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, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Xuan F, Souami F, Miller M, Germa C, O Shaughnessy J
The Role of CDK4/6 in HR+ Breast Cancer M ER/PgR NF-kB Pl3K/mTOR MAPKs STATs Wnt/β-catenin PR b G2 G0 G1 Cyclin DCDK4/6 E2F Restriction point S Ribociclib Rb E2F p53 p21 p16 Complexed, inactive E2F Gene (tumor suppressor) transcription Rb binding inactivates E2F, which regulates genes important for transition through the G1/S cell cycle restriction point 1,2 Phosphorylation of Rb by CDK4/6 leads to dissociation of E2F from Rb and cell cycle progression 1,2 Increased CDK4/6 activity driven by perturbations of other pathways is associated with endocrine therapy resistance 1,2 Ribociclib (LEE011) is an orally bioavailable, selective CDK4/6 inhibitor 3 CDK, cyclin-dependent kinase; Rb, retinoblastoma. 1. Hosford S, et al. Pharmgenomics Pers Med. 2014;7:203-215. 2. Thangavel C, et al. Endocr Relat Cancer. 2011;18(3):333-345. 3. Infante JR, et al. Clin Cancer Res. 2016 Apr 19. [Epub ahead of print].
Activity of Ribociclib + Letrozole in Early Studies Inhibition of tumor growth in ER+ breast cancer xenograft model HBX34 1 Patients with ER+/HER2 advanced breast cancer; first-line ribociclib + letrozole group 2 (n = 24) Tumor Volume (mm³) ± SEM 1000 800 600 400 200 0 Vehicle Ribociclib 75 mg/kg QD Letrozole 2.5 mg/kg QD Letrozole + ribociclib 0 10 20 30 40 50 60 Time (days) Sum of Longest Diameters % Change From Baseline 60 40 20 0-20 -40-60 -80-100 CR PR PR PR PR PR PR SD SD SD SD SD SD PR PR PR PR SD SD SD SD PD PDPD CR PR SD PD CR, complete response; PD, progressive disease; PR, partial response; QD, once daily; SD, stable disease. 1. O Brien NA, et al. Presented at: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, California. Abstract 4756. 2. Juric D, et al. J Clin Oncol. 2016;34(Suppl): Abstract 568. 3
MONALEESA-2: A Phase III, Double-Blind, Placebo-Controlled Study of Ribociclib + Letrozole Postmenopausal women with HR+/HER2 advanced breast cancer No prior therapy for advanced disease N = 668 Randomization (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) Placebo + Letrozole (2.5 mg/day) Primary endpoint PFS (locally assessed per RECIST v1.1) Secondary endpoints Overall survival (key) Overall response rate Clinical benefit rate Safety Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter 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<.0000129
Accrual and Analysis Details 668 patients randomized between January 24, 2014 and March 24, 2015 Data cut-off date: January 29, 2016 Median follow up: 15.3 months Ribociclib + Letrozole N = 334 Full analysis set Placebo + Letrozole N = 334 Received treatment Safety set Received treatment n = 330 PFS events n = 93 PFS events n = 150 PFS crossed prespecified boundary at interim analysis
Key Enrollment Criteria Key Inclusion Criteria Key Exclusion Criteria Postmenopausal women with locally advanced or metastatic breast cancer Histologically/cytologically confirmed ER+ and/or PgR+ disease Any prior systemic therapy for advanced/metastatic breast cancer, including endocrine therapy or chemotherapy Inflammatory breast cancer HER2-negative disease confirmed by in situ hybridization or IHC Active cardiac disease or history of cardiac dysfunction 1 measurable lesion (RECIST 1.1) or 1 predominantly lytic bone lesion QTcF >450 msec ECOG performance status 1 ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; IHC, immunohistochemistry; PgR, progresterone receptor; QTcF, Fridericia s corrected QT interval
Patient Demographics and Baseline Characteristics Characteristic Ribociclib + Letrozole Placebo + Letrozole Median age, years (range) 62 (23 91) 63 (29 88) Race, n (%) Caucasian 269 (81) 280 (84) 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 (%) 0 205 (61) 202 (60) 1 129 (39) 132 (40) Metastatic sites, n (%) Visceral disease 197 (59) 196 (59) Bone-only disease 69 (21) 78 (23) De novo metastatic disease, n (%) 114 (34) 113 (34) Disease-free interval since end of (neo)adjuvant therapy, n (%)* 12 months 4 (1.2) 10 (3.0) >12 months 216 (65) 210 (63) Prior (neo)adjuvant systemic therapy, n (%) Chemotherapy and endocrine therapy 123 (37) 120 (36) Endocrine therapy only 52 (16) 51 (15) Chemotherapy only 23 (6.9) 25 (7.5) *1 patient in the placebo + letrozole arm had an unknown disease-free interval
Patient Disposition Ribociclib + Letrozole Placebo + Letrozole Characteristic Treatment ongoing, n (%) 195 (58) 154 (46) Treatment discontinued, n (%) 139 (42) 180 (54) Primary reason for treatment discontinuation, n (%) Disease progression 87 (26) 146 (44) Adverse events 25 (7.5) 7 (2.1) Patient decision 12 (3.6) 13 (3.9) Physician decision 10 (3.0) 13 (3.9) Protocol deviation 3 (0.9) 1 (0.3) Death 2* (0.6) 0 Most common adverse events leading to treatment discontinuation of both ribociclib and letrozole were ALT (2.7%) and AST (2.4%) elevations and vomiting (1.5%) ALT, alanine aminotransferase; AST, aspartate aminotransferase *1 sudden death in the context of grade 2 QTcF prolongation and grade 3 hypokalemia; 1 death of unknown cause
Primary Endpoint Was Met Early 100 Probability of Progression-free Survival (%) 80 60 40 20 0 PFS (Investigator Assessment) Ribociclib + Let Placebo + Let Number of events, n (%) 93 (28) 150 (45) Median PFS, months (95% CI) NR (19.3 NR) 14.7 (13.0 16.5) Hazard ratio (95% CI) 0.556 (0.429 0.720) One-sided P value.00000329 0 4 8 12 16 20 24 No. of patients at risk Time (months) Ribociclib + Let 334 294 277 257 240 226 164 119 68 20 6 1 0 Placebo + Let 334 279 264 237 217 192 143 88 44 23 5 0 0 PFS results by independent central review: Hazard ratio 0.592 (95% CI: 0.412-0.852; P =.002) Let, letrozole; NR, not reached
Subgroup Analysis: Combination Effective Across Subgroups NSAI, non-steroidal aromatase inhibitor *Excludes patients who had received tamoxifen 0.1 1 10
Secondary Endpoints Overall survival data were immature at the cut-off date for interim analysis All patients Patients with measurable disease Rate (%) 100 80 60 40 P =.000155 41 28 Rate (%) 100 80 60 40 P =.00028 53 37 Ribociclib + letrozole Placebo + letrozole 20 20 0 Overall Response ORR Rate 0 Overall Response ORR Rate Clinical benefit rate in patients with measurable disease: 80% ribociclib arm vs 72% placebo arm (P =.02)
Hematologic Adverse Events Regardless of Study Treatment Relationship Adverse Event 5% in Either Arm, % Ribociclib + Letrozole Placebo + Letrozole n = 330 All Grade 3 Grade 4 All Grade 3 Grade 4 Neutropenia 74 50 9.6 5.2 0.9 0 Leukopenia 33 20 1.2 3.9 0.6 0 Anemia 19 0.9 0.3 4.5 1.2 0 Lymphopenia 11 5.7 1.2 2.1 0.9 0 Thrombocytopenia 9.0 0.6 0 0.6 0 0 Febrile neutropenia occurred in 5 (1.5%)* patients in the ribociclib arm vs none in the placebo arm *5 cases, which includes 1 case of febrile neutropenia recorded incorrectly
Nonhematologic Adverse Events Regardless of Study Treatment Relationship Ribociclib + Letrozole Placebo + Letrozole n = 330 Adverse Event 15% in Either Arm, % All Grade 3 Grade 4 All Grade 3 Grade 4 Nausea 52 2.4 0 29 0.6 0 Infections 50 3.6 0.6 42 2.1 0.3 Fatigue 37 2.1 0.3 30 0.9 0 Diarrhea 35 1.2 0 22 0.9 0 Alopecia 33 16 Vomiting 29 3.6 0 16 0.9 0 Arthralgia 27 0.6 0.3 29 0.9 0 Constipation 25 1.2 0 19 0 0 Headache 22 0.3 0 19 0.3 0 Hot flush 21 0.3 0 24 0 0 Back pain 20 2.1 0 18 0.3 0 Cough 20 0 18 0 Decreased appetite 19 1.5 0 15 0.3 0 Rash 17 0.6 0 7.9 0 0 ALT increased 16 7.5 1.8 3.9 1.2 0 AST increased 15 4.8 0.9 3.6 1.2 0 In the ribociclib arm 10 (3.0%) patients experienced grade 2 QTcF (481-500 ms) and 1 (0.3%) patient experienced grade 3 QTcF (>500 ms); no dose reductions were required
Treatment Exposure and Dose Adjustments Treatment exposure Median duration of exposure, months Median relative dose intensity, % Dose adjustments Ribociclib + letrozole Placebo + letrozole n = 330 Ribociclib Letrozole Placebo Letrozole 12 13 12 12 88 100 100 100 Dose interruptions, n (%) 257 (77) 132 (40) 134 (41) 107 (32) Dose reductions due to AEs, n (%) 169 (51) 14 (4.2) Adverse events were predictable, manageable, and reversible
MONALEESA-2 met primary endpoint early Patients receiving ribociclib with letrozole had a statistically significant and clinically meaningful increase in PFS compared with letrozole alone (HR = 0.556; P =.00000329) Treatment benefit was consistent across patient subgroups and for other secondary endpoints Ribociclib was well tolerated Conclusions Common grade 3/4 adverse events were neutropenia and leukopenia Ribociclib received FDA Breakthrough Therapy designation in combination with letrozole Ongoing phase III trials: MONALEESA-3: Ribociclib + fulvestrant in men and postmenopausal women with advanced breast cancer (1 st or 2 nd line) MONALEESA-7: Ribociclib + tamoxifen/nsai + goserelin in pre/perimenopausal women with advanced breast cancer FDA, US Food and Drug Administration