RIBOCICLIB EN PRIMERA LINEA DE TRATAMIENTO. Dra. Elena Aguirre H.U. Miguel Servet

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1 RIBOCICLIB EN PRIMERA LINEA DE TRATAMIENTO Dra. Elena Aguirre H.U. Miguel Servet

INTRODUCTION ADVANCED BREAST CANCER HR+/HER2- YES Consider Chemo VISCERAL CRISIS?

many therapies, HR-+, HER2)- ABC is rarely curable.

cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly transforming this

2 INTRODUCTION ADVANCED BREAST CANCER HR+/HER2- YES Consider Chemo VISCERAL CRISIS? NO Endocrine Therapy X3 Toxicity Progresive disease Despite the availability of many therapies, HR-+, HER2)- ABC is rarely curable. Treatment paradigm: sequencing ET, targeted therapy, and/or chemo The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly transforming this treatment landscape There are currently three CDK4/6 inhibitors approved by FDA: palbociclib, ribociclib, and abemaciclib

once daily on a 3-weeks-on/1-week-off schedule 3 1. Kim S et al. AACR-NCI-EORTC 2013; abstr B264; 2.

3 Ribociclib: An oral, selective CDK4/6 inhibitor Ribociclib is an orally bioavailable, selective CDK4/6 inhibitor 1 Ribociclib demonstrates in vitro and in vivo antitumor activity Ribociclib RP2D is 600 mg once daily on a 3-weeks-on/1-week-off schedule 3 1. Kim S et al. AACR-NCI-EORTC 2013; abstr B264; 2. Rader J et al. Clin Cancer Res 2013;19: ; 3. Infante JR et al. Clin Cancer Res 2016;22:

Mechanism of Action of CDK4/6 Inhibitors CDK4/6 inhibitors act at the G1- to-s checkpoint (controlled by D- type cyclins and CDK4 and CDK6). CDK4/CDK6 are activated by cyclins: phosphorylate prb.

4 Mechanism of Action of CDK4/6 Inhibitors CDK4/6 inhibitors act at the G1- to-s checkpoint (controlled by D- type cyclins and CDK4 and CDK6). CDK4/CDK6 are activated by cyclins: phosphorylate prb. Suspends prb s suppression of the E2F transcription factor Activation cell cycle and divide. In HR+ breast cancer, cyclin D overexpression is common and loss of prb is rare, making the G1-to-S checkpoint an ideal therapeutic target

5 MONALEESA-2 Postmenopausal women with HR+, HER2 ABC No prior therapy for advanced disease N=668 R 1:1 Stratified by the presence/absence of liver and/or lung metastases Ribociclib (600 mg/day) 3-weeks-on/1-week-off + Letrozole (2.5 mg/day) n=334 Placebo + Letrozole (2.5 mg/day) n=334 Primary endpoint PFS (locally assessed per RECIST v1.1) Secondary endpoints OS (key) ORR CBR Safety QoL Tumor assessments performed every 8 weeks for 18 months, then every 12 weeks Final analysis planned after 302 PFS events 93.5% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5% Interim analysis planned after ~70% PFS events Two-look Haybittle Peto stopping criteria: hazard ratio 0.56 and p< At the interim analysis data cut-off date (Jan 29, 2016), 243 PFS events had occurred (80% information fraction) Hortobagyi GN et al. N Engl J Med 2016;375: ; Hortobagyi GN et al. Ann Oncol 2016;27(Suppl 6): abstr LBA 3552 (oral) Hortobagyi GN et al. Ann Oncol

6 Patient demographics and baseline characteristics Characteristic Ribociclib + Letrozole n=334 Placebo + Letrozole n=334 Median age, years (range) 62 (23 91) 63 (29 88) Race, n (%) White 269 (80.5) 280 (83.8) Asian 28 (8.4) 23 (6.9) Black 10 (3.0) 7 (2.1) Other/unknown 27 (8.1) 24 (7.2) ECOG performance status, n (%) (61.4) 202 (60.5) (38.6) 132 (39.5) Metastatic sites, n (%) Visceral disease 197 (59.0) 196 (58.7) Bone-only disease 69 (20.7) 78 (23.4) De novo metastatic disease, n (%) 114 (34.1) 113 (33.8) Disease-free interval, n (%)* 12 months 4 (1.2) 10 (3.0) >12 months 216 (64.7) 210 (62.9) Prior (neo)adjuvant systemic therapy, n (%) Chemotherapy and ET 123 (36.8) 120 (35.9) ET only 52 (15.6) 51 (15.3) Chemotherapy only 23 (6.9) 25 (7.5)

7 Probability of PFS (%) 100 Up-Date Efficacy No. at Risk Ribociclib + Letrozole Placebo + Letrozole 0 Ribociclib Placebo + Letrozole n=334+ Letrozole n=334 Number of events, n (%) 140 (41.9) 205 (61.4) Median PFS, months (95% CI) 25.3 ( ) 16.0 ( ) Hazard ratio (95% CI) ( ) p value 9.63 x Time (Months) Hortobagyi GN et al. ASCO 2017; abstr 1038 (poster) Hortobagyi GN et al. Annals of Oncology, 2018

8 Probability of OS (%) 100 OS data remain immature at 26 months No. at Risk Ribociclib + Letrozole Placebo + Letrozole 0 Ribociclib Placebo + Letrozole n=334+ 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 Time (Months) Hortobagyi GN et al. ASCO 2017; abstr 1038 (poster) Hortobagyi GN et al. Annals of Oncology, 2018

9 Subgroup MONALEESA-2: Efficacy Ribociclib + Letrozole Events n/n Favors Ribociclib + Letrozole Favors Placebo + Letrozole Placebo + Letrozole Hazard ratio 95% CI All patients 140/ / ECOG PS 0 82/ / /129 82/ Age <65 years 82/ / years 58/150 78/ Race Asian 14/28 19/ Non-Asian 121/ / HR status ER+ and PgR+ 109/ / Other 31/65 43/ Liver or lung No 59/152 80/ metastases Yes 81/ / Bone-only disease No 114/ / Yes 26/69 46/ De novo disease No 97/ / Yes 43/114 61/ NSAI and others 15/30 17/ Previous ET TAM and/or EXE 63/ / None 62/158 86/ Previous No 69/ / chemotherapy Yes 71/ / Hazard ratio (95% CI)

11 MONALEESA-2: QoL QoL deterioration Improved pain score

12 MONALEESA-2: Safety Most common Grade 3/4 AE 1 (ribociclib arm): neutropenia Febrile neutropenia 1.5% (no associated treatment discontinuations) Median time to first occurrence of Grade 3 neutropenia 29.0 days All-grade ALT elevations in 16% vs 4% in the ribociclib vs placebo arm Grade 3/4 ALT elevations in 8% and 2% in ribociclib 1% and 0% in the placebo arm 2 All-grade AST elevations in 15% in the ribociclib vs 4% in the placebo Grade 3/4 AST elevations in 5% and 1% in the ribociclib vs 1% and 0% in the placebo AEs led to dose interruptions 68 vs 12.3% and dose reductions 50.6 vs 4.2% 7.5 vs 2.1% discontinued the study drug due to AEs (ribo vs placebo), most common AES leading to discontinuation in both arms were ALT (2.7%) and AST (2.4%) elevations and vomiting (1.5%) In the ribociclib arm, 3% of patients had 1 average post-baseline QTcF interval >480 msec vs <1% in the placebo arm

13 Probability of PFS, % Probability of PFS, % Analyses in patients by age Ribociclib significantly improved PFS in 65 (HR=0.608) and in <65 (HR=0.523) Treatment benefit consistent in both subgroups (interaction test p =0.589) Tolerability was similar in both groups Ribociclib arm, dose reductions due to AEs in 53% and 49% (patients 65 and <65 years old) AEs as the cause of treatment discontinuation in 7% vs 1% and 9% vs 3% in the ribociclib + letrozole vs placebo + letrozole in patients 65 and <65 years old, respectively AE, adverse event; CI, confidence interval; L, letrozole; NR not reached; P, placebo; PFS, progression-free survival; R, ribociclib. 1. Sonke GS et al. ECCO 2017; abstr 2LBA (oral) Time (Months) 100 Age 65 years (n=295) Median PFS, months (95% CI) Hazard ratio (95% CI) Median PFS, months (95% CI) Hazard ratio (95% CI) R + L n=184 NR (NR NR) P + L n= ( ) ( ) R + L n=150 NR (19.3 NR) P + L n= (15.0 NR) ( ) Age <65 years (n=373) Time (Months)

(ribo patients) vs 32.9 months in placebo (hazard ratio=0.65; 95% CI: 0.50 0.

14 First subsequent chemotherapy in the MONALEESA-2 study The most frequent agents used in 1 st subsequent chemo were capecitabine, paclitaxel and cyclophosphamide Median time to chemo was NR (ribo patients) vs 32.9 months in placebo (hazard ratio=0.65; 95% CI: Blackwell KL, et al. San Antonio Breast Cancer Symposium, December , San Antonio, TX, USA. P

MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/nsai + goserelin Pre/perimenopausal women with HR+, HER2 ABC No prior endocrine therapy for advanced disease 1 line of

15 MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/nsai + goserelin Pre/perimenopausal women with HR+, HER2 ABC No prior endocrine therapy for advanced disease 1 line of chemotherapy for advanced disease N=672 Randomization (1:1) Stratified by: Presence/absence of liver/lung metastases Prior chemotherapy for advanced disease Endocrine therapy partner (tamoxifen vs NSAI) Ribociclib (600 mg/day; 3-weeks-on/1- week-off) + tamoxifen/nsai + goserelin* n=335 Placebo + tamoxifen/nsai + goserelin* n=337 Primary endpoint PFS (locally assessed per RECIST v1.1) Secondary endpoints Overall survival (key) Overall response rate Clinical benefit rate Safety Patient-reported outcomes Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter Primary analysis planned after ~329 PFS events 95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm 1,2 ), and a sample size of 660 patients Debu Tripathy. SABCS 2017 Tripathy D. Lancet 2018 NSAI, non-steroidal aromatase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors. *Tamoxifen = 20 mg/day; NSAI: anastrozole = 1 mg/day or letrozole = 2.5 mg/day; goserelin = 3.6 mg every 28 days; PFS by Blinded Independent Review Committee conducted to support the primary endpoint. 1. Klijn JG, et al. J Clin Oncol 2001;19: ; 2. Mourisden H, et al. J Clin Oncol 2001;19:

16 Probability of PFS (%) Primary endpoint: PFS (investigator-assessed) PFS (investigator assessment) Ribociclib + tamoxifen/nsai n=335 Number of events, n (%) Median PFS, months 23.8 (95% CI) (19.2 NR) Hazard ratio (95% CI) ( ) One-sided p value Placebo + tamoxifen/nsai n= (39.1) 187 (55.5) 13.0 ( ) No. at risk Time (months) Ribociclib + tamoxifen/nsai Placebo + tamoxifen/nsai CI, confidence interval; NR, not reached. Goserelin included in all combinations.

17 PFS by endocrine therapy partner (investigator-assessed) PFS (investigator assessment) Ribociclib arm n=87 Tamoxifen Placebo arm n=90 Ribociclib arm n=248 NSAI Placebo arm n=247 Number of events, n Median PFS, months (95% CI) 22.1 ( ) 11.0 ( ) 27.5 (19.1 NR) Hazard ratio (95% CI) ( ) ( ) 13.8 ( ) Goserelin included in all combinations.

Rate (%) Rate (%) Secondary endpoints 1712054696 All patients Patients with measurable disease p=0.00098 p=0.

18 Rate (%) Rate (%) Secondary endpoints All patients Patients with measurable disease p= p= Ribociclib + tamoxifen/nsai Placebo + tamoxifen/nsai The CBR in patients with measurable disease was 79.9% for ribociclib + tamoxifen/nsai vs 67.3% for placebo + tamoxifen/nsai (p= ) Overall survival data were immature at the cut-off date CBR, clinical benefit rate. CBR = complete response + partial response + (stable disease + non-complete response/non-progressive disease 24 weeks). Goserelin included in all combinations. Debu Tripathy. SABCS 2017

19 Hematologic adverse events Regardless of study treatment relationship AEs 5% in either arm, % Ribociclib + tamoxifen/nsai n=335 Placebo + tamoxifen/nsai n=337 All Grade 3 Grade 4 All Grade 3 Grade 4 Neutropenia Leukopenia Anemia Thrombocytopenia Febrile neutropenia in 2.1% of patients in the ribociclib arm vs 0.6% in the placebo arm Goserelin included in all combinations. Debu Tripathy. SABCS 2017

20 Non-hematologic adverse events Regardless of study treatment relationship AEs 20% in either arm, % Ribociclib + tamoxifen/nsai n=335 Placebo + tamoxifen/nsai n=337 All Grade 3 Grade 4 All Grade 3 Grade 4 Hot flush Nausea Arthralgia Fatigue Headache Diarrhea Post-baseline QTcF >480 msec, based on ECG data, occurred in 23 patients (6.9%) in the ribociclib arm vs 4 patients (1.2%) in the placebo arm Post-baseline QTcF >500 msec occurred in 5 patients (1.5%) vs 1 patient (0.3%) Treatment discontinuation due to QT prolongation AEs occurred in 1 patient (0.3%) in the ribociclib arm vs 2 patients (0.6%) in the placebo arm QT prolongation events were not associated with clinical symptoms or arrhythmia ECG, electrocardiogram. Goserelin included in all combinations. Debu Tripathy. SABCS 2017

22 MONALEESA-3: Phase III placebocontrolled study of ribociclib + fulvestrant Presented By Dennis Slamon at 2018 ASCO Annual Meeting

23 PRIMARY ENDPOINT: PFS (investigator) PFS (blinded independent review comitee) Presented By Dennis Slamon at 2018 ASCO Annual Meeting

24 PFS by prior endocrine therapy status Presented By Dennis Slamon at 2018 ASCO Annual Meeting

25 SECONDARY ENDPOINTS: ORR SECONDARY CBR 70,2% VS 62.8% (P = 0.020) OS: immature data Dose intensity: > 90% Neutropenia 70% (G4 <7%) Nausea, fatigue, diarrhea, vomiting G3 <2% (0% G4) QTc > 480ms (5,6 vs 2,5%) G3/4 elevated AST/ALT (6.6 vs 4.8%) Presented By Dennis Slamon at 2018 ASCO Annual Meeting

Efficacy (Prior Chemotherapy) MONALEESA-7 Subgroup Analysis With prior chemotherapy for ABC n=94 Ribociclib arm n=47 Placebo arm n=47 No prior chemotherapy for ABC n=578 Ribociclib arm n=288 Placebo

26 Efficacy (Prior Chemotherapy) MONALEESA-7 Subgroup Analysis With prior chemotherapy for ABC n=94 Ribociclib arm n=47 Placebo arm n=47 No prior chemotherapy for ABC n=578 Ribociclib arm n=288 Placebo arm n=290 Median age, years (range) 44 (25 55) 42 (30 52) 43 (26 58) 45 (29 58) Race, n (%) Asian 10 (21) 19 (40) 89 (31) 80 (28) Caucasian 28 (60) 22 (47) 159 (55) 179 (62) Other* 6 (13) 3 (6) 23 (8) 16 (6) Unknown 3 (6) 3 (6) 17 (6) 15 (5) ECOG performance status, n (%) 0 35 (74) 33 (70) 210 (73) 222 (77) 1 12 (26) 14 (30) 75 (26) 64 (22) Disease-free interval, n (%) De novo disease 18 (38) 19 (40) 118 (41) 115 (40) Non-de novo disease 29 (62) 28 (60) 170 (59) 175 (60) 12 months 8 (17) 6 (13) 15 (5) 7 (2) >12 months 21 (45) 22 (47) 155 (54) 168 (58) CONCLUSIONS: Addition of RIBO to tamoxifen/nsai + goserelin prolonged PFS in premenopausal women with HR+ ABC, irrespective of prior Chemo for advanced disease Hurvitz S, et al. American Society of Clinical Oncology Annual Meeting, June , Chicago, IL, POSTER 1047.

27 Preliminary Results From the Phase 3b CompLEEment-1 Trial At the time of data cut-off, 953 patients (94.5%) were still receiving study treatment: Adverse events were the most common reason for treatment discontinuation (18 patients, 1.8%) Within the 56-day follow-up, 958 patients (95.0%) experienced an AE, with 528 patients (52.4%) experiencing a grade 3/4 event Only 18 patients (1.8%) discontinued due to an AE 7 on-treatment deaths (5 due to serious SAEs) SAEs with a fatal outcome included bradycardia, cardiac disorder, and sepsis The most common overall AEs were neutropenia, nausea, fatigue, and diarrhea The most common grade 3/4 events included neutropenia, leukopenia, increased ALT levels, and increased AST levels De Laurentiis M, et al. American Society of Clinical Oncology; June 1-5, 2018; Chicago, IL, USA. Abstract 1056

28 Maintenance of Health-Related Quality of Life in Elderly Patients Treated in MONALEESA-2 In a subset analysis of MONALEESA-2 a PFS benefit was observed with ribo +LET in 65 years patients [95% CI, ] Similar safety profile (rates of dose interruptions and reductions) Objective: To explore efficacy, safety, and patient-reported HRQoL aged 65 years (Of the 668 enrolled 45% in the ribociclib (n=150/334) and 43% in the placebo (n=145/334) were aged 65 years Howard A. Burris. Presented at the American Society of Clinical Oncology Annual Meeting June 1 5, 2018 Chicago, IL

men No limitations regarding the PFI after adjuvant therapy Fasching PA, et

29 RIBECCA: Results of the First Interim Analysis N: 338 Patients pretreated with 1 line of chemo and/or maximum of 2 lines ET Premenopausal patients and men No limitations regarding the PFI after adjuvant therapy Fasching PA, et al. American Society of Clinical Oncology, June 1 5, 2018, Chicago, IL. Poster 1051

MONALEESA-2 Biomarker Analyses The addition of RIBO: PFS benefit across all gene expression subgroups A trend for >benefit high vs low ESR1 expression, high vs low cell-cycle-control gene expression,

30 MONALEESA-2 Biomarker Analyses The addition of RIBO: PFS benefit across all gene expression subgroups A trend for >benefit high vs low ESR1 expression, high vs low cell-cycle-control gene expression, and low vs high RTK gene expression. The shorter PFSm for placebo + LET in patients with high expression of cellcycle-control genes suggests that high expression in these genes may incur resistance to LET alone Genes implicated preclinically in mechanisms of resistance to CDK4/6 inhibitors require further investigation Hortobagyi GN, et al. American Society of Clinical Oncology, June 1 5, 2018, Chicago, IL. Poster 1022

31 Final conclusions Consistent activity of Ribociclib: FIRST LINE: MONALEESA-2 met its primary endpoint: PFS 25.3 months vs 16.0 Treatment benefit maintained in all pre-specified patient subgroups, including: De novo ABC, Visceral metastases, Bone-only disease, Age 65 years old and <65 years old, Receipt of prior (neo)adjuvant CT or ET, Baseline biomarker status FIRST PREMENOPAUSAL: MONALEESA-7 PFS 23.8 months vs 13.0 months; hazard ratio = 0.553; p= ) Treatment benefit consistent regardless of endocrine partner FIRST and SECOND in combination with Fulvestrant: MONALEESA-3 PFS vs placebo + Fv (HR 0.59): Prolonged PFS was observed with first-line (HR 0.577) and in second-line setting (HR 0,565) Manageable safety profile; neutropenia and leukopenia the most common Grade 3/4 35

Fist/ Second MONALEESA-3 III 2 Ribo + Fv vs placebo + Fv 20.5 vs 12.8 HR: 0.

32 Fist/ Second MONALEESA-3 III 2 Ribo + Fv vs placebo + Fv 20.5 vs 12.8 HR: NR vs st (HR 0.577) 9.1 vs nd (HR 0.565) 40.9 vs 28.7% Pending

First-Line Ribociclib + Letrozole for Postmenopausal Women With HR+, HER2-, Advanced Breast Cancer: First Results From the Phase III MONALEESA-2 Study

First-Line Ribociclib + Letrozole for Postmenopausal Women With HR+, HER2-, Advanced Breast Cancer: First Results From the Phase III MONALEESA-2 Study Abstract LBA1 Hortobagyi GN, Stemmer SM, Burris HA,