (2009) 2 100% 68% 43% 23% Bernardo et al. (2010) 3 100% 82% 36% 11% Planchat et al. (2011) 4 100% 76% 56% 37% Current study; Jackisch et al. (2014) 5 100% 70% 46% 27% Jackisch et al, P ,SABCS Dufresne A, et al. Breast Cancer Res Treat 2008, 107:275-9; 2. Tacca O, et al. Cancer Invest 2009, 27:81-5; 3. Bernardo G, et al. Cancer Res 2010, 70(24 Suppl.): 446s, P ; 4. Planchat E, et al. Breast 2011, 20:574-78; 5. Jackisch C, et al. BMC Cancer. 2014, 14:924 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

33 All enrolled ER+ MBC pts n = F-FES CT/PET Harbeck, ESMO 2017 SUV 18F-FES >2 SUV 18F-FES < 2 R 16α-[18F]-fluoro-17β-estradiol (FES) PET tracer for Assessment of Endocrine Responsiveness Endocrine Therapy (Physician choice), until PD ARM A - control Endocrine Therapy until PD ARM B - exp CT or ET + biological agent until PD 18 FDG 18F-FES Homogeneous Heterogeneous A. Gennari ET-FES EU Group 33

34 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

35 35 Luminal ABC Prof. Harbeck Phase IV PRECYCLE Study: Interactive e-health support for oral therapy in MBC HR+/HER2- metastatic breast cancer Inclusion criteria as indicated by drug label/soc (1 st line & > 2nd line) Co-PIs: M. Schmidt (LKP), P. Fasching, D. Lüftner, and N. Harbeck Recruitment start ~ Q KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

36 36 Luminal ABC Prof. Harbeck KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

37 Luminal ABC: How to sequence available options Endocrine therapy (ET) is the therapeutic backbone unless there is life-threatening disease ET alone is (still) a valid option CDK 4/6i + ET are effective in first line and beyond Palbociclib, ribociclib, and abemaciclib are registered > 1 st line (+ AI / fulvestrant) in pre- and postmenopausal patients CDK 4/6i differ regarding side effects, and specific indications; potentially regarding monotherapy activity and CNS penetrance Exemestane and everolimus effective after ET-failure So far, there is no specific biomarker and no OS advantage for any of the endocrine-based options Not a single optimal sequence: Patients need to be informed about all available evidence-based options 37 Luminal ABC Prof. Harbeck KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

38 38 Luminal ABC Prof. Harbeck CDK 4/6i + CDK 4/6i Note: only one line of CDK4/6i is evidence-based so for modified after Harbeck & Gnant, Lancet 2017 KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

39 39 Luminal ABC Prof. Harbeck Luminal ABC: A lot more work to do Proactive side effect management Adherence Management of oral therapies over several lines of therapies Optimal sequence and underlying tumor biology Treatment beyond progression Biomarkers Study participation strongly recommended: Access to novel agents Answer open clinical questions KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

40 EVIDENCE-BASED, PATIENT-ORIENTED BREAST CANCER THERAPY The Digital Diary for Every Patient Annually revised, evidence-based recommendations for diagnosis and treatment AGO (DKG, DGGG) KLINIKUM DER UNIVERSITÄT MÜNCHEN Brustzentrum Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

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42 Lisbon, November 2017 Managing New Toxicities Carlos H. Barrios, M.D. Hospital do Câncer Mãe de Deus Latin American Cooperative Group, LACOG Porto Alegre, Brazil

43 POTENTIAL CONFLICTS OF INTEREST 2017 Clinical Research: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, Abbvie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium Academic Research Projects: CPO, PUCRS, LACOG, GBECAM, INCA-Brazil. Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai. No financial conflicts to declare.

44 Hazard Ratio for Relapse of Breast Cancer Between and (BCCA) Although the pattern of relapse remains similar, there has been a significant improvement in BC relapse-free survival. Outcomes have improved for all BC subtypes, especially HER2-positive and TNBC, with the early spike in disease recurrence markedly decreased. Cossetti R, et al. JCO, 32:2014. Published Ahead of Print on November 24,

45 Real World Data on OS in MBC Year of Diagnosis OS (m) HR+ HER2- (N=9.908) HER2+ (N=2.861) HR- HER2- (N=2.317) 43.7 ( ) 38.6 ( ) 15.1 ( ) 42.0 ( ) 42.3 ( ) 15.1 ( ) 40.9 ( ) 40.1 ( ) 14.7 ( ) 42.0 ( ) 42.3 ( ) 14.0 ( ) 44.5 ( ) 51.1 (46.5-ND) 13.9 ( ) 40.3 (37.8-ND) Not Reached 14.1 ( ) Delaloge S, et al. ASCO 2017.

46 Endocrine Therapy Modulation Improves PFS Compared to Endocrine Monotherapy in the First-Line Setting Study N Median PFS, months HR (95% CI) P Value MONALEESA PALOMA MONARCH PALOMA-3 3 (1st-line subset) BOLERO-2 5 (1st-line subset) Ribociclib + letrozole: 25.3 Letrozole: 16.3 Palbociclib + letrozole: 24.8 Letrozole: 14.5 Abemaciclib + letrozole: NR Letrozole or anastrozole: 14.7 Palbociclib + fulvestrant: 9.5 Fulvestrant: 5.4 Everolimus + exemestane: 11.5 Exemestane: ( ) < ( ) < ( ) < ( ) ( ) Not Reported 1. Hortobagyi G, et al. N Engl J Med. 2016;375(18): ; 2. Finn RS, et al. ASCO Abstract 507 [oral]; 3. Cristofanilli M, et al. Lancet Oncol. 2016;17(4): ; 4. Di Leo A, et al. ESMO 2017; 5. Beck JT, et al. Breast Cancer Res Treat. 2014;143(3):

47 Combination Therapy ALSO Improves PFS Compared With Endocrine Monotherapy After Progression on ET Study N Median PFS, months HR (95% CI) P Value BOLERO PALOMA MONARCH MONALEESA-3 Everolimus + exemestane: Exemestane: 3.2 ( ) Palbociclib + fulvestrant: Fulvestrant: 4.6 ( ) Abemaciclib + fulvestrant: Fulvestrant: 9.2 ( ) Ongoing trial of ribociclib + fulvestrant < < < Results from patients with disease progression on ET for advanced disease Limited evidence exists for treatment sequencing post-cdk4/6 inhibitor 1. (NCT ); 2. Cristofanilli M, et al. Lancet Oncol. 2016;17(4): ; 3. Sledge GW, et al. ASCO Abstract 1000 [oral]; 4. Yardley DA, et al. Adv Ther. 2013;30(10):

48 CDK inhibition Chen P, et al. Mol Cancer Ther; 15(10) October 2016

49 Absolute Risk of Serious Adverse Event 7 randomized trials and 1,332 patients Pooled Absolute Risk All-causality serious AE (838/1332): 16% (95% CI, 12-22) All Grade Neutropenia: 79% (95% CI, 74-82) Grade 3/4 Neutropenia: 57% (95% CI, 50-63) Neutropenic Fever: 1% Infections: 3% Costa R, et al.

50 Absolute Risk of Treatment Discontinuation due to Toxicity 7 randomized trials and 1,332 patients Pooled Absolute Risk Discontinuations: 8% (95% CI, 5-11) Costa R, et al.

51 Myelosuppression with CDK4/6 Inhibitors Abemaciclib Single Agent 1 MONARCH-1 Palbociclib + Ribociclib Single Agent 2 Letrozole 3 PALOMA-2 Ribociclib + Letrozole 4 MONALEESA-2 Palbociclib + Abemaciclib + Fulvestrant Fulvestrant 5 6 PALOMA-3 N = 132 N = 63 N =444 N = 334 N = 19 N = 345 AEs, % All Gr Gr 3/4 All Gr Gr 3/4 All Gr Gr 3 /4 All Gr Gr 3/4 All Gr Gr 3/4 All Gr Gr 3/4 Neutropenia Anemia Thrombocytopenia NA NA Leukopenia Note: Data shown are from multiple studies of CDK inhibitors as monotherapies or in combination with various endocrine therapy partners. Doses and terms for adverse events may vary between trials. Not intended for cross-comparison. PALOMA-2: FN rate 1.6% MONALEESA-2: FN rate 1.5% 1. Dickler MN, et al. ASCO abstract 510 [oral]; 2. Infante. ASCO Abstract 2528 [poster]; 3. Finn R, et al. ASCO Abstract 507 [oral]; 4. Hortobagyi G, et al. N Engl J Med Oct 8 [Epub ahead of print]; 5. Tolaney. SABCS Abstract P [poster]; 6. Turner N, et al. N Engl J Med. 2015;373(3):

52 Proliferating Early Neutrophil Precursors Depend on Cyclin D CDK4/6 Activity Hematopoietic stem cells and early neutrophil precursors depend on cyclin D CDK4/6 activity to enter and traverse the cell cycle and proliferate 1 3 Non-dividing mature neutrophils, show down-regulation of cyclin D, CDK 4/6, and Rb proteins and up-regulation of CDK inhibitor p27kip1 1,2 Cyclin D1 CDK4, CDK6 P130, p-prb p27kip1 p130 = Rb-like protein 2 p-prb = phosphorylated retinoblastoma protein p27kip1 = CDK inhibitor Cell cycle proteins during granulopoiesis 1 Myeloblast Promyelocyte Myelocyte Metamyelocyte Band cell Segmented neutrophil Polymorphonuclear leukocyte 1. Klausen P, et al. J Leukoc Biol. 2004;75: Kumar S, Fillippi M-D. In Gabrilovich D, ed. The Neutrophils. 3 rd ed. London: Imperial College Press; 2013: Roberts PJ, et al. J Natl Cancer Inst. 2012;104: Graphic adapted from: Klausen P, et al. J Leukoc Biol. 2004;75:569 78

53 CDK 4/6 Inhibitor and Chemotherapy-induced Neutropenia are caused by Different Mechanisms Stem cell Mechanism Multipotent progenitor Cells affected by drug treatment Common myeloid progenitor Granulocytemacrophage Myeloblast Promyelocyte Myelocyte Metamyelocyte Neutrophil progenitor Dividing cells CDK 4/6 inhibitor-induced neutropenia 1,2 Cell cycle arrest but no death of proliferating neutrophil precursors Non-dividing cells Chemotherapy-induced neutropenia 2-4 DNA damage and apoptosis of proliferating neutrophil precursors Reversibility Usually with a rapid recovery May have a delayed recovery 1. Johnson SM, et al. J Clin Invest. 2010;120: Sacaan A, Hu W. Pfizer data on file Helleday T, et al. Nat Rev Cancer. 2008;8: Curtin NJ. Nat Rev Cancer. 2012;12:801 17

54 Thrombocytopenia PALOMA-3: Summary of Hematologic Toxicity Time to onset of hematologic toxicity a Neutropenia Anemia 16.0 (13 293) 17.0 (13 147) 0.0 (0 0) 15.0 (15 24) 26.5 (15 92) 39.5 (15 225) Median (range) time to onset from first dose of palbociclib to first episode (days) a Palbociclib + fulvestrant arm only; b By episode by grade analysis. Percentages are based on number of episodes in each subgroup. For multiple time to recovery periods within a subject, average was taken prior to summarizing across subjects Data cutoff March used for final analysis; median follow-up 8.9 months Neutropenia Anemia Thrombocytopenia Grade 3 Grade 4 Duration of each episode a 0.0 (0 0) b 7.0 (1 98) b 7.0 (1 141) b 8.0 (1 15) b 7.0 (1 27) b 7.0 (1 8) b Median (range) duration of each episode (days) Verma S, et al. The Oncologist 2016;0097

55 Management of Neutropenia Spring et al. Published Ahead of Print on July 13, 2017 as /theoncologist

56 CBC Monitoring Palbociclib Prior to the start of each cycle Mid-cycle for the first two cycles Then, as clinically indicated Ribociclib Prior to the start of the first two cycles Mid-cycle for the first two cycles At the start of each subsequent 4 cycles Then, as clinically indicated Spring et al. Published Ahead of Print on July 13, 2017 as /theoncologist

57 Class Effects With CDK4/6 Inhibitors Abemaciclib Single Agent 1 MONARCH-1 Palbociclib + Ribociclib Single Agent 2 Letrozole 3 PALOMA-2 Ribociclib + Letrozole 4 MONALEESA-2 Abemaciclib + Fulvestrant 5 Palbociclib + Fulvestrant 6 PALOMA-3 N = 132 N = 63 N = 444 N = 334 N = 19 N = 345 AEs, % All Gr Gr 3/4 All Gr Gr 3/4 All Gr Gr 3/4 All Gr Gr 3/4 All Gr Gr 3/4 All Gr Gr 3/4 Diarrhea Nausea < Vomiting < Grade 1 Alopecia (Palbociclib): 33% (vs. 16% with letrozole) Note: Data shown are from multiple studies of CDK inhibitors as monotherapies or in combination with various endocrine therapy partners. Doses and terms for adverse events may vary between trials. Not intended for cross-comparison. 1. Dickler MN, et al. ASCO abstract 510 [oral]; 2. Infante. ASCO Abstract 2528 [poster]; 3. Finn R, et al. ASCO Abstract 507 [oral]; 4. Hortobagyi G, et al. N Engl J Med Oct 8 [Epub ahead of print]; 5. Tolaney. SABCS Abstract P [poster]; 6. Turner N, et al. N Engl J Med. 2015;373(3):

58 Other Notable Ribociclib Toxicities (Monaleesa-2) Toxicity Ribociclib and letrozole Letrozole and placebo Increased AST (grade 3/ 4) 9.3 % 1.2 % Increased ALT (grade 3/ 4) 5.7 % 1.2 % QTc prolongation* 3.3 % 0.3 % * > 1 post baseline QTc interval > 480 ms The QT interval should be assessed via ECG at baseline, day 14, the beginning of cycle two, and then as clinically necessary. Median Onset Hepatobiliary: 8.1 weeks from initiation (Repeat LFTs and follow dose reduction guidelines) QTc prolongation: 15 days from initiation (Attention with QTc prolonging drugs) Hortobagyi G, et al. N Engl J Med Oct 8 [Epub ahead of print];

59 Abemaciclib induced G2/3 Diarrhea Pre and Post-Dose Amendment Sledge, G, et al. J Clin Oncol DOI:

60 CDK 4/6 Inhibitors Dosage, Metabolism and Food Interaction Drug Dose Metabolism Food Interaction Palbociclib 125mg (3/1 w) Hepatic: CYP3A/SULT2A1 Take with food Ribociclib 600mg (3/1 w) Hepatic: CYP3A4 Not affected Abemaciclib 200mg (12/12h daily) Hepatic: CYP3A Not affected Spring LM, et al Published Ahead of Print on July 13, 2017 as /theoncologist

61 Drug-drug Interactions Spring LM, et al Published Ahead of Print on July 13, 2017 as /theoncologist

62 Financial Toxicity: Distribution of New Medicines Sales in the last 5 years New medicines cover all new active ingredients marketed for the first time on the world during the period US, EU, Japan: 89,5% Pharmerging: 1.1% ROW: 9.4% Europe Top 5: Germany, France, Italy, Spain and UK Pharmerging: 21 countries Algeria, Argentina, Bangladesh, Brazil, Colombia, Chile, China, Egypt, India, Indonesia, Kazakhstan, Mexico, Nigeria, Pakistan, Philippines, Poland, Russia, Saudi Arabia, South Africa, Turkey and Vietnam Source: IMS Health, MIDAS, May accessed August 2017.

63 Take Home CDK4/6 inhibitors are well-tolerated agents. The most common AE with palbociclib and ribociclib is neutropenia. However, febrile neutropenia is rare. Ribociclib is also associated with hepatobiliary toxicity and QT prolongation, requiring additional monitoring and dose modifications. Gastrointestinal toxicity, particularly diarrhea, and fatigue are more common with abemaciclib. Early recognition, patient education and active communication strategies are required to optimize the therapeutic efficacy associated with these agents.

64 Lisbon, November 2017 Managing New Toxicities Carlos H. Barrios, M.D. Hospital do Câncer Mãe de Deus Latin American Cooperative Group, LACOG Porto Alegre, Brazil

65

66 MECHANISMS OF RESISTANCE TO ENDOCRINE & BIOLOGICAL AGENTS Stephen RD Johnston C4 Conference Professor of Breast Cancer Medicine The Royal Marsden Hospital, Chelsea, London, UK. esmo.org

67 Treatment of HR+ Metastatic Breast Cancer Role of endocrine therapy in HR+ MBC Aromatase Inhibitors have been standard of care as 1 st Line Rx in HR+ MBC Success limited by development of endocrine resistance (after median 14 months 1 st line) Mechanisms of Resistance to Aromatase Inhibitors Loss of ER Ligand-independent activation of ER (ie. ESR1 mutations) & alternative ER associated signalling pathways Attempts to delay endocrine resistance by targeting growth factor / cell cycle pathways Targeted Combination Rx (ie. CDK 4/6i or mtori) to treat established endocrine resistance C4 Conference Understanding Resistance Pathways to Targeted Therapies Retention of ER & adaptive re-wiring of signaling pathways Optimal Sequencing of Endocrine Therapies

68 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 C4 Conference

69 ABC3 guidelines: Postmenopausal pts with ER+/HER2- ABC 1L 2L NO (includes visceral disease) ET is the preferred option AI or tamoxifen or fulvestrant (1A) AI + palbociclib a (1A) AI + everolimus for some women with PD after NSAI (1B) Tamoxifen ± everolimus (2B) Different AI ± everolimus (1A) Fulvestrant ± palbociclib (1A) Tamoxifen ± everolimus (1A) Megestrol acetate or estradiol (1A) a Except for relapse <12 mths from finishing adjuvant AI ABC, advanced breast cancer; AI, aromatase inhibitor; ER, oestrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor-2; NSAI, non-steroidal AI; PD, progressive disease ER+/HER2 ABC Postmenopausal Is the patient in visceral crisis? OR concern/proof of endocrine resistance? Visceral crisis, endocrine resistance or PD YES Chemotherapy C4 Conference Adapted from Cardoso F, et al. Ann Oncol 2017;28:16 33

70 Network of intra-cellular signaling pathways involved in Endocrine Resistance in HR+ BC ER 3 key pillars Cell Cycle PI3K / Akt / mtor C4 Conference Johnston S. J Natl Cancer Inst. 2015;107(10)

71 Mechanisms of Endocrine Resistance & Therapeutic Strategies E2-driven ER E2 Loss of ER E 2 ER Ligand-independent ER activation Alternative ER associated (cross-talk) signalling EGFR / HER2 E 2 ER SERD ESR1 Mutation, ER-Phosphorylation Remove ER C4 Conference PIK3CA / Akt / mtor E2F cell cycle ER Combination Therapy

72 Alteration Percentage Genomic mutations in ER+ advanced breast cancer Genomic alterations in ER+ tumors TP53 PIK3CA CCND1 MCL1 MYC FGFR1 P <.05 ESR1 ERBB2 Primary Metastasis AKT1 NF1 PTEN ESR1 mutations occur in ~20% of endocrine resistant ER positive breast cancer Cluster of mutations in amino acids in ligand-binding domain reported in AI pretreated pts, conferring constitutive activation C4 Conference Zhang Q.X et al. Cancer Res 1997 Li S et al. Cell Reports 2013 Toy W et al. Nat Gen 2013 Robinson DR et al. Nat Gen 2013 Merenbakh-Lamin K et al. Cancer Res 2013 Jeselsohn R et al. Clin Cancer Res 2014

73 ESR1 mutations in SoFEA trial HR+ve Metastatic Breast Cancer with prior sensitivity to NSAI (n = 723) N=161 blood samples available for testing Johnston SR, et al. Lancet Oncol. 2013;14(10): Fulvestrant arms merged for analysis Fulvestrant 250mg + Placebo Fulvestrant 250mg + Anastrozole Exemestane C4 Conference Mutation D538G Y537S E380Q Y537N Y537C S463P L536R Unknown Polyclonal FALSE TRUE

74 ESR1 mutated ESR1 wild type ESR1 wild type C4 Conference Fribbens C, et al. J Clin Onc. 2016;34(25):2961-8

75 Can targeting growth factor receptors in ER+ HER2- MBC delay PFS when added to endocrine therapy? MCF7 MCF7/HER Tumor volume (mm 3 ) De novo Tam-R Tam-S Tam 1 st -line clinical trials in ER+ HER2- MBC: Acquired Tam-R EGFR HER2 + E2 Days TAM S Acq TAM R Osborne et al, JNCI 1994 C4 Conference In 2 small phase II studies, gefitinib + tamoxifen/anastrozole might improve PFS in subset endocrine naïve patients (median PFS 14.6 vs 8.2 months) 1, 2 1. Osborne et al. Clin Can Res. 2011;17: Cristofanilli et al. Clin Can Res. 2010;16:

76 Can targeting growth factor receptors in ER+ HER2- MBC delay PFS when added to endocrine therapy? MINT: PFS Endocrine-therapy naïve AZD mg + anastrozole Median PFS, 10.9 months HR (95% CI vs placebo) 1.37 ( ) P value: AZD mg + anastrozole Median PFS, 13.8 months HR (95% CI vs placebo) 1.16 ( ) P value: Johnston S et al. Br Ca Res Treat. 2016;160:91-9 Placebo + anastrozole Median PFS, 14.0 months EGF30008: PFS Endocrine sensitive* * 6 mo since D/C of tam (33%) or no tam (67%) Median tam duration 5 y; Median time since d/c 3.5 y C4 Conference Johnston S et al. J Clin Oncol. 2009;27:

77 1st Line Trials of Endocrine Rx + Dual Targeting in ER+ HER2+ MBC Event-free Probability (%) Phase II PERTAIN Trial PERT+TRAS+AI TRAS+AI n=129 n=129 Events, n (%) 74 (57) 92 (71) Pertuzumab + Trastuzumab + AI Trastuzumab + AI Median PFS, months % CI [14.1, 27.7] [11.0, 18.6] HR; vs TRAS+AI (95% CI) [0.48, 0.89] P-value Months Rimawi M, et al. SABCS 2016 Proportion Alive and Progression Free Phase III ALTERNATIVE Trial LAP+TRAS+AI TRAS+AI n=120 n=117 Events, n (%) 62 (52) 75 (64) Median PFS, months % CI [8.3, 13.8] [5.5, 8.4] HR; vs TRAS+AI (95% CI) [0.45, 0.88] P-value % concurrent CT 0% concurrent CT C4 Conference LAP+TRAS+Al TRAS+Al Time Since Randomization (Months) Gradishar W, et al. ASCO 2017 (JCO in press)

78 Cyclin Dependent Kinase (CDK) 4/6 in ER+ Breast Cancer The growth of HR+ breast cancer is dependent on Cyclin D1, a direct transcriptional target of ER Cyclin D1 activates CDK 4/6 resulting in G1 S phase transition and entry into the cell cycle 1 Resistance to endocrine therapy is associated with continued dependence on Cyclin D1 & CDK 4/6 CDK1/2 Cyclin A CDK1 Cyclin B G2 S M G1 ERα CDK2 Cyclin E Mitogenic signalling CDK4/6 Cyclin D P P P prb prb E2F E2F S phase transcription program G1/S transition C4 Conference Figure adapted from Asghar, et al. Nat Rev Drug Dis. 2015;14:

79 Selective CDK 4/6 inhibitors IC 50 Palbociclib Ribociclib Abemaciclib CDK nm 10 nm 2 nm CDK6 15 nm 39 nm 5 nm CDK2 >10 µm >50 µm >500 nm CDK9 ND ND 57 nm Kinase selectivity tree : Bigger circles = more inhibition Chen P, et al. Mol Cancer Ther 2016;15: Asghar U, et al. Nat Rev Drug Discov 2015;14:130 46; C4 Conference

80 PFS Benefit in 1 st Line AI + CDK 4/6 inhibitor Phase III Trials PALOMA-2 mpfs (months) Palbociclib letrozole: 24.8 Placebo letrozole: 14.5 Finn R, et al. NEJM. 2016;375(20): MONALEESA-2 Hortobagyi G, et al. NEJM 2016; 375(18): MONARCH-3 C4 Conference Goetz MP, et al. J Clin Oncol DOI: /jco _suppl.tps624

81 PFS Benefit in 2 nd Line Fulvestrant + CDK 4/6 inhibitor Phase III Trails PALOMA-3 MONARCH-2 C4 Conference Turner N, et al. SABCS 2016 (Abstract P ); Sledge GW, et al JCO 2017;35:

82 Role of PI3K / AKT / mtor pathway in Endocrine Resistance Long term estrogen deprivation (LTED) & acquired endocrine resistance: Studies have demonstrated persistence of an active ER pathway 1 LTED can ERα levels & activation of the PI3K/mTOR pathway 2 Hyper-activation of the PI3K/mTOR pathway is a key mediator 3 1. Martin LA, et al. J Biol Chem. 2003;278: ; 2. Santen RJ, et al. Endo-Rel Cancer. 2005;12:S61-S73; 3. Miller TW, et al. J Clin Invest. 2010;120(7): Weigel et al Breast Cancer Res (3):R78. C4 Conference

83 Probability of Event, % Combinations of mtor inhibitors and AIs as 2 nd line or 1 st line therapy for ER+ MBC BOLERO-2 EXE + EVEROL: EXE + placebo: Median PFS (central) 11.0 mo 4.1 mo HR = 0.38 (95% CI: ) Log-rank P value: < % prior endocrine response Time, weeks Baselga J et al, N Engl J Med ; Progression-free survival HORIZON Median PFS LET + TEMSIROL: 9.2 mo LET + placebo: 9.2 mo HR = 0.92 (95% CI: ) 56% no prior Endocrine Rx C4 Conference Time (months) Wolff AC, et al. J Clin Oncol 2013; 31;

84 Treatment of HR+ Metastatic Breast Cancer Role of endocrine therapy in HR+ MBC Aromatase Inhibitors have been standard of care as 1 st Line Rx in HR+ MBC Success limited by development of endocrine resistance (after median 14 months 1 st line) Mechanisms of Endocrine Resistance ESR1 mutations are common (40%) at progression on AI, but can respond to a SERD HER2 over-expression in ER+ MBC predicts resistance to endocrine therapy, and dual HER2 targeting + AI can be an effective non-chemotherapy option Co-targeting growth factor receptors in ER+ HER2- MBC does not prevent endocrine resistance Combination AI + CDK 4/6 inhibitor can delay secondary endocrine resistance C4 Conference Established endocrine resistance should be treated by endocrine + targeted therapy combinations: Fulvestrant + CDK 4/6 inhibitor Exemestane + mtor inhibitor

85 Mechanisms of Resistance to mtor inhibitors in ER+ Br Ca mtor inhibitors ER IGF-1R, EGFR, ERBB2, IGFBPs, IGF, IRS1, nucleus Activating mutations in PIK3CA (fcy 30-40%), Akt (fcy 5-8%) and loss of PTEN (fcy 15-35%) may all drive pathway, and directly activate ER mtori leads to loss of negative feedback loop on IRS-1 with increased IGFR / PI3K signalling mtorc-2 signalling may not be inhibited by everolimus, thus overcoming pathway blockade C4 Conference mtor (via S6K) can phosphorylate ER independent of E2 ligand

86 BOLERO-2: Benefit maintained in patients regardless of gene alterations in PIK3CA or Cell Cycle PIK3CA Mutation Status # PI3K Pathway Activation Cell Cycle Control Genes C4 Conference PIK3CA / cell cycle alterations do not predict response to mtor inhibitors Hortobagyi G et al J Clin. Oncol ;

87 PI3K / TORC / AKT inhibitors in clinical development Alpelisib Taselisib Vistusertib Buparlisib Pictilisib Probability of Progression-free Survival, % BELLE-2 Buparlisib + fulvestrant (n/n=349/576) Placebo + fulvestrant (n/n=435/571) Time (months) Baselga J et al, Lancet Oncol Jul;18(7): FERGI C4 Conference Krop IE. Lancet Oncol Jun;17(6):

88 BELLE-2 (post NSAI): PFS by ctdna PIK3CA Mutant status Probability of Progression-free Survival, % Tissue (WT) Median PFS, months (95% CI) HR (95% CI) ctdna (WT) Median PFS, months (95% CI) HR (95% CI) Buparlisib + Fulvestrant 2.8 ( ) Placebo + Fulvestrant 2.7 ( ) 0.83 ( ); p= BELLE-3 (post 0 Everolimus): PFS by 14 ctdna PIK3CA Mutant status ctdna PIK3CA WT (n=387) Buparlisib + fulvestrant (n/n=124/199) Wild-type Placebo + fulvestrant (n/n=126/188) Time (months) Buparlisib + Fulvestrant 3.9 ( ) Placebo + Fulvestrant 2.7 ( ) 0.73 ( ); p= Time, Months Probability of Progression-free Survival, % Probability of PFS, % Probability of PFS, % Baselga J et al, Lancet Oncol : ctdna PIK3CA mutant (n=200) 6 Mutant Buparlisib + fulvestrant (n/n=48/87) Placebo + fulvestrant (n/n=90/113) Tissue (mutant) Median PFS, months (95% CI) HR (95% CI) 8 10 Buparlisib + Fulvestrant 4.7 ( ) ctdna (mutant) Buparlisib + Fulvestrant Median PFS, months (95% CI) HR (95% CI) ( ) Placebo + Fulvestrant 1.4 ( ) 0.39 ( ); p< Time (months) DiLeo et al. Lancet Oncology 2017 (in press) Placebo + Fulvestrant 1.6 ( ) 0.46 ( ); p<0.001 C4 Conference Time, Months 20 26

89 How effective are subsequent therapies after Palbociclib? PALOMA-3: Median duration on 1 st treatment after progression Most common treatments were everolimus, capecitabine, paclitaxel and exemestane (with or without everolimus) n=142 n=107 n=124 n=88 n=57 n=47 n=44 n=42 Time from first dose to end of study treatment a PCB + FUL 3.7 ( ) PCB + FUL 3.7 ( ) PCB + FUL 4.2 ( ) PCB + FUL 4.0 ( ) PAL + FUL 6.9 ( ) PAL + FUL 6.1 ( ) PAL + FUL 7.6 ( ) PAL + FUL 7.1 ( ) All therapies 5.7 ( ) Chemotherapy 5.9 ( ) ET 4.4 ( ) Targeted therapy 5.0 ( ) Median time (95% CI), months Determined using the Kaplan-Meier method CI, confidence interval; ET, endocrine therapy; FUL, fulvestrant; PAL, palbociclib; PCB, placebo Time from start to end of the immediate follow-up therapy a All therapies 4.3 ( ) Chemotherapy 4.8 ( ) ET 3.4 ( ) Targeted therapy 3.4 ( ) C4 Conference Turner NC, et al. SABCS 2016 (Abstract P )

90 CDK4/6 Resistance: Re-wiring of cell signalling pathways Adaptive network changes make it difficult to identify dominant drivers ER transcriptional activity Up-regulation of PI3K/AKT/mTOR pathway CDK1/2 Cyclin A Adaptive changes in CDK and Cyclin signalling and G2M checkpoints CDK1 Cyclin B M G2 G1 S ERα CDK2 Cyclin E CDK4/6 Cyclin D P P P prb Mitogenic signalling Strategies against CDK4/6 resistance 1. Switch to other CDK4/6i + endocrine therapy 2. Target other cell cycle regulators (CDK1/2, CDK7, Wee-1) 3. Co-targeting other cell signalling pathways (mtor) prb E2F E2F Loss of Rb S phase transcription program G1/S transition Redundancy in CDK function Increased Cyclin D expression C4 Conference Lenihan SABCS 2016; Martin et al, SABCS 2016

91 Median'Z'score'' Median'Z'score'' Median Median Z score Z score Median'Z'score' Median'Z'score' Median Median Z score Z score Median'Z'score' Median'Z'score' Median Median Z score Z score Median'Z'score' Median'Z'score' Median Median Z score Z score sirna kinome identifies G2/M checkpoint proteins as potential therapeutic targets MCF7 991R MCF7'991R' MCF7 991R RET ERBB3, CDK2, CDK7, CHEK1 CDK5 STK11 PIK3CA RET ERBB3, CDK2, CDK7, CHEK1 CDK5 STK11 PIK3CA MCF7'991R' 709'kinases'siRNA' MCF7 LTED 991R 709'kinases'siRNA' T47D'991R'' MCF7 LTED 991R T47D'991R'' CDK4 ERBB3,RET,STK11 CDK2 CDK9 WEE1,PIK3CA CDK4 ERBB3,RET,STK11 CDK2 CDK9 WEE1,PIK3CA CHEK1 CHEK1 709'kinases'siRNA' 709'kinases'siRNA' T47D 991R MCF7'LTED'991R'' T47D 991R STK11 WEE1, RET,PIK3CA MCF7'LTED'991R'' STK11 WEE1, RET,PIK3CA 709'kinases'siRNA' T47D LTED 991R 709'kinases'siRNA' T47D'LTED'991R'' T47D LTED 991R CDK1, RET WEE1, CHEK1 CDK9, PIK3CA T47D'LTED'991R'' CDK1, RET WEE1, CHEK1 CDK9, PIK3CA 709'kinases'siRNA' 709'kinases'siRNA' SELECTED TARGETS SELECTED'TARGETS'' SELECTED CDK4 TARGETS SELECTED'TARGETS'' CDK7 CDK4 CDK9 CDK7 WEE1 CDK9 PIK3CA WEE1 C4 Conference CDK, cyclin-dependent kinase; PI3KCA, phosphoinositide 3-kinase. Martin et al, SABCS 2016

92 Cell lines resistant to CDK4/6 inhibition remain sensitive to mtorc1 inhibition MCF7 991R MCF7 LTED 991R T47D 991R T47D LTED 991R C4 Conference CDK, cyclin-dependent kinase; mtorc, mammalian target of rapamycin complex 1. Martin et al, SABCS 2016