Metastatic HR+ Breast Cancer - CDK 4/6 Inhibitors Charting the Path. Sandy Sehdev MD FRCPC

Transcription

1 Metastatic HR+ Breast Cancer - CDK 4/6 Inhibitors Charting the Path Sandy Sehdev MD FRCPC

2 Objectives To understand the approach to the treatment of hormone sensitive metastatic breast cancer and the use of CDK4/6 inhibition role in Rx sequencing benefits and toxicities appropriate patient monitoring

3 Evaluation Were the concepts presented clearly and logically? Do you feel comfortable managing these patients in the clinic?

4 Disclosure: Dr. Sehdev Grants/research support: none Honoraria: AZ and Novartis advisory boards, CAGPO presentation Consulting fees: none Patents: none Other: travel support for this meeting Probono advocacy work uottawa.ca Faculté de médecine Faculty of Medicine

5 Mitigating potential bias Neither Pfizer nor any other industry source has had direct input into the development of content Only generic names will be used, without logos The evidence basis for recommendations will be highlighted uottawa.ca Faculté de médecine Faculty of Medicine

6 Overview Approach to met ER+ disease Background evidence: CDK 4/6 inhibition Mechanism Supportive data : palbociclib / ribociclib / abemaciclib Role in Rx / sequencing Resistance Dosing / adjustments Toxicities uottawa.ca Faculté de médecine Faculty of Medicine

7 Changing Realities Increasing long term survival with metastatic ER+ breast cancer Busier clinics More complex Rx algorithms Sequencing challenges Funding lags data Survivorship challenges living with cancer living with treatments!

8 SERMs Example: Tamoxifen Tablets (mixed agonistic/ antagonistic effects on ER signaling) 1 E2 ER E2 E2 ER ER E2 ER E2 E2 ER ER Direct estrogen-dependent genomic pathway NUCLEUS Indirect estrogen-independent, genomic pathway ERE Src RTKs ER Non- ERE PI3K Akt ERK ER Ras Amphiregulin TGF-alpha TF TF Akt PI3K Src FAK Non-genomic activity E2 E2 ER ER ER ERK? PELP1S rc Rb E2F ER G1 G0 ER Cyclin D1 CDK4/6 CELL CYCLE M CELL MEMBRANE S CYTOPLASM Tamoxifen activates nongenomic ER 2 Enhanced proliferation and tumor growth P P Rb P E2F Cyclin D1 G2

9 AROMATASE INHIBITORS Examples: Exemestane Tablets (steroidal) 1 Anastrozole Tablets (non-steroidal) 2 Letrozole Tablets (non-steroidal) 3 E2 ER E2 E2 ER ER E2 ER E2 E2 ER ER Direct estrogen-dependent genomic pathway NUCLEUS Indirect estrogen-independent, genomic pathway ERE Src RTKs ER Non- ERE PI3K Akt ERK ER Ras Amphiregulin TGF-alpha TF TF Akt PI3K Src FAK Non-genomic activity E2 E2 ER ER ER ERK PELP1S rc Rb E2F ER G1 G0 ER Cyclin D1 CDK4/6 CELL CYCLE M CELL MEMBRANE S CYTOPLASM Enhanced proliferation and tumor growth P P Rb P E2F Cyclin D1 G2

10 SERDs Example: Fulvestrant Injection (competitively antagonizes ER signaling; has no known agonist activity) 1 E2 ER E2 E2 ER ER E2 ER E2 E2 ER ER Direct estrogen-dependent genomic pathway NUCLEUS Indirect estrogen-independent, genomic pathway ERE Src RTKs ER Non- ERE PI3K Akt ERK ER Ras Amphiregulin TGF-alpha TF TF Akt PI3K Src FAK Non-genomic activity E2 E2 ER ER ER ERK PELP1S rc Rb E2F ER G1 G0 ER Cyclin D1 CDK4/6 CELL CYCLE M CELL MEMBRANE S CYTOPLASM Enhanced proliferation and tumor growth P P Rb P E2F Cyclin D1 G2

11 First-Line Endocrine Therapy in HR-positive Advanced Breast Cancer Treatments CBR (%) ORR (%) TTP (mo) PFS (mo) TAM vs Toremifene vs vs 4.9 ANA vs TAM vs vs vs 7.0 LET vs TAM 3 49 vs vs vs 6.0 EXE vs TAM 4 46 vs vs 5.8 FUL vs TAM vs vs 8.3 FACT: FUL + ANA vs ANA vs vs vs 10.2 SWOG S0226: ANA + FUL vs ANA vs 13.5

12 68F Past L breast cancer 1992: LN - Past R breast CA 2004 ER/PR + TAM x 5 yrs Back pain x 2 mo Mets to T6, sacrum, ribs 3 small lung lesions up to 11 mm Lung bx = ER+ Her2 neg

13 Plan: Denosumab 120 mg sc monthly and 1. Letrozole alone 2. Fulvestrant 500 mg monthly 3. Weekly paclitaxel chemo 4. Oral capecitabine chemo 5. LET + palbociclib

14 82F with de novo metastatic breast CA Bone mets - multiple Liver mets - multiple up to 3cm Breast mass in situ - 2 cm ER/PR ++ Her 2 negative Mild dementia Atrial fibrillation, controlled

15 Plan: Denosumab 120 mg sc monthly and 1. Letrozole alone 2. Fulvestrant 500 mg monthly 3. Weekly paclitaxel chemo 4. Oral capecitabine chemo 5. LET + palbociclib

16 Patient Age Menopausal status Comorbidities Performance status, Symptoms Expectations and preferences Toxicities to previous treatments Adherence, compliance Disease Site of metastasis Tumor burden, Pace of Disease Symptomatology and / or need for rapid response Previous endocrine treatment Disease-free interval on adjuvant setting (>12m?) Degree of response to previous ET Duration of response to previous ET *Predictive biomarkers for endocrine therapy in HR+ ABC are not available and developments in this field should be a priority of future research. Therapy Selection: Clinical Factors Agent Mechanism of action Expected toxicities Pharmacological interactions Availability, Access Cost Route of administration Tumor Histological subtype Expression of hormone receptors HER2 amplification Intrinsic subtype Predictive biomarkers* Other issues Availability of clinical research Existing guidelines Financial hardship Social support

17 Fulvestrant (Faslodex ) Estrogen Receptor Dysregulator uottawa.ca Faculté de médecine Faculty of Medicine

18 FALCON: PHASE III STUDY DESIGN Postmenopausal women Locally advanced or metastatic breast cancer ER+ and / or PgR+ HER2- Endocrine therapy-naïve Fulvestrant 500 mg (500 mg IM on Days 0, 14 and 28, then every 28 days) Primary endpoint: PFS a + placebo Secondary endpoints 1:1 OS b Anastrozole 1 mg (daily PO) + placebo Randomised, double-blind, parallel-group, international, multicentre study Follow-up for disease progression and survival ORR CBR DoR, EDoR DoCB, EDoCB HRQoL (FACT-B total and TOI) Safety Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (log-rank test) Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic disease Subgroup analysis of PFS for pre-defined baseline covariates a Assessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; b Interim analysis at the time of PFS analysis EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy Breast; TOI, Trial Outcome Index

19 FALCON Inclusion/Exclusion Criteria Inclusion criteria Exclusion criteria Postmenopausal Any prior endocrine therapy ER+ and/or PgR+ Locally advanced or metastatic disease Prior systemic therapy for breast cancer, other than one line of chemotherapy Radiotherapy completed < 28 days before randomisation 1 line of chemotherapy allowed for breast cancer HER2+ 1 lesion that can be assessed at baseline and suitable for repeated measurement Visceral crisis Clinicaltrials.gov, NCT ; available at: FALCON Clinical Study Protocol, 01 May 2012.

20 FALCON: BASELINE PATIENT CHARACTERISTICS Fulvestrant (N=230) Anastrozole (N=232) Median age, years (range) 64.0 (38 87) 62.0 (36 90) Race, n (%) White 175 (76.1) 174 (75.0) Any prior chemotherapy, n (%) 79 (34.3) 81 (34.9) Advanced disease 36 (15.7) 43 (18.5) Adjuvant / neoadjuvant 35 / 11 (15.2 / 4.8) 27 / 16 (11.6 / 6.9) WHO performance status, n (%) 0 / 1 / / 106 / 7 (50.9 / 46.1 / 3.0) 115 / 105 / 12 (49.6 / 45.3 / 5.2) Receptor status, n (%) ER+ / PgR+ 175 (76.1) 179 (77.2) ER+ / PgR- 44 (19.1) 43 (18.5) ER+ / PgR unknown 10 (4.3) 7 (3.0) ER- / PgR+ 1 (0.4) 3 (1.3) ER- / PgR- 0 0 Overall disease classification, n (%) Locally advanced disease 28 (12.2) 32 (13.8) Metastatic disease 202 (87.8) 200 (86.2) Visceral disease, n (%) 135 (58.7) 119 (51.3) Measurable disease, n (%) 193 (83.9) 196 (84.5)

21 FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE Proportion of patients alive and progression-free HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Without visceral disease Fulvestrant (n=95) Anastrozole (n=113) Proportion of patients alive and progression-free HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months With visceral disease Fulvestrant (n=135) Anastrozole (n=119) Time (months) Time (months) Post hoc interaction test p<0.01 A circle represents a censored observation

22 FALCON: SECONDARY ENDPOINTS Endpoint Fulvestrant (N=230) Anastrozole (N=232) ORR a 46.1% (89 / 193) 44.9% (88 / 196) CBR 78.3% (180 / 230) 74.1% (172 / 232) Odds ratio (95% CI) 1.07 (0.72, 1.61); p=0.729 Odds ratio (95% CI) 1.25 (0.82, 1.93); p=0.305 Median DoR 20.0 months 13.2 months - Median DoCB 22.1 months 19.1 months - EDoR 11.4 months 7.5 months EDoCB 21.9 months 17.5 months Median time to deterioration in FACT-B total score 13.8 months 11.1 months Ratio (95% CI) 1.52 (1.23, 1.89); p<0.001 Ratio (95% CI) 1.26 (1.13, 1.39); p<0.001 HR (95% CI) 0.84 (0.66, 1.07); p=0.159 a In patients with measurable disease at baseline

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24 Targeted Rx: CDK 4/6 Inhibition Palbociclib (Ibrance ), Ribociclib (Kisqali ) approved; abemaciclib (Verzenio ) uottawa.ca Faculté de médecine Faculty of Medicine

25 Combination Therapy: Rationale Growth factor RTK (eg, EGFR, HER2) Cell membrane Idelalisib Buparlisib Everolimus PI3K mtor RAS RAF MEK Dabrafenib Vemurafenib Cobimetinib Trametinib P Cyclin D D CDK4/ CDK6 X Rb E2F Rb P Nucleus AI Fulvestrant Tamoxifen ER Palbociclib Ribociclib Abemaciclib E2F G1-S transition gene expression O Leary B, et al. Nat Rev Clin Oncol. 2016;13:

26 Pl3K/Akt (ER/PR/AR) Wnt/β-catenin NF-κB STATs MAPKs p53 p21 Active tumor suppressor Cyclin D CDK4/6 M G0 E2F Rb p16 G2 S G1 Gene transcription E2F R P P P P Rb Inactive

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28 PALBOCICLIB (IBRANCE ) uottawa.ca Faculté de médecine Faculty of Medicine

29 PALOMA-1 / TRIO 18: First Line Palbociclib and Letrozole in Advanced Breast Cancer Phase 2 Palbociclib Plus Letrozole for First-Line Treatment of ER+ HER2- Advanced Breast Cancer Finn RS, et al. Lancet Oncol 2015;16:25-35

30 Cohort 1 Cohort 2 ER+/HER2 ABC R A N D O M I Z A T I O N a Palbociclib 125 mg/day b + letrozole 2.5 mg/day 1:1 Letrozole 2.5 mg/day ER+/HER2 ABC with CCND1 amplification and/or loss of P16 R A N D O M I Z A T I O N a Palbociclib 125 mg/day b + letrozole 2.5 mg/day 1:1 Letrozole 2.5 mg/day n=66 n=99 Randomized, phase II, open-label trial at 50 centres in 12 countries (NCT ) Key eligibility criteria: inoperable locally recurrent disease, postmenopausal status, no prior therapy for ABC, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.0) or bone-only disease, ECOG PS 1, adequate bone marrow and renal function

31 PFS PFS probability (%) PAL + LET (N=84) LET (N=81) No. of events (%) 41 (49) 59 (73) Median PFS, months (95% CI) HR (95% CI) 20.2 ( ) ( ) P value ( ) Palbociclib + letrozole Letrozole Time (months) No. of patients at risk PAL + LET LET

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33 PALOMA-3: Study Design 1 4 Phase III, double-blind study involving 144 centers in 17 countries (NCT ) HR+, HER2 MBC Pre/perimenopausal a,b or postmenopausal b Progressed on prior endocrine therapy: 2:1 Randomization N=521 c n=347 Palbociclib (125 mg QD; 3 weeks on/1 week off) + fulvestrant d (500 mg IM Q4W) on or within 12 months of completion of adjuvant treatment on or within 1 month after treatment for MBC 1 prior chemotherapy regimen for advanced cancer Stratification: Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs. postmenopausal n=174 Placebo (3 weeks on/1 week off) + fulvestrant d (500 mg IM Q4W)

34 Characteristic Pt Characteristics - 1 Palbociclib + fulvestrant (n=347) ITT population Placebo + fulvestrant (n=174) Median age, years (range) 57 (30 88) 56 (29 80) Self-reported race, n (%) White 252 (73) 133 (76) Asian 74 (21) 31 (18) Black or other 21 (6) 10 (6) ECOG PS, n (%) (59) 116 (67) (41) 58 (33) Menopausal status, n (%) Pre- or perimenopausal 72 (21) 36 (21) Postmenopausal 275 (79) 138 (79) Non-measurable disease, n (%) Bone 75 (22) 36 (21) Others 4 (1) 0 Measurable disease, n (%) Any measurable disease 268 (77) 138 (79) Visceral disease a 206 (59) 105 (60) Lung involvement 100 (29) 45 (26) Liver involvement 127 (37) 81 (47) Peritoneal involvement 2 (1) 1 (1) Brain or pleural involvement, or both 4 (1) 2 (1)

35 Pt Characteristics - 2 ITT population Characteristic Palbociclib + fulvestrant (n=347) Placebo + fulvestrant (n=174) No. of previous lines of endocrine treatment, n (%) (46) 91 (52) (40) 61 (35) 3 47 (14) 22 (13) Purpose of most recent treatment a, n (%) Adjuvant therapy 74 (21) 40 (23) Treatment of advanced or MBC 273 (79) 133 (76) Disease-free interval b, n (%) Data available 233 (67) 123 (71) >24 months 192 (82) 101 (82) months 30 (13) 19 (15) <12 months 11 (5) 3 (2) Previous chemotherapy, n (%) Neoadjuvant or adjuvant therapy only c 139 (40) 74 (43) Treatment of metastatic disease (with or without adjuvant or neoadjuvant) 113 (33) 64 (37)

36 Pt Characteristics - 3 ITT population Palbociclib + fulvestrant (n=347) Placebo + fulvestrant (n=174) Characteristic Previous endocrine therapy, n (%) AI 137 (39) 70 (40) Tamoxifen 51 (15) 23 (13) AI and tamoxifen 159 (46) 81 (47) Previous sensitivity to endocrine therapy a, n (%) Yes 274 (79) 136 (78) No 73 (21) 38 (22) ER or PR status confirmed by central laboratory testing, n (%) ER+ and PR+ Median of distribution 81 (23) 40 (23) <Median of distribution 71 (20) 29 (17) ER+ or PR+ Median of distribution 179 (52) 100 (57) <Median of distribution 165 (48) 90 (52) Central laboratory tested, median H-score (IQR); mean (SD) b, n (%) ER 110 (40 160); 107 (74) 114 (23 150); 99 (72) PR 10 (0 100); 53 (68) 20 (0 100); 51 (62)

37 Time to first dose delay : 64 days (range, ) Average duration of dose delay : 3 days (range, 2 16) Time to first dose interruption : 18 days (range, 1 482) Average duration of interruption for any reason: 6 days (range, 1 20) Time to dose reduction ( ): 57 days (range, ) Time to dose reduction (125 75): 36 days (range, 29 85) Time to dose reduction ( ): 34 days (range, ) Time to dose reduction from (125 75): 120 days (range, ) Delays and Interruptions 1st dose reduction 1st dose reduction; 2 dose reductions (n=22); 0,06 Percent 1st dose reduction; Dose Delay (n=123 ); 0,36 1st dose reduction; Dose Interruption (n=187 ) ; 0,54 1st dose reduction; 1 dose reduction (n=95); 0,28

38 PFS: Central Review PFS probability (%) Palbociclib + fulvestrant Placebo + fulvestrant PAL + FUL (n=147) PBO + FUL (n=64) Median PFS, months (95% CI) NE 3.8 ( ) HR (95% CI) 0.37 ( ) P value < Time (months)

39 PFS - subgroups

40 PFS - subgroups

41 Magnitude of ER Tumour hormone receptor expression was quantified by the central laboratory in 250 patients in the palbociclib + fulvestrant group and 130 patients in the placebo + fulvestrant group around 60% of patients in each group provided metastatic tissue samples The level of hormone receptor expression did not influence the magnitude of PFS benefit from palbociclib (sub premium interaction P=0.32 for ER and P=0.54 for PR)

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43 PALMOMA-2: First Line Palbociclib and Letrozole in Advanced Breast Cancer Phase III Richard S. Finn, Miguel Martin, Hope S. Rugo, Stephen Jones, Seock-Ah Im, Karen Gelmon, Nadia Harbeck, Oleg N. Lipatov, Janice M. Walshe, Stacy Moulder, Eric Gauthier, Dongrui R. Lu, Sophia Randolph, Véronique Diéras, Dennis J. Slamon N Engl J Med 2016 Nov 17;375(20):

44 PALOMA-2: Phase III Study Design in Postmenopausal Patients with ER+, HER2 Advanced Breast Cancer Phase III, randomized, double-blind trial at 186 centres in 17 countries Treatment continued until objective disease progression, unacceptable toxicity, or withdrawal of consent. Crossover was not allowed Palbociclib/placebo dose reductions were allowed per protocol. Letrozole dose reductions were not permitted Postmenopausal ER+, HER2 advanced breast cancer No prior systemic treatment for advanced disease Prior (neo)adjuvant treatment with anastrozole or letrozole was allowed if the disease-free interval was 12 months from completion of therapy Measurable disease according to RECIST v1.1 or bone-only disease ECOG PS 0 2 Adequate organ function No advanced, symptomatic visceral spread at risk of short-term life-threatening complications N=666 a 2:1 RANDOMIZATION Palbociclib (125 mg QD, 3/1 schedule b ) + letrozole (2.5 mg QD) Placebo (3/1 schedule) + letrozole (2.5 mg QD)

45 PALOMA-2: Demographics and Baseline Characteristics (ITT Population) Age, n (%) Palbociclib + letrozole (N=444) Placebo + letrozole (N=222) Median (range) 62 (30 89) 61 (28 88) <65 years 263 (59.2) 141 (63.5) 65 years 181 (40.8) 81 (36.5) Race, n (%) White 344 (77.5) 172 (77.5) Asian 65 (14.6) 30 (13.5) Black 8 (1.8) 3 (1.4) Other 27 (6.1) 17 (7.7) ECOG PS, n (%) (57.9) 102 (45.9) (40.1) 117 (52.7) 2 9 (2.0) 3 (1.4) Disease site, n (%) Visceral a 214 (48.2) 110 (49.5) Non-visceral 230 (51.8) 112 (50.5) Bone-only 103 (23.2) 48 (21.6) No. of disease sites (31.1) 66 (29.7) (26.4) 52 (23.4) (25.2) 61 (27.5) 4 77 (17.3) 43 (19.4) Disease-free interval, b n (%) Newly metastatic disease 167 (37.6) 81 (36.5) 12 months 99 (22.3) 48 (21.6) >12 months 178 (40.1) 93 (41.9)

46 PALOMA-2: Demographics and Baseline Characteristics (ITT Population) Disease stage at initial diagnosis, n (%) Palbociclib + letrozole (N=444) Placebo + letrozole (N=222) I 51 (11.5) 30 (13.5) II 137 (30.9) 68 (30.6) III 72 (16.2) 39 (17.6) IV 138 (31.1) 72 (32.4) Unknown 36 (8.1) 12 (5.4) Other or data missing a 10 (2.3) 1 (0.5) Recurrence type, n (%) Locoregional 2 (0.5) 2 (0.9) Local 6 (1.4) 3 (1.4) Regional 3 (0.7) 1 (0.5) Distant 294 (66.2) 145 (65.3) Newly diagnosed 139 (31.3) 71 (32.0) Prior adjuvant or neoadjuvant therapy, n (%) Chemotherapy 213 (48.0) 109 (49.1) Neoadjuvant 54 (12.2) 32 (14.4) Adjuvant 180 (40.5) 89 (40.1) Adjuvant hormonal therapy b 249 (56.1) 126 (56.8) Tamoxifen 209 (47.1) 98 (44.1) Anastrozole 56 (12.6) 29 (13.1) Letrozole 36 (8.1) 16 (7.2) Exemestant 30 (6.8) 13 (5.9) Goserelin 5 (1.1) 6 (2.7) Toremifene 7 (1.6) 1 (0.5) Other 3 (0.7) 4 (1.8)

47 PFS: Central Review PFS probability (%) Median (95% CI) PFS 19.3 months ( ) HR 0.65 (95% CI 0.51, 0.84) 2-sided P=0.001 Palbociclib + letrozole (n=444) Median (95% CI) PFS 30.5 months (27.4 NE) Placebo + letrozole (n=222) Time from randomization (months) Number of patients at risk PAL + LET PCB + LET

48 PFS: Subgroups Subgroup Palbociclib Letrozole, n (%) Placebo Letrozole, n (%) HR (95% CI) All randomized patients 444 (100) 222 (100) 0.58 ( ) Age Race Site of metastatic disease at baseline Prior hormonal therapy Disease-free interval Region <65 years 65 years White Asian Visceral a Non-visceral Yes No ECOG performance status 0 1/2 Bone-only disease at baseline Measurable disease Prior chemotherapy Most recent therapy Number of disease sites Histopathological classification Newly metastatic disease 12 months >12 months North America Europe Asia/Pacific Yes No Yes No Yes No Aromatase inhibitor Antiestrogen 1 2 Ductal carcinoma Lobular carcinoma 263 (59.2) 181 (40.8) 344 (77.5) 65 (14.6) 214 (48.2) 230 (51.8) 249 (56.1) 195 (43.9) 167 (37.6) 99 (22.3) 178 (40.1) 168 (37.8) 212 (47.7) 64 (14.4) 257 (57.9) 187 (42.1) 103 (23.2) 341 (76.8) 338 (76.1) 106 (23.9) 213 (48.0) 231 (52.0) 91 (20.5) 154 (34.7) 138 (31.1) 306 (68.9) 356 (80.2) 68 (15.3) 141 (63.5) 81 (36.5) 172 (77.5) 30 (13.5) 110 (49.5) 112 (50.5) 126 (56.8) 96 (43.2) 81 (36.5) 48 (21.6) 93 (41.9) 99 (44.6) 95 (42.8) 28 (12.6) 102 (45.9) 120 (54.1) 48 (21.6) 174 (78.4) 171 (77.0) 51 (23.0) 109 (49.1) 113 (50.9) 44 (19.8) 75 (33.8) 66 (29.7) 156 (70.3) 184 (82.9) 30 (13.5) 0.57 ( ) 0.57 ( ) 0.58 ( ) 0.48 ( ) 0.63 ( ) 0.50 ( ) 0.53 ( ) 0.63 ( ) 0.67 ( ) 0.50 ( ) 0.52 ( ) 0.61 ( ) 0.57 ( ) 0.49 ( ) 0.65 ( ) 0.53 ( ) 0.36 ( ) 0.65 ( ) 0.66 ( ) 0.35 ( ) 0.53 ( ) 0.61 ( ) 0.55 ( ) 0.56 ( ) 0.51 ( ) 0.61 ( ) 0.59 ( ) 0.46 ( ) In favor of PAL + LET In favor of PCB + LET

49 PALOMA-2: Overall Response (ITT population) All randomized patients, n ORR, a % (95% CI) CBR, b % (95% CI) Median DoR, months Patients with measurable disease ORR, a % (95% CI) CBR, b % (95% CI) Median DoR, months Palbociclib + letrozole (N=444) Placebo + letrozole (N=222) ( ) 84.9 ( ) 22.5 ( ) 34.7 ( ) 70.3 ( ) 16.8 c ( ) ( ) 84.3 ( ) 22.5 ( ) 44.4 ( ) 70.8 ( ) 16.8 ( ) Odds ratio (95% CI) 1.40 ( ) 2.39 ( ) NR 1.55 ( ) 2.23 ( ) NR 2-sided P value (exact) 0.06 < NR 0.03 <0.001 NR

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51 PALOMA-2: All-causality Hematological AEs Occurring in 15% of Patients in Either Arm (As-treated Population) Palbociclib + letrozole (N=444) Placebo + letrozole (N=222) Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4 Any AE, % Neutropenia a Leukopenia Anemia a Thrombocytopenia a

52 Non Hematological AEs (>15%) Palbociclib + letrozole (N=444) Placebo + letrozole (N=222) Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any AE (%) Fatigue Nausea Arthralgia Alopecia a Diarrhea Cough Back pain Headache Hot flush Constipation Rash b Asthenia Vomiting Pain in extremity Stomatitis

53 Quality of Life on Rx

54 A different balance of CDK4 vs. CDK6 may contribute to differential toxicities The unique role of CDK6, rather than CDK4, in hematologic cells indicates that such cells could be more sensitive to CDK6 inhibition vs. CDK4 inhibition Abemaciclib has a different balance of selectivity for CDK4 vs. CDK6 CDK4/Cyclin D1 Ki [ATP] CDK6/Cyclin D3 Ki [ATP] Abemaciclib Palbociclib 0.6 nm 2.9 nm 14X 1.4X 8.2 nm 4.0 nm CDK4>CDK6 CDK4 CDK6 Differential inhibition of CDK4 vs. CDK6 may contribute to: Different toxicological profile vs. other CDK4&6 inhibitors Lower neutropenia Continuous dosing Facilitating sustained target inhibition 1. Scheicher et al. Blood, 2015; 125(1), Laurentix E et al Stem Cell 2015; 16: Torres et al.. Poster presented at AACR Abstract 310

55 POST EVEROLIMUS

56 Post EVEROLIMUS PFS 2.9 mo PALOMA-3 PFS 9.5 mo

57 RIBOCICLIB (Kisqali ) uottawa.ca Faculté de médecine Faculty of Medicine

58 MONALEESA-2: Ribociclib + Letrozole as First-Line Therapy Prolonged PFS in Patients With HR+, HER2 ABC N = 668 Postmenopausal HR+, HER2 ABC No prior therapy for advanced disease Stratification: Presence/absence of liver and/or lung metastases R 1:1 Ribociclib + Letrozole Placebo + Letrozole Endpoints Primary: PFS Secondary: OS ORR CBR ECOG PS deterioration Safety QoL

59 Published on October 8, Hortobagyi G, et al. NEJM, 2016 DOI: /NEJMoa MONALEESA-2: Patient Characteristics

60 MONALEESA-2 ASCO 2017 Update

61 MONALEESA-2 - Subgroups

62 MONALEESA-2:OS Data Immature 100 Probability of OS (%) Ribociclib + Letrozole n=334 Placebo + Letrozole n=334 Number of events, n (%) 50 (15.0) 66 (19.8) Median OS, months (95% CI) NR (NR NR) 33.0 (33.0 NR) Hazard ratio (95% CI) ( ) p value No. at Risk Ribociclib + Letrozole Placebo + Letrozole Time (Months)

63 MONALEESA-2: Duration of Response

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65 MONALEESA-7 First-Line Therapy With Ribociclib + ET in Premenopausal Women N = 672 Pre/perimenopausal women with HR+, HER2 ABC No prior endocrine therapy for advanced disease 1 line of CT for advanced disease RIBO a + TAM/NSAI + GOS PBO + TAM/NSAI + GOS Primary endpoint: PFS Secondary endpoints: OS, CBR, ORR, safety, TTR, DOR, HRQoL Tripathy D, et al. SABCS Abstract GS2-05 [oral presentation].

66 PFS: Central Review

67 Response Rates

68 Toxicity

69 Toxicity

70 Kaplan-Meier Plot of Progression-free Survival in Patients With Visceral Metastases Probability of PFS (%) Ribociclib + Letrozole n=197 Placebo + Letrozole n=196 Number of events, n(%) 58 (29.4) 97 (49.5) Median PFS, months (95% CI) NR (19.3 NR) 13.0 ( ) Hazard ratio (95% CI) ( ) Ribociclib + Letrozole Placebo + Letrozole No. of patients still at risk Time (months) Ribociclib + Letrozole Placebo + Letrozole Mod. Burris H et al. SABCS 2016, Poster Session 4 Treatment: Advanced Therapy Targeted, Abstract No. P

71 ABEMACICLIB uottawa.ca Faculté de médecine Faculty of Medicine

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73 Monarch-2: Abemaciclib (CDK4/6 inhibitor) + fulvestrant vs. placebo+fulvestrant ER+, HER2- mbc - Postmenopausal women with HR+ HER2-, metastatic BC - Resistant to or discontinued AIs, anti-estrogens, chemo/radio/immunotherapy - Patients who received previous CDK4/6 inhibitors are excluded. - Phase 3 - N=630 Randomization 2:1 Abemaciclib (150 mg once/12hrs in 28d cycle)+ Fulvestrant (500mg on day 1 + day 15 in cycle 1 then Day 1 of cycle 2 and beyond) Placebo (once/12hrs in 28d cycle)+ Fulvestrant (500mg on day 1 + day 15 in cycle 1 then Day 1 of cycle 2 and beyond) Primary endpoint: PFS Secondary endpoint: OS, ORR, DoR, DCR, CBR, PK

74 PFS: Central Review

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83 Are we changing practice or outcomes?

84 Targeted Rx: PI3K Inhibitors Buparlisib, Apelisib (SOLAR-1), Taselisib (SANDPIPER) uottawa.ca Faculté de médecine Faculty of Medicine

85 ESR1 Mutations and Resistance Mechanisms Frequency, relevance, effective strategies uottawa.ca Faculté de médecine Faculty of Medicine

86 Endocrine therapy resistance may be de novo or acquired 1 Only 30% of patients with metastatic disease have objective regression of tumor with initial endocrine treatment 1 The majority of patients with advanced or metastatic ER-positive disease will acquire resistance within 2-3 years of endocrine therapy 2 Almost all patients with MBC and as many as 40% of patients receiving adjuvant tamoxifen eventually relapse and die from their disease 3 Patients with HR+ MBC are often treated with multiple rounds of hormonal therapy 4 The median PFS for MBC patients treated with 1 st line hormonal therapy is The response rate for MBC patients to 2 nd line hormonal therapy is ~20% ~6-12 MONTHS 4 and declines as more therapy lines are added 4

87 ESR1 mutation is emerging as an important mechanism for acquired resistance 1,2 ESR1 mutations are uncommon in treatment-naïve primary tumours, but highly enriched in endocrine resistant HR+ MBC 2,3 Circulating tumor DNA (ctdna) can be analyzed to detect the presence of mutations in the plasma of MBC patients 4 Genetic alteration in primary versus metastatic breast cancer % Rate of ESR1 mutations in patients with metastatic ER+ endocrine-resistant breast cancer 5 Adapted from Jeselsohn 2014

88 Functional and structural analysis has revealed aberrant characteristics of ER mutants: Exhibits enhanced estrogen independent transcriptional activity 1,2 Mutant ERα Confers cell proliferation advantage over WT ER under estrogen deprivation 3 Varying degrees of resistance to endocrine therapies 3,4 E2 ER ER E2 E2 ER E2 ER E2 E2 ER ER Direct estrogen-dependent genomic pathway NUCLEUS Indirect estrogen-independent, genomic pathway ERE Src RTKs ER Non- ERE PI3K Akt ERK ER Ras Amphiregulin TGF-alpha TF TF Akt PI3K Src FAK Non-genomic activity E2 E2 ER ER ER ERK PELP1 Src Rb E2F ER G1 G0 ER Cyclin D1 CDK4/6 CELL CYCLE M CELL MEMBRANE CYTOPLASM Enhanced proliferation and tumor growth P P Rb P E2F S Cyclin D1 G2

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90 ESR1 Mutation Frequency Across 3 Trials Trial Experimental Comparator Patient population Patients with tumors with at least 1 ESR1 mutation at baseline* PALOMA-3 2,3 Fulvestrant + Palbociclib (n=347) Fulvestrant + Placebo (n=174) HR+, HER2 advanced breast cancer; pre-/peri- or postmenopausal; progressed on prior endocrine therapy; 1 prior chemotherapy regimen for advanced cancer (n=521) 25% (91/360) FERGI 1 Fulvestrant + Pictilisib Fulvestrant + Placebo Postmenopausal women aged 18 years with estrogen receptor +, HER2-negative breast cancer relapsed during or 6 months of AI in the adjuvant setting, or with progression during treatment in the metastatic setting (n=168) 37% (57/153) SoFEA 2 Fulvestrant-containing regimen (n = 474) Exemestane (n = 249) HR+ advanced breast cancer; post-menopausal; Prior sensitivity to AIs (n=723) 39% (63/161) Baseline ESR1 mutations across these 3 trials ranged from 25% to 39%

91 Royal Marsden Study Patients with ESR1 mutations had a significantly shorter PFS on subsequent AI-based therapy ESR1 Mutations Predict Lack of Sensitivity to Subsequent AI Therapy PFS on AI Therapy Progression-Free Survival PFS on Subsequent AI-based Therapy HR, 3.1; 95% CI, p= Years

92 At baseline, 25% of the patient population had an ESR1 mutation ESR1 mutated (n=91) PALOMA-3: 2 nd -line Efficacy Associated with Baseline Incidence of ESR1 Mutation ESR1 wild type (n=269) Fulvestrant + palbociclib improved PFS compared with fulvestrant alone in both ESR1 mutant and wild type patients

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94 Presented By Ingrid Mayer at 2017 ASCO Annual Meeting Presented By Ingrid Mayer at 2017 ASCO Annual Meeting

95 Endocrine Therapy Modulation: 1 ST LINE PFS Study N Median PFS, months HR (95% CI) P Value MONALEESA PALOMA MONARCH Ribociclib + letrozole: 25.3 Letrozole: 16.3 Palbociclib + letrozole: 24.8 Letrozole: 14.5 Abemaciclib + letrozole: NR Letrozole or anastrozole: ( ) < ( ) < ( ) < PALOMA-3 3 (1st-line subset) 114 Palbociclib + fulvestrant: 9.5 Fulvestrant: ( ) 0.02 BOLERO-2 5 (1st-line subset) 137 Everolimus + exemestane: 11.5 Exemestane: ( ) Not Reported

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99 NCCN GUIDELINE

100 Dosing and Adjustments uottawa.ca Faculté de médecine Faculty of Medicine

101 PALBOCICLIB

102 PALBOCICLIB

103 RIBOCICLIB

104 ECG BASELINE DAY 14 PRE CYCLE 2 RIBOCICLIB CONSIDER BASELINE ECG PRE ALL CDK 4/6 INHIBITORS

105 RIBOCICLIB

106 Future Advances Around the corner uottawa.ca Faculté de médecine Faculty of Medicine

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112 LETROZOLE + PALBOCICLIB 68F Past L breast cancer 1992 Past R breast CA 2004 ER/PR + Back pain x 2 mo Mets to T6, sacrum, ribs 3 small lung lesions up to 11 mm Lung bx = ER+ Her2 neg

113 LETROZOLE + PALBOCICLIB 82F with de novo metastatic breast CA Bone mets - multiple Liver mets - multiple up to 3cm Breast mass in situ - 2 cm ER/PR ++ Her 2 negative Mild dementia Atrial fibrillation, controlled

114 ISSUES: rebiopsy on progression value of genomic sequencing? sequencing, funding? Rx beyond progression? OS benefit?

115 THANK YOU Questions, Discussion