Ribociclib + fulvestrant in postmenopausal women with ......Ribociclib + fulvestrant in...

Dennis J. Slamon, M.D., Ph.D.

Ribociclib + fulvestrant in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from MONALEESA-3Dennis J. Slamon,1, Patrick Neven,2 Stephen Chia,3 Seock-Ah lm,4 Peter A. Fasching,5

Michelino De Laurentiis,6 Katarina Petrakova,7 Giulia Val Bianchi,8 Francisco J. Esteva,9

Miguel Martín,10 Xavier Pivot,11 Gena Vidam,12 Yingbo Wang,13 Karen Rodriguez Lorenc,12

Michelle Miller,12 Tetiana Taran,12 Guy Jerusalem14

1UCLA Medical Center, Santa Monica, CA; 2Multidisciplinary Breast Centre, Universitair Ziekenhuis Leuven, Leuven, Belgium; 3BC Cancer Agency, Vancouver, BC, Canada; 4Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; 5University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; 6Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy; 7Masaryk Memorial Cancer Institute, Brno, Czech Republic; 8Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 9NYU Langone Health, New York, NY; 10Instituto de Investigacion Sanitaria Gregorio Marañon, Centro de Investigación Biomédica en Red de Cáncer, Grupo Español de Investigación en Cáncer de Mama, Universidad Complutense, Madrid, Spain; 11Institut Régional du Cancer, Strasbourg, France; 12Novartis Pharmaceuticals Corporation, East Hanover, NJ; 13Novartis Pharma AG, Basel, Switzerland; 14CHU Liege and Liege University, Liège, Belgium


CDK, cyclin-dependent kinase; G, gap phase; M, mitotic phase; Rb, retinoblastoma; S, synthesis phase.1. Hosford S and Miller T. Pharmgenomics Pers Med 2014;7:203–215.

Rb as the master regulator of the G1/S cell cycle checkpoint

• CDK protein kinases control cell cycle progression by binding to specific regulatory subunits, known as cyclins1

• CDKs 4 and 6 (CDK4/6) function in complex with D-type cyclins1

• p16 is a negative regulator of the cyclin-D–CDK4/6 complex

• The resulting active cyclin-D–CDK4/6 complexes initiate hyperphosphorylation of Rb1

• Hyperphosphorylation of Rb results in it’s inactivation, which allows the cell to progress from G1 to S-phase1

2

Can inhibiting cyclin D–CDK4/6 prevent Rb hyperphosphorylation and cell cycle progression?

MG2

G1

S R point

B–CDC2

D–CDK4/6

E–CDK2A–CDK2

A–CDC2

Rbdephosphorylation

Figure adapted from The Biology of Cancer (Figure 8.19) by R. Weinberg (© Garland Science 2007).


Introduction• In the Phase III MONALEESA-2 and MONALEESA-7 trials, addition of ribociclib to

endocrine therapy significantly improved PFS vs placebo plus endocrine therapyin pre-, peri-, and postmenopausal women with HR+/HER2– ABC1,2

• CDK4/6 inhibitor and fulvestrant combinations have demonstrated efficacy in patients with HR+ breast cancer that has progressed on prior endocrine therapy3,4

• No study has evaluated CDK4/6 inhibitor + fulvestrant combinations in patients withde novo HR+/HER2– ABC, or in patients who have relapsed >12 months after priorendocrine therapy with no subsequent treatment for advanced disease

• MONALEESA-3 is investigating ribociclib with fulvestrant in postmenopausal women with HR+/HER2– ABC who were treatment-naive or had received up to 1 line of prior endocrine therapy in the advanced setting

ABC, advanced breast cancer; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; PFS, progression-free survival.Advanced breast cancer refers to locoregionally recurrent or metastatic disease.

1. Hortobagyi GN, et al. N Engl J Med 2016;375:1738–1748; 2. Tripathy D, et al. SABCS 2017;abstract GS2-05; 3. Cristofanilli M, et al. Lancet Oncol 2016;17:425–439; 4. Sledge GW, et al. J Clin Oncol 2017;35:2875–2884.

3


9

700

0 3 6 1512 2718 21 24

600

500

400

300

200

100

0

Tum

or v

olum

e ±

SEM

(m

m³)

Inhibition of tumor growth in patient-derived ER+ breast cancer xenograft model ZR7511

Time (days)

Ribociclib (75 mg/kg QD)

Vehicle

Ribociclib (75 mg/kg QD) + fulvestrant (5 mg/kg QW)

Activity of ribociclib + fulvestrant in early studiesCLEE011X2108: postmenopausal women (N=28) with

HR+/HER2– ABC that progressed after prior AI therapy2

0

20

40

60

80

100

Overall response rate Clinical benefit rate

Rate

(%

)

Ribociclib (intermittent) +fulvestrantRibociclib (600 mg/day; intermittent) + fulvestrant

Ribociclib (400 mg/day; continuous) + fulvestrant

AI, aromatase inhibitor; ER+, estrogen receptor-positive; QD, once daily; QW, once weekly; SEM, standard error of the mean.Overall response rate = complete response + partial response; clinical benefit rate = confirmed complete response + partial response + stable disease ≥24 weeks.

1. O’Brien NA, et al. Cancer Res 2014;74(19 suppl):abstract 4756; 2. Juric D, et al. Cancer Res 2017;77(13 suppl):abstract CT087.

4


MONALEESA-3: Phase III placebo-controlled study of ribociclib + fulvestrant

• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter

• Primary analysis planned after ~364 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), and a sample size of 660 patients

ECOG PS, Eastern Cooperative Oncology Group performance status; RECIST, Response Evaluation Criteria In Solid Tumors.*Fulvestrant administered intramuscularly on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of every 28-day cycle thereafter.

Stratified by:• Presence/absence of liver/lung metastases• Prior endocrine therapy

Primary endpoint• PFS (locally assessed per RECIST v1.1)

Secondary endpoints• Overall survival• Overall response rate• Clinical benefit rate• Time to response• Duration of response• Time to definitive deterioration of ECOG PS• Patient-reported outcomes• Safety• Pharmacokinetics

• Postmenopausal women and men with HR+/HER2–ABC

• No or ≤1 line of prior endocrine therapy for advanced disease

• N=726

Randomization (2:1)

Ribociclib (600 mg/day orally;

3-weeks-on/1-week-off) +

fulvestrant(500 mg)*

n=484

Placebo+

fulvestrant(500 mg)*

n=242

5


Key enrollment criteria

QTcF, Fridericia's corrected QT interval.

• Prior treatment with chemotherapy for ABC, fulvestrant, or any CDK4/6 inhibitor

• Inflammatory breast cancer• Clinically significant cardiac

arrhythmias and/or uncontrolledheart disease, including QTcF >450 ms

• Ineligible for endocrine therapy dueto disease burden

Key exclusion criteria

• Postmenopausal women and men• ≥1 measurable lesion (RECIST 1.1)

or ≥1 predominantly lytic bone lesion• No or ≤1 line of prior endocrine

therapy for ABC• ECOG PS of ≤1

Key inclusion criteria

6


Accrual and analysis details726 patients randomized between June 2015 and June 2016Data cut-off date: November 3, 2017 (361 events)Median time from randomization to data cut-off date: 20.4 months

Full Analysis Set

Ribociclib + fulvestrantn=484

Placebo + fulvestrantn=242

SafetySet

Received treatmentn=483

Received treatmentn=241

PFS eventsn=210

PFS eventsn=151

7


Prior endocrine therapy status criteria

8

First line(i.e. treatment-naive for ABC)

Second line + early relapsers(i.e. received up to 1 line of prior endocrine therapy for ABC)

• Relapse >12 months after completion of (neo)adjuvant endocrine therapy

OR

• De novo advanced/metastatic disease (no prior exposure to endocrine therapy)

• Early relapse on or ≤12 months from completion of (neo)adjuvant endocrine therapy

OR

• Relapse >12 months from completion of (neo)adjuvant endocrine therapy with subsequent progression after 1 line of endocrine therapy (antiestrogen/AI) for ABC

OR

• ABC at diagnosis that progressed after 1 line of endocrine therapy (antiestrogen/AI) for ABC


Patient demographics and baseline characteristics

Characteristic* Ribociclib + fulvestrantn=484


Median age, years (range) 63 (31–89) 63 (34–86)Race

Caucasian 406 (83.9) 213 (88.0)Asian 45 (9.3) 18 (7.4)Other‡ 33 (6.8) 11 (4.5)

ECOG PS§0 310 (64.0) 158 (65.3)1 173 (35.7) 83 (34.3)

Metastatic sitesVisceral disease 293 (60.5) 146 (60.3)Bone-only disease 103 (21.3) 51 (21.1)

Prior endocrine therapy statusǁFirst line¶ 238 (49.2) 129 (53.3)Second line + early relapsers** 236 (48.8) 109 (45.0)

Prior endocrine therapy setting(Neo)adjuvant 289 (59.7) 142 (58.7)Advanced 110 (22.7) 40 (16.5)

Prior (neo)adjuvant chemotherapy 261 (53.9) 126 (52.1)*All values are n (%), unless stated otherwise;

‡‘Other’ includes Black, Native American, other, and unknown; race unknown for 15 (3.1%) patients in the ribociclib arm and 5 (2.1%) patients in the placebo arm;§ECOG PS missing for 1 (0.2%) patient in the ribociclib arm and 1 (0.4%) patient in the placebo arm;

ǁ14 patients were not included in the prior endocrine therapy status subgroup due to missing data or criteria not being met; ¶Treatment naive for ABC; **Received up to 1 line of prior endocrine therapy for ABC.

9


Patient disposition

AE, adverse event.

Disposition, n (%)Ribociclib + fulvestrant

n=484Placebo + fulvestrant

n=242

Treatment ongoing 204 (42.1) 76 (31.4)

Treatment discontinued 279 (57.6) 165 (68.2)

Primary reason for treatment discontinuation

Disease progression 193 (39.9) 142 (58.7)

AEs 41 (8.5) 10 (4.1)

Physician decision 22 (4.5) 7 (2.9)

Patient/guardian decision 21 (4.3) 5 (2.1)

Death 2 (0.4) 0

Protocol deviation 1 (0.2) 1 (0.4)

Technical problems 0 1 (0.4)

10

Dennis J. Slamon, M.D., Ph.D. 11

Primary endpoint: PFS (investigator-assessed)

• The hazard ratio of 0.593 corresponds to a 41% reduction in risk of progression in the ribociclib vs placebo arm

No. at risk

Ribociclib + fulvestrantPlacebo + fulvestrant

484242

403195

365168

347156

324144

305134

282116

259106

23595

15553

7827

5214

134

00

PFS (investigator assessment)

Ribociclib +fulvestrant

n=484

Placebo + fulvestrant

n=242Events, n (%) 210 (43.4) 151 (62.4)

Median PFS, months (95% CI)

20.5(18.5–23.5)

12.8(10.9–16.3)

Hazard ratio (95% CI) 0.593 (0.480–0.732)One-sided p value 0.00000041

Time (months)

Prob

abili

ty o

f PF

S (%

)100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

CI, confidence interval.


No. at risk

Ribociclib + fulvestrantPlacebo + fulvestrant

19397

16166

14650

13647

12843

11439

10137

9533

8730

5318

228

174

60

00

Prob

abili

ty o

f PF

S (%

)

0 2 4 6 8 10 12 14 16 18 20 22 24 26

12

Supportive analysis: PFS (Blinded Independent Review Committee*)

BIRC, Blinded Independent Review Committee; NR, not reached.*Audit-based review of 40% of randomized patients.

Based on the prespecified thresholds to trigger a full BIRC review of all patients’ data, a full BIRC review was not required.

PFS (BIRC)Ribociclib +fulvestrant

n=193


n=97Events, n (%) 72 (37.3) 54 (55.7)

Median PFS, months (95% CI)

NR(18.2–NR)

10.9(3.8–17.2)

Hazard ratio (95% CI) 0.492 (0.345–0.703)

Time (months)

100

80

60

40

20

0


SubgroupEvents, n/n Favors ribociclib Favors placebo Hazard

ratio 95% CIRibociclib + fulvestrant Placebo + fulvestrant

All patients 210/484 151/242 0.593 0.480–0.732Prior endocrine therapy*

First line‡ 76/238 66/129 0.577 0.415–0.802Second line + early relapsers§ 131/236 84/109 0.565 0.428–0.744

Liver or lung involvement

Yes 116/242 77/121 0.645 0.483–0.861No 94/242 74/120 0.563 0.415–0.764

Bone lesion only Yes 36/103 35/51 0.379 0.234–0.613No 174/381 116/190 0.658 0.519–0.833

Age <65 years 115/258 81/129 0.607 0.454–0.810≥65 years 95/226 70/113 0.597 0.436–0.818

Race Asian 22/45 7/18 1.353 0.574–3.186Caucasian 174/406 136/213 0.562 0.448–0.704Other 8/18 3/6 0.881 0.199–3.907

ECOG PS 0 126/310 95/158 0.559 0.427–0.7331 83/173 56/83 0.633 0.450–0.890

Number ofmetastatic sites

<3 126/309 92/149 0.586 0.447–0.768≥3 84/175 59/92 0.621 0.441–0.874

Prior tamoxifen Yes 79/193 63/104 0.620 0.443–0.866No 131/291 88/137 0.562 0.428–0.738

Prior AI Yes 135/257 80/118 0.670 0.507–0.886No 75/227 71/123 0.481 0.345–0.669

13

0.125 0.25 0.5 1 2 4 8Hazard ratio (95% CI)

PFS subgroup analysis

*14 patients were not included in the prior endocrine therapy subgroup analysis due to missing data or criteria not being met; ‡Treatment naive for ABC; §Received up to 1 line of prior endocrine therapy for ABC.

Hazard ratios were estimated based on stratified Cox proportional hazards model except in the subgroups related to the stratificationfactors (presence or absence of lung or liver metastases and prior endocrine therapy), where an unstratified analysis was used.


Prob

abili

ty o

f PF

S (%

)

26222016121086420 1814 24

0

20

40

60

80

100

Time (months)

Prob

abili

ty o

f PF

S (%

)

26181614121086420 20 22 24

0

20

40

60

80

100

Time (months)

PFS by prior endocrine therapy status

14

First line* Second line + early relapsers‡



n=236


n=109

Events, n (%) 131 (55.5) 84 (77.1)

Median PFS, months 14.6 9.1

Hazard ratio (95% CI) 0.565 (0.428–0.744)



n=238


n=129

Events, n (%) 76 (31.9) 66 (51.2)

Median PFS, months NR 18.3

Hazard ratio (95% CI) 0.577 (0.415–0.802)

No. at risk

Ribociclib + fulvestrant


238

129

205

109

189

99

180

91

173

88

166

85

159

78

149

75

141

68

97

40

49

18

31

10

7

4

0

0

No. at risk



236

109

188

83

167

67

159

63

143

54

132

47

117

36

104

29

91

25

55

12

28

8

20

4

5

0

0

0

*Treatment naive for ABC; ‡Received up to 1 line of prior endocrine therapy for ABC.


Secondary endpoints: ORR and CBR

• In all patients, the CBR was 70.2% for ribociclib + fulvestrant vs 62.8% for placebo + fulvestrant (p=0.020)

• In patients with measurable disease, the CBR was 69.4% for ribociclib + fulvestrant vs 59.7% for placebo + fulvestrant (p=0.015)

CBR, clinical benefit rate; ORR, overall response rate.Overall response rate = complete response + partial response.

Clinical benefit rate = complete response + partial response + (stable disease + non-complete response/non-progressive disease ≥24 weeks) in all patients and complete response + partial response + (stable disease ≥24 weeks) in patients with measurable disease.

0

20

40

60

80

100

Rate

(%

)

ORR

p=0.003

Patients with measurable disease

0

20

40

60

80

100

Rate

(%

)

ORR

p=0.000912

All patients


Placebo + fulvestrant32.4

21.5

40.9

28.7

15


Overall survival

• Overall survival data were immature at the cut-off date‒ Results did not cross the prespecified O’Brien–Fleming stopping boundary

16



Events, n (%) 70 (14.5) 50 (20.7)


Treatment exposure and dose adjustments



Treatment exposure

Median duration of exposure to ribociclib/placebo, months 12.7 11.1

Median ribociclib/placebo dose intensity, mg/day 552.4 600.0

Median relative ribociclib/placebo dose intensity, % 92.1 100.0

Ribociclib/placebo dose adjustments, n (%)

Dose reductions 183 (37.9) 10 (4.1)

Dose reductions due to AEs 160 (33.1) 8 (3.3)

Dose interruptions 364 (75.4) 105 (43.6)

Dose interruptions due to AEs 331 (68.5) 45 (18.7)

17


Treatment exposure and dose adjustments



Treatment exposure

Median duration of exposure to ribociclib/placebo, months 12.7 11.1

Median ribociclib/placebo dose intensity, mg/day 552.4 600.0

Median relative ribociclib/placebo dose intensity, % 92.1 100.0

Ribociclib/placebo dose adjustments, n (%)

Dose reductions 183 (37.9) 10 (4.1)

Dose reductions due to AEs 160 (33.1) 8 (3.3)

Dose interruptions 364 (75.4) 105 (43.6)

Dose interruptions due to AEs 331 (68.5) 45 (18.7)

18


Hematologic adverse events

• Febrile neutropenia was observed in 5 (1.0%) patients in the ribociclib arm vs none in the placebo arm

*Includes “neutropenia”, “decreased neutrophil count”, “febrile neutropenia”, and “neutropenic sepsis”; ‡Includes “leukopenia”, “decreased white blood cell count”, “lymphopenia”, and “decreased lymphocyte count”;

§Includes “anemia”, “decreased hemoglobin”, and “decreased red blood cell count”; ǁIncludes “thrombocytopenia” and “decreased platelet count”.

Regardless of study treatment relationship

AEs ≥5% in either arm, %Ribociclib + fulvestrant


n=241All Grade 3 Grade 4 All Grade 3 Grade 4

Neutropenia* 69.6 46.6 6.8 2.1 0 0

Leukopenia‡ 28.4 13.5 0.6 1.7 0 0

Anemia§ 17.2 3.1 0 5.4 2.1 0

Thrombocytopeniaǁ 8.5 0.8 0.2 1.7 0 0

19


Non-hematologic adverse events

• Post-baseline QTcF >480 ms, based on ECG data, occurred in 27 patients (5.6%) in the ribociclib arm vs 6 patients (2.5%) in the placebo arm

• Grade 3/4 elevated ALT and AST occurred in 32 (6.6%)/9 (1.9%) and 23 (4.8%)/6 (1.2%) patientsin the ribociclib arm, respectively

• Two patients in the ribociclib arm were confirmed Hy’s Law cases; AST, ALT, and TBIL levels returned to normal following ribociclib discontinuation

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; TBIL, total bilirubin.

Regardless of study treatment relationship

AEs ≥25% in either arm, %Ribociclib + fulvestrant


n=241All Grade 3 Grade 4 All Grade 3 Grade 4

Nausea 45.3 1.4 0 28.2 0.8 0

Fatigue 31.5 1.7 0 33.2 0.4 0

Diarrhea 29.0 0.6 0 20.3 0.8 0

Vomiting 26.7 1.4 0 12.9 0 0

Arthralgia 24.0 0.6 0 26.6 0.4 0

20


Conclusions• Patients receiving ribociclib + fulvestrant had a statistically significant and clinically

meaningful improvement in PFS vs placebo + fulvestrant• Hazard ratio: 0.593; p=0.00000041; 41% reduction in risk of disease progression vs placebo

• Ribociclib treatment benefit was consistent across patient subgroups

• Prolonged PFS was observed with first-line ribociclib + fulvestrant (hazard ratio: 0.577; 95% CI: 0.415–0.802)• Benefit was also observed in patients who received treatment in the second-line setting (hazard ratio: 0.565;

95% CI: 0.428–0.744)

• Ribociclib + fulvestrant demonstrated a manageable safety profile, consistent with previous Phase III ribociclib studies

• Ribociclib combined with fulvestrant may be a new first- or second-line treatment option for postmenopausal women with HR+/HER2– ABC

• This is the first study to show that CDK4/6 inhibitor + fulvestrant combinations are efficacious in patients with de novo ABC and patients with disease that relapsed >12 months after completion of prior (neo)adjuvant endocrine therapy

21


Acknowledgments• Patients and their families who participated in

MONALEESA-3

• Members of the Study Steering Committee, all investigators, research coordinators, and site staff

• Members of the Data Monitoring Committee

• This study was sponsored by Novartis Pharmaceuticals Corporation, who provided financial support for medical editorial assistance from ArticulateScience Ltd.

Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals

ItalyLebanonMalaysiaMexicoNorwayPolandPortugalRepublic of KoreaRussia

AustraliaAustriaBelgiumBulgariaCanadaCzech RepublicDenmarkFranceGermany

SingaporeSpainSwedenSwitzerlandThailandThe NetherlandsTurkeyUnited KingdomUnited States

Countries with active centers

22


http://ascopubs.org/doi/abs/10.1200/JCO.2018.78.9909DOI: 10.1200/JCO.2018.78.9909

http://ascopubs.org/doi/abs/10.1200/JCO.2018.78.9909

Ribociclib + fulvestrant in postmenopausal women with ......Ribociclib + fulvestrant in...

Documents

Transcript of Ribociclib + fulvestrant in postmenopausal women with ......Ribociclib + fulvestrant in...