inhibidores de cdk 4/6 en cáncer de mama: datos recientes · palbociclib (pd0332991) pfizer...
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Inhibidores de CDK 4/6 en
cáncer de mama: datos
recientes
Miguel Martín
Instituto de Investigación Sanitaria
Hospital Gregorio Marañón
Universidad Complutense
Madrid
CDK4/6 inhibitors- current status of development
Agent Company Development Status
Palbociclib
(PD0332991)
Pfizer
(Ibrance)
Approved MBC
Phase III Adjuvant
Ribociclib
(LEE011)
Novartis
(Kisqali)
Approved MBC
Phase III Adjuvant
Abemaciclib
(LY28335219)
Lilly
(Verzenio)
Approved MBC
Phase III Adjuvant
Efficacy of CDK 4/6 inhibitors (1)
• In the first-line setting, they have been examined in the PALOMA-
2 (palbociclib), MONALEESA-2 (ribociclib) and MONARCH-3
(abemaciclib) trials.
• In patients with prior Ais, they have been examined in combination
with fulvestrant in the PALOMA-3, and MONARCH-2 trials.
PALOMA 2 (2:1) MONALEESA 2 (1:1)
Median PFS
abemaciclib + NSAI: not reachedplacebo + NSAI: 14.7 m
HR (95% CI): 0.543 (0.409, 0.723) p = 0.000021
MONARCH 3 (2:1)
Median PFS
Ribociclib + NSAI: 25.3 mplacebo + NSAI: 16 m
HR (95% CI): 0.568 (0.457, 0.704) p = 0.000000096
Number of patients at risk
PCB + LET
222
171
148
131
116
98 81 54 22 12 4 2
PAL + LET
444
395
360
328
295
263
238
154
69 29 10 2
Progression-F
ree S
urvival, %
Time, months
100
90
80
70
60
50
40
30
20
10
0 0 3 6 9 12 15 18 24 27 30 33 21
Number of Events, n (%)
Median (95% CI) PFS
HR (95% CI); 1-sided P value
194 (44)
24.8 (22.1-NR)
0.58 (0.46-0.72); P<0.000001
137 (62)
14.5 (12.9-17.1)
PAL+LET (N=444)
PCB+LET
(N=222)
Median PFS
Palbociclib + NSAI: 24.8 mplacebo + NSAI: 14.5 m
HR (95% CI): 0.58 (0.46, 0.72) p =<0.000001
CDK 4/6 inhibitors in first-line, endocrine sensitive
disease
CDK 4-6 inhibitors in patients with prior AIs
MONARCH 2: PFS
abemaciclib + fulvestrant: 16.44 months (N = 446)
placebo + fulvestrant: 9.27 months (N = 223)
HR, 0.553 (95% CI, 0.449 to 0.681)p <.0000001
Efficacy of CDK 4/6 inhibitors (2)
• In subgroup analysis it does not appear to be one groupthat necessarily benefits more or less in the trials.
• A meta-analysis of the raw data from five registration trials of CDK4/6 inhibitors showed that every patient benefits about equally from the addition of CDK4/6 inhibitors1.
• Higher-risk patients with features such as liver metastasesobtain high OR rates; CDK 4/6 plus hormones is an exclentalternative to chemotherapy in these patients.
1Gao F et al, 2018 ASCO Annual Meeting
Subset AI orfulvestrant
CDK4/6 inhibitor
Placebo Hazard ratio
ITT pooled population (n = 3,002) Both 20.5 mo 11.8 mo 0.59
ITT pooled population (n = 1,817) AI 26.5 mo 15.1 mo 0.56
PR-negative (n = 490) Both 16.5 mo 7.4 mo 0.50
Lobular cancer (n = 264) Both 16.1 mo 9.2 mo 0.58
Bone-only metastases (n = 875) Both 27.9 mo 15.5 mo 0.55
De novo metastatic (n = 617) AI 27.8 mo 16.8 mo 0.59
Disease-free > 12 months (n = 929) AI 25.7 mo 14.2 mo 0.55
CDK4/6 Inhibitors in Advanced Breast Cancer: Median PFS by Disease
Subset- Pooled data of first-line CDK 4/6 inhibitor trials
Toxicity of CDK 4/6 inhibitors
Palbociclib phase III studies
Trial N
pts
Design Population Primary
Endpoint
Status
PALOMA-2 (TRIO) 450 Palbo+LET vs
Pbo+LET
1L MBC PFS Final results on PFS
reported
PALOMA-3 417 Palbo+FULV vs
Pbo+FULV
after ED failure
MBC
PFS Final results on PFS and OS
reported
PEARL (GEICAM) 597 Palbo+EXE/FULV
vs
Capecitabine
MBC with
resistance to
NSAIs
PFS Enrollment ended
Efficacy analysis planned for
QI 2019
PENELOPE-B
(GBG)
1250 Palbo+ED vs
Pbo+ED
after NACT
(residual disease
high risk CPS-EG
score)
iDFS Enrollment ended
Efficacy interim analysis
planned for QII 2019
PALLAS (BIG) 5600 Palbo+ED vs
Pbo+ED
adjuvant
(moderate to
high risk)
iDFS Enrollment ended
Turner et al, NEJM 2015
Turner et al, NEJM 2015
Turner et al, SABCS 2016
PALOMA 3: Post- Progression Therapies
Turner et al, NEJM 2015
PALOMA 3
Overall Survival with Palbociclib and Fulvestrant
in Advanced Breast Cancer (PALOMA 3 trial)
• OS was secondary endpoint
• Study not powered to show clinically meaningful
differences in OS
• OS in subgroups unplanned
Overall Survival with Palbociclib and Fulvestrant in
Advanced Breast Cancer (PALOMA 3 trial)
The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib group
and 28.0 months (95% CI, 23.6 to 34.6) in the placebo group (hazard ratio for death, 0.81;
95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months).
Turner N et al, N Engl J Med 2018;379:1926.
Overall Survival with Palbociclib and Fulvestrant in
Advanced Breast Cancer (PALOMA 3 trial)
The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib group
and 28.0 months (95% CI, 23.6 to 34.6) in the placebo group (hazard ratio for death, 0.81;
95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months).
Turner N et al, N Engl J Med 2018;379:1926.
Turner N et al, N Engl J Med 2018;379:1926.
Overall Survival with Palbociclib and Fulvestrant
in Advanced Breast Cancer (PALOMA 3 trial)
Turner N et al, N Engl J Med 2018;379:1926.
Among 410 patients with sensitivity to previousendocrine therapy*, the median overall survival was39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months).
*Relapse after at least 2 years of endocrine therapy or progression after
at least 24 weeks on endocrine therapy for metastatic disease
PALOMA-3 PRO Analysis: Global QoL results
Harbeck N at al, Annals of Oncology 27: 1047–1054, 2016
PALOMA-3 PRO Analysis: Global QoL results
Harbeck N at al, Annals of Oncology 27: 1047–1054, 2016
PALOMA-3 PRO Analysis: Global QoL results
Harbeck N at al, Annals of Oncology 27: 1047–1054, 2016
Biomarkers of palbociclib efficacy
Finn R et al. Presented at: 40th San Antonio Breast Cancer Symposium (SABCS); December 5-9, 2017; San Antonio, TX. Abstract P2-09-10
Ribociclib phase III studies
Trial N Design Population Primary
Endpoint
Status
MONALEESA-2 668 Ribo+LET vs
Pbo+LET
1L MBC postmen. PFS Final results on PFS
reported
MONALEESA-3 726 Ribo+FULV vs
Pbo+FULV
1L, 2L MBC
postmen.
PFS Final results on PFS
reported
MONALEESA-7 672 Ribo+TAM or AI +
Goserelin vs
TAM or AI plus
Goserelin
MBC with
resistance to NSAIs
Pre/perimen.
PFS Efficacy analysis on PFS
reported
NATALEE (TRIO) 5250 Ribo+ED vs
Pbo+ED
adjuvant,
moderate to high-
risk patients
iDFS Enrollment just started
Dennis J. Slamon, M.D., Ph.D.
Ribociclib + fulvestrant in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from MONALEESA-3
Dennis 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
Dennis J. Slamon, M.D., Ph.D.25
Dennis J. Slamon, M.D., Ph.D.
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.
26
Dennis J. Slamon, M.D., Ph.D.
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
27
Dennis J. Slamon, M.D., Ph.D.
Key enrollment criteria
QTcF, Fridericia's corrected QT interval.
• Prior treatment with chemotherapy for ABC
• 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
28
Dennis J. Slamon, M.D., Ph.D.
Prior endocrine therapy status criteria
29
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
Dennis J. Slamon, M.D., Ph.D.
Patient demographics and baseline characteristics
Characteristic*Ribociclib + fulvestrant
n=484Placebo + fulvestrant
n=242
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 statusǁ
First 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.
30
Dennis J. Slamon, M.D., Ph.D.31
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 + fulvestrant
Placebo + fulvestrant
484
242
403
195
365
168
347
156
324
144
305
134
282
116
259
106
235
95
155
53
78
27
52
14
13
4
0
0
PFS (investigator assessment)
Ribociclib +fulvestrant
n=484
Placebo + fulvestrant
n=242
Events, 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)
Pro
babilit
y o
f PFS (
%)
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
CI, confidence interval.
Dennis J. Slamon, M.D., Ph.D.32
SubgroupEvents, n/n Favors ribociclib Favors placebo Hazard
ratio95% CI
Ribociclib + fulvestrant Placebo + fulvestrant
All patients 210/484 151/242 0.593 0.480–0.732
Prior endocrine therapy*
First line‡ 76/238 66/129 0.577 0.415–0.802
Second line + early relapsers§ 131/236 84/109 0.565 0.428–0.744
Liver or lung involvement
Yes 116/242 77/121 0.645 0.483–0.861
No 94/242 74/120 0.563 0.415–0.764Bone lesion only Yes 36/103 35/51 0.379 0.234–0.613
No 174/381 116/190 0.658 0.519–0.833Age <65 years 115/258 81/129 0.607 0.454–0.810
≥65 years 95/226 70/113 0.597 0.436–0.818Race Asian 22/45 7/18 1.353 0.574–3.186
Caucasian 174/406 136/213 0.562 0.448–0.704
Other 8/18 3/6 0.881 0.199–3.907ECOG PS 0 126/310 95/158 0.559 0.427–0.733
1 83/173 56/83 0.633 0.450–0.890Number ofmetastatic sites
<3 126/309 92/149 0.586 0.447–0.768
≥3 84/175 59/92 0.621 0.441–0.874Prior tamoxifen Yes 79/193 63/104 0.620 0.443–0.866
No 131/291 88/137 0.562 0.428–0.738Prior AI Yes 135/257 80/118 0.670 0.507–0.886
No 75/227 71/123 0.481 0.345–0.669
32
0.125 0.25 0.5 1 2 4 8
Hazard 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.
Dennis J. Slamon, M.D., Ph.D.
Pro
babilit
y o
f PFS (
%)
26222016121086420 1814 24
0
20
40
60
80
100
Time (months)
Pro
babilit
y o
f PFS (
%)
26181614121086420 20 22 24
0
20
40
60
80
100
Time (months)
PFS by prior endocrine therapy status
33
First line* Second line + early relapsers‡
PFS (investigator assessment)
Ribociclib +fulvestrant
n=236
Placebo + fulvestrant
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)
PFS (investigator assessment)
Ribociclib +fulvestrant
n=238
Placebo + fulvestrant
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
Placebo + 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
Ribociclib + fulvestrant
Placebo + fulvestrant
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.
Dennis J. Slamon, M.D., Ph.D.
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
Ribociclib + fulvestrantPlacebo + fulvestrant
32.4
21.5
40.9
28.7
34
Dennis J. Slamon, M.D., Ph.D.
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
35
Abemaciclib studies
Trial N Design Population Primary
Endpoint
Status
MONARCH-1 132 Abemaciclib 200
mg
pretreated MBC
postmen.
PFS Final results on PFS/OS/RR
reported
nextMONARCH 234 abema 150 vs
abema 200 vs
abema 150 +
tamoxifen
Pretreated MBC
Postmen.
PFS Final results to be reported
at SABCS 2018
MONARCH-2 463 Abema + FULV vs
Placebo + FULV
1L postmen. PFS Final results on PFS already
reported
MONARCH-3 493 Anbema+ AI vs
Plac + AI
Final results on PFS
reportedrecently
neoMONARCH 597 Abema +
anastrozol
Early bteast cancer PFS Final results reported
MONARCH-E 4080
+1000
Abema+ED vs
ED
adjuvant,
moderate to high-
risk patients
iDFS Enrollment ongoing
MONARCH 1• 200 mg of single agent abemacivlib was administered orally on a continuous
schedule every 12 hours until disease progression or unacceptable toxicity.
• The primary objective of MONARCH 1 was investigator-assessed objectiveresponse rate (ORR).
• Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastaticsites
• 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
Dickler M, et al, Clin Cancer Res. 2017 Sep 1;23(17):5218-5224.
nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or
abemaciclib alone in HR+, HER2-advanced breast cancer
Erika Hamilton1, Javier Cortes2,3, Veronique Dieras4, Ozgur Ozyilkan5,
Shin-Cheh Chen6, Katarina Petrakova7, Aleksey Manikhas8,
Guy Jerusalem9, Roberto Hegg10, Yi Lu11, Melissa M. Bear11,
Erica L. Johnston11, Miguel Martin12
1Sarah Cannon Research Institute, Tennessee Oncology PLLC, Nashville, TN, USA; 2Ramon y Cajal University Hospital, Madrid, Spain; 3Vall d'Hebron Institute of Oncology, Barcelona, Spain;
4Centre Eugene Marquis UNICANCER, Rennes Cedex, France; 5Baskent University Department of Medical Oncology, Adana, Turkey; 6Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan; 7Masarykuv Onkologický Ustav,
Brno, Czech Republic; 8City Clinical Oncology Dispensary, St. Petersburg, Russia; 9Centre Hospitalier Universitaire,Liege, Belgium; 10Hospital Pérola Byington/FMUSP, Centro de Referência da Saúde da Mulher, São Paulo, Brazil;
11Eli Lilly and Company, Indianapolis, IN, USA; 12Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERONC, Madrid, Spain
PD1-11
OBJECTIVES
♦ Primary objective: investigator-assessed Progression-free Survival (PFS)
♦ Key secondary objectives: Overall Response Rate (ORR), Clinical Benefit Rate
(CBR), Overall Survival (OS) and safety
METHODS - Study Design
a during cycle 2 and beyond, loperamide was administered at investigator’s discretion
Statistics: PFS analysis tested superiority of Arm A to C at ~110 events across the 2 arms assuming a hazard ratio (HR) of .667 to achieve ~80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR was <1.2
Enrollment: From September 2016 to June 2017, patients were enrolled in 60 sites in 14 countries
Inclusion criteria
• HR+, HER2- MBC
• Progression on or after prior ET• Prior treatment with ≥2
chemotherapy regimens− 1-2 prior chemotherapies
in metastatic setting• Measurable disease• ECOG PS ≤ 1
abemaciclib: 150 mg Q12H (continuous schedule)
tamoxifen: 20 mg QD
Random
ization
1:1:1
abemaciclib: 150 mg Q12H
(continuous schedule)
abemaciclib: 200 mg Q12H (continuous schedule)
prophylactic loperamide: 2 mg QD (during cycle 1)a
A
B
CSame population as MONARCH 1 without prior taxane mandation
N = 234
Stratification factors
• Presence of liver metastases at baseline (yes or no)• Prior tamoxifen in the advanced/metastatic setting (yes or no)
MONARCH 3: Abemaciclib as initial therapy for patients with HR+, HER2- advanced breast cancer –
Results from the preplanned final PFS analysis
Matthew P. Goetz1, Miguel Martin2, Angelo Di Leo3, Seock-Ah Im4, Ahmad Awada5, Tammy Forrester6, Martin Frenzel6, Joanne Cox7,
Susana Barriga8, Masakazu Toi9, Hiroji Iwata10, Stephen Johnston11
1Mayo Clinic, Rochester, MN; 2Instituto De Investigacion Sanitaria Gregorio Marañon, Ciberonc, Geicam; Universidad Complutense, Madrid, Spain; 3Hospital of Prato, Prato, Italy; 4Seoul National University College of Medicine, Seoul, South
Korea; 5Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium; 6Eli Lilly and Company, Indianapolis, IN; 7Eli Lilly and Company, Windlesham, UK; 8Eli Lilly and Company, Madrid, Spain; 9Kyoto University, Kyoto, Japan; 10Aichi Cancer
Center Hospital, Nagoya, Japan; 11The Royal Marsden NHS Foundation Trust, London, UK
MONARCH 3: Study Design
♦Statistics: 240 PFS events for 80% power at one-sided α of .025 assuming a hazard ratio of .67
Enrollment: From November 2014 to November 2015 patients enrolled in 158 centers from 22 countries
Median follow-up: 26.7 months (final analysis)
Overall Survival: OS immature at this time
• HR+, HER2- ABC
• Postmenopausal
• Metastatic or locoregionally recurrent disease with no prior systemic therapy in this setting
• If (neo)adjuvant ET administered, a disease free interval of >12 months since completion of ET
• ECOG PS ≤1
abemaciclib: 150 mg BID
(continuous schedule) plus
anastrozole: 1 mg or a
letrozole: 2.5 mg QD until PD
placebo: BID (continuous
schedule) plus
anastrozole: 1 mg or a
letrozole: 2.5 mg QD until PD
a per physician’s choice: 79.1 % received letrozole, 19.9 % received anastrozole
Ra
nd
om
iza
tion
2 :1
N = 493
Abbreviations: AI, aromatase inhibitor; ABC, advanced breast cancer; BID, twice daily dose; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ET, endocrine therapy; HER2-, human epidermal growth factor receptor 2-; HR+, hormone receptor-positive; PD, progressive disease; PFS, progression-free survival; QD, daily; OS, overall survival
Primary endpoint:
Investigator-assessed PFS
Secondary endpoint:
OS, Response rates, Safety
Stratification factors:
- Metastatic site (visceral, bone only, or other)- Prior ET (AI, no ET, or other)
Patient and Disease Characteristics (ITT)
Median age (range) 63 (38 – 87) 63 (32 – 88)
Race a
Caucasian 186 (56.7) 102 (61.8)
Asian 103 (31.4) 45 (27.3)
Other 11 (3.4) 7 (4.2)
Measurable diseaseYes 267 (81.4) 132 (80.0)
No 61 (18.6) 33 (20.0)
Disease settingb
Locoregionally recurrent 11 (3.4) 5 (3.0)
Metastatic recurrent 182 (55.5) 99 (60.0)
De novo metastatic 135 (41.2) 61 (37.0)
Metastatic siteb
Visceral 173 (52.7) 89 (53.9)
Bone-only 69 (21.0) 40 (24.2)
Other 86 (26.2) 36 (21.8)
Prior (neo)adjuvant chemotherapy
Yes 125 (38.1) 66 (40.0)
No 203 (61.9) 99 (60.0)
Prior (neo)adjuvantendocrine therapy
No endocrine therapy 177 (54.0) 85 (51.5)
Aromatase inhibitor therapy 85 (25.9) 50 (30.3)
Other endocrine therapy 66 (20.1) 30 (18.2)
Treatment free interval b,c
<36 months 44/151 (29.1) 32/80 (40.0)
≥36 months 95/151 (62.9) 40/80 (50.0)
Unknown 12/151 (7.9) 8/80 (10.0)
placebo + NSAIn = 165
abemaciclib + NSAIn = 328
a 28 patients in abemaciclib arm and 11 in placebo arm were not identified by race due to country law; bPercentage does not equal 100% as the result of
rounding; cTreatment-free interval calculated only for patients with prior endocrine therapy
Investigator-assessed PFS
PFS benefit confirmed by blinded independent central review: HR (95% CI): 0.465 (0.339-0.636); p <0.000001
PFS: Pre-specified Subgroup Analysis (ITT)placebo + NSAI
abemaciclib + NSAI
Change in Tumor Size and Response Rate
placebo + NSAI
abemaciclib + NSAI
Abbreviations: CBR, clinical benefit rate; CR, complete response; ITT, intent-to-treat; ORR, objective response rate
Change in Tumor Size by Cycle and Duration of Response
aInvestigator assessment
♦ Duration of responsea was measured from the time of initial response (time = 0) to progression
♦ Median time to response was 3.6 months in abemaciclib arm and 3.7 months in the placebo arm
Treatment-Emergent Adverse Events
≥ 20% occurrence in abemaciclib arm, n (%) All Grade 3 Grade 4 All Grade 3 Grade 4
Any adverse event 323 (98.8) 169 (51.7) 22 (6.7) 152 (94.4) 36 (22.4) 4 (2.5)
Diarrhea 269 (82.3) 31 (9.5) 0 52 (32.3) 2 (1.2) 0
Neutropenia 143 (43.7) 72 (22.0) 6 (1.8) 3 (1.9) 1 (0.6) 1 (0.6)
Fatigue 135 (41.3) 6 (1.8) - 54 (33.5) 0 -
Nausea 135 (41.3) 4 (1.2) - 33 (20.5) 2 (1.2) -
Anemia 103 (31.5) 23 (7.0) 0 13 (8.1) 2 (1.2) 0
Abdominal pain 102 (31.2) 6 (1.8) - 21 (13.0) 2 (1.2) -
Vomiting 99 (30.3) 5 (1.5) 0 21 (13.0) 4 (2.5) 0
Alopecia 90 (27.5) - - 18 (11.2) - -
Decreased appetite 86 (26.3) 5 (1.5) 0 17 (10.6) 1 (0.6) 0
Leukopenia 72 (22.0) 27 (8.3) 1 (0.3) 4 (2.5) 0 1 (0.6)
Blood creatinine increased 67 (20.5) 6 (1.8) 1 (0.3) 7 (4.3) 0 0
Note: An imbalance of venous thromboembolic events was observed between the abemaciclib arm (all Grade, n = 20 [6.1%]; Grade 3+, n = 10 [3.1%]) and the placebo arm
(all Grade: n = 1 [0.6%]; Grade 3+, n = 1 [0.6%]
Deaths due to AEs:
• abemaciclib arm: 11 (lung infection [4], embolism [2], respiratory failure [2], cerebral ischemia [1], cerebrovascular accident [1], pneumonitis [1]);
• placebo arm: 2 (general physical health deterioration [1], sudden death [1])
placebo + NSAIn = 161
abemaciclib + NSAIn = 327
Relationship Between Early Toxicity and PFS
abemaciclib + NSAI vs placebo + NSAI, median PFSabemaciclib arm with diarrhea: 28.2 monthsabemaciclib arm without diarrhea: 29.1 monthsplacebo arm: 14.8 months
HR = 0.49 (95% CI, 0.35-0.67)HR = 0.58 (95% CI, 0.43-0.78)
CONCLUSIONS
♦ Abemaciclib plus NSAI significantly improved PFS and ORR as initial therapy of HR+, HER2- advanced breast cancer in postmenopausal patients
♦ Benefit from abemaciclib plus NSAI was consistent across preplanned subgroups, including patients with concerning clinical characteristicsa
♦ Responses observed in patients who received abemaciclib generally occurred early, were maintained over time, and led to substantial tumor shrinkage
♦ Abemaciclib in combination with NSAI was generally well-tolerated and the safety profile was consistent with other abemaciclib studies
aAbstract CT099: The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3;
Poster will be presented on Monday April 16th, 1:00 PM - 5:00 PM at McCormick Place South, Hall A, Poster Section 42; Poster Board # 20
Final results of neoMONARCH: A phase 2 neoadjuvant study of abemaciclib in
postmenopausal women with hormone receptor positive, HER2 negative breast
cancer
Miguel Martin1, Sara Hurvitz2, David Chan3, María Fernandez-Abad4, Edgar Petru5, Regan Rostorfer6, Valentina Guarneri7, Chiun-Sheng Huang8, Michael F. Press9, and Dennis Slamon2
1Hospital General Universitario Gregorio Marañón, Madrid, España; 2University of California, Los Angeles, CA, Estados Unidos; 3Cancer Care Associates, Redondo Beach, CA, Estados Unidos; 4Hospital Universitario Ramón y Cajal, Madrid, España; 5Medical University Graz, Graz, Austria; 6UF Health Cancer Center at Orlando Health, Orlando, FL, Estados Unidos; 7University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italia; 8National Taiwan University Hospital, Taipei, Taiwan; 9University of Southern California, Los Angeles, CA, Estados Unidos; 10Eli Lilly and Company, Indianapolis, IN, Estados Unidos; 11Eli Lilly and Company, Madrid, España.
Sociedad Española de Oncología Médica (SEOM); Madrid, España; 25 al 28 de septiembre de 2018
O5
METHODSFigure 2. NeoMONARCH study design, and consort diagram
Patients: ♦ Post-menopausal women with HR+, HER2-−
breast cancer stage: I (T ≥ 1 cm), II, IIIA, or IIIB suitable for neoadjuvant endocrine therapy
Primary objective: ♦ Compare the change from baseline in Ki67
expression after 2 weeks of therapy
Secondary objectives (after week 16): ♦ Safety and tolerability♦ Clinical, radiological and pathological
response
♦ Pharmacokinetics of abemaciclib and anastrozole
Exploratory objectives:♦ Association between biomarkers and clinical
outcomes
♦ Relationship between abemaciclib exposure and response variables (i.e. Ki67, change in tumor size, and clinical response)
Statistical design:♦ 220 randomized patients required to achieve
50 evaluable patients in each arm♦ 80% power at 1-sided alpha of 0.1, assuming:
• mean reduction of 85 % for anastrozole
alone and 91% for combination
aStratified for PR status, tumor sizeb2 mg loperamide was administered prophylactically with each abemaciclib dose for the
first 28 days and then at the investigator’s discretioncParticipants who experience benefit following 14 weeks may remain on neoadjuvant
therapy for up to 8 additional weeksAbbreviations: QD=every day; Q12H=every 12 hours
223 Patients treated
224 Patients randomizeda
(Core biopsy at baseline)
Randomized but never treated, n = 1
167 Patients evaluable for Ki67 at Week 2
(Core biopsy after 2 weeks of treatment; Primary Endpoint)
Patients on abemaciclib 150 mg Q12H + anastrozole 1 mg QD until Week 16c
(Core biopsy after 14 weeks of treatment c; 138 Patients evaluable for Ki67 at Week 16; Secondary endpoints)
Surgery (optional)
Patients not evaluable:
Discontinued prior to Day 14, n = 6Baseline Ki67 positive <5%, n = 14Baseline and/or Week 2 notavailable at time of analysis, n = 36
Abemaciclibb 150 mg Q12H
n = 75
Anastrozole 1 mg QD
n = 74
Abemaciclib b 150 mg Q12H + Anastrozole 1 mg QD
n = 74
RESULTSFigure 3. Update of primary endpoint: percent change in Ki67 from baseline to week 2
© 2016 Eli Lilly and Company53
a Geometric Mean Ratio (GMR), 2-sided 90 % confidence interval (CI), p-value. p-values are based on a one-sided hypothesis test from a linear model with treatment progesterone receptor status (positive versus negative/unknown) and tumor size (<2 cm versus ≥2 cm and <5 cm versus ≥ 5 cm) as fixed effectsbA responder is identified as a patient with a ln(Ki67) value of less than 1. Odds ratio (OR), 2-sided 90 % CI, p value. p value is calculated by Fisher's Exact test of a one-sided hypothesis. Abbreviations: ANZ, anastrozole
Geometric Mean Change(Primary Endpoint of Study)
GMRa =
Me
an
Ch
an
ge
in
Ki6
7 (
%)
0
-20
-40
-60
-80
-100
0.19 (0.13, 0.28)
p<0.001a0.25 (0.17, 0.38)
p<0.001a
n = 59 n = 52 n = 56
- 92.86 - 90.52 - 62.78
8.2 (3.4, 20.0)
p<0.001b
Complete Cell Cycle Arrest
(Ki67 index <2.7% at 2 weeks)
OR =
Re
sp
on
se
Ra
te (
%)
100
80
40
60
20
0
Responders b: 40 30 8
67.8 57.7 14.3
12.6 (5.3, 30.7)
p<0.001b
Abemaciclib + ANZ
ANZ
Abemaciclib
♦ 167/223 treated patients were evaluable for primary objective. 78 patients achieved complete cell cycle
arrest (Ki67 <2.7%) with 40/59 patients treated with abemaciclib + ANZ, 30/52 patients treated with
abemaciclib and 8/56 patients treated with ANZ
RESULTS (continued)Figure 7. Analysis of PIK3CA and ESR1 mutation status on Ki67 expression change from baseline to 2 weeks
♦ PIK3CA mutation status had no effect on Ki67 expression change from baseline to 2 weeks
in response to combination or abemaciclib, compared to ANZ
♦ No analysis was performed on ESR1 mutation status for the outcome of Ki67 change due to
the small number of mutation positive patients
Mutation Status:
PIK
3C
AE
SR
1
+-
+-
+-
+-+-
+-
0 40 60 80 10020
n= 14n= 20
n= 8n= 19
n= 11n= 22
n= 2n= 33
n= 1n= 28
n= 4n= 29
PIK3CA and ESR1 mutation status per patient by arm (%)
Abemaciclib + ANZ vs ANZ
GMR = 0.166, p<.001
PIK3CA
Mutant:
Mean
Ch
an
ge in
Ki6
7 (
%)
0
-20
-40
-60
-80
-100
n = 14 n = 11 n = 20 n = 22+ + - -
P= 0.441
0.267, p=.001
Interaction mutation
vs Ki67 outcome
-92.5 -54.9 -92.5 -71.9
Abemaciclib vs ANZ
PIK3CA
Mutant:
Mean
Ch
an
ge in
Ki6
7 (
%)
0
-20
-40
-60
-80
-100
n =8 n = 11 n = 19 n = 22+ + - -
GMR = 0.136, p=.001
P= 0.445
0.230, p<.001
Interaction mutation
vs Ki67 outcome
-93.9 -54.9 -93.5 -71.9
Geometric Mean Change
Abemaciclib + ANZ (N = 39a,d) Anastrozole (N = 36c,f)Abemaciclib (N = 34b,e) Mutant gene + Wild type gene-a,b,cPIK3CA mutation status was undetermined in 5 patients in the abemaciclib + ANZ arm, 7 patients in the abemaciclib arm, and 3 patients in the ANZ armd,e,fESR1 mutation status was undetermined in 4 patients in the abemaciclib + ANZ arm, 5 patients in the abemaciclib arm, and 3 patients in the ANZ arm
RESULTS (continued)Figure 6. Caliper, radiological, and pathological responses at the completion of study treatment (16 weeks)
Note: pCR is defined as absence of invasive disease in breast and sampled
axillary lymph nodes. pCR rate is reported as the percentage of randomized
patients with a pCR. aconfidence interval (CI) was based on the exact test for
the binomial. bP-value was calculated by 1-sided right tailed binomial exact
test. cOnly 190 patients underwent surgery
C. Pathological response (pCR)n = 190c
ORR (CR/PR)n (%) 95% CIa
120 (53.6) 46.8 – 60.2
A. Caliper response n = 224
17 (7.6)CR
103 (45.9)PR
36 (16.1)SD2 (0.9)PD
66 (29.5)*NE
Patients, n (%)
11 (4.9)CR
93 (41.5)PR
68 (30.4)SD5 (2.2)PD
47 (21.0)*NE
Patients, n (%)
B. Radiological response n = 224
ORR (CR/PR)n (%) 95% CIa
104 (46.4) 39.8 - 53.2
Note: Caliper and radiological
response were evaluated by
RECIST1.1. *The elevated %
of NE patients was due to the
absence of assessment at
the end of treatment
Abbreviations:
CR, complete response; PR,
partial response;
SD, stable disease;
PD, progressive disease; NE,
not evaluable;
ORR, overall response rate. aconfidence interval (CI) was
based on the exact test for
the binomial
n % 90% CIa P-valueb
pCR 7 3.7 2.1, 100.0 0.842
♦ The majority of patients showed tumor shrinkage, and 7 (3.7%) patients achieved pCR
RESULTS (continued)Table 1. Treatment-emergent adverse events at the end of treatment (16 weeks)
© 2016 Eli Lilly and Company56
Investigator assessed TEAEs ≥ 10% (N=223)
CTCAE Grade, n (%)
Grade 1 Grade 2 Grade 3 Grade 4 All Grades
Pts ≥ 1 TEAE 44 (19.7) 87 (39.0) 80 (35.9) 4 (1.8) 215 (96.4)
Diarrhea 92 (41.3) 34 (15.2) 11 (4.9) 0 137 (61.4)
Constipationa 72 (32.3) 21 (9.4) 4 (1.8) 0 97 (43.5)
Nausea 66 (29.6) 22 (9.9) 5 (2.2) - 93 (41.7)
Fatigue 57 (25.6) 25 (11.2) 6 (2.7) - 88 (39.5)
Abdominal pain 35 (15.7) 7 (3.1) 8 (3.6) - 50 (22.4)
Decreased appetite 32 (14.3) 12 (5.4) 4 (1.8) 0 48 (21.5)
Neutropenia 6 (2.7) 19 (8.5) 21 (9.4) 0 46 (20.6)
ALT increased 13 (5.8) 3 (1.3) 12 (5.4) 3 (1.3) 31 (13.9)
Vomiting 21 (9.4) 8 (3.6) 2 (0.9) 0 31 (13.9)
Anemia 13 (5.8) 14 (6.3) 2 (0.9) 0 29 (13.0)
Hot flush 24 (10.8) 5 (2.2) 0 - 29 (13.0)
Dysgeusia 18 (8.1) 7 (3.1) - - 25 (11.2)
Rash 14 (6.3) 7 (3.1) 3 (1.3) 0 24 (10.8)
AST increased 8 (3.6) 9 (4.0) 5 (2.2) 1 (0.4) 23 (10.3)
Headache 20 (9.0) 2 (0.9) 1 (0.4) - 23 (10.3)
Leukopenia 14 (6.3) 7 (3.1) 1(0.4) 1(0.4) 23 (10.3)a2 mg loperamide was administered prophylactically with each abemaciclib dose for the first 28 days and then at the investigator’s discretionNote: No Grade 5 was observed
Abbreviations: ALT, alanine aminotransferase, AST , aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events v4.0;
EOT, end of treatment
Markers of response to CDK4 & 6 inhibition from neoMONARCH: a phase II
neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive, HER2 negative breast
cancerSara Hurvitz1, Miguel Martin2, Sameera Wijayawardana3, Manisha Brahmachary3, Philip J Ebert3, Suzanne Young3, Valerie Jansen3,
Dennis Slamon1
1University of California, Los Angeles, CA; 2Instituto de Investigacion Sanitaria Gregorio Marañon, Universidad Complutense, Ciberonc, Madrid, Spain; 3Eli Lilly and Company,
Indianapolis, IN
P3-10-08
RESULTSFigure 4. Addition of abemaciclib to ANZ therapy led to complete cell cycle arrest in majority of ANZ-resistant tumors
♦ Data from 19 tumors with available Ki67 IHC at all 3 timepoints that were treated with ANZ (n = 5, ANZ-sensitive tumors; n = 14, ANZ-resistant tumors) for 2 weeks followed by 14 weeks of abemaciclib and ANZ.
♦ Ki67 IHC expression in tumor specimens was measured at baseline, 2 weeks after initial treatment with ANZ alone, and EOT after 14 weeks of combination therapy. All patients received abemaciclib + ANZ after 2 weeks of initial treatment.
♦ ANZ-sensitive tumors (n = 5) were defined by an expression of Ki67 ≤ 2.7% at 2 weeks
♦ ANZ-resistant/abemaciclib+ANZ-sensitive tumors (n= 9) were defined by Ki67 >7.4% at 2 weeks, and Ki67 ≤ 2.7% at EOT
♦ ANZ-resistant/abemaciclib+ANZ-resistant tumors (n= 5) had an expression of Ki67>2.7% at 2 weeks, and Ki67 >7.4% at EOT
Note: Numbers represent the patient 1-6 who have IHC staining shown in Figure 5Abbreviations: ANZ, anastrozole; EOT, end of treatment
Figure 11. Differential baseline gene expression in intrinsically resistant subgroup from RNAseq analysis
♦ Intrinsically resistant tumors displayed higher expression (relative to sensitive tumors) of
genes in pathways involved in cell cycle and immune response and lower expression of
genes in pathways involved with estrogen signaling and metabolism
♦ These results suggest baseline gene expression analysis might be used to predict
response to abemaciclib plus endocrine therapy
(A) GSEA of resistant versus sensitive subgroups at baseline for the top downregulated and upregulated pathways (FDR cutoff at 0.05). (B) Heatmap of the top differentiated genes between resistant and sensitive groups at baseline. Patient tumors were categorized by the post-treatment Ki67 expression as either sensitive (Ki67 ≤2.7 at 2 and 16 weeks) or intrinsically resistant (Ki67 ≥7.4 at 2 and 16 weeks)
Cell cycle
Estrogen signaling
Immune response
CONCLUSIONS
♦ Both MODAplex and RNAseq analyses revealed differential gene expression between
resistant and sensitive early-stage HR+, HER2- BC tumors from patients treated on the
neoMONARCH study
♦ High RB1 mRNA and low Rb-loss-of-function gene expression signature were associated
with sensitivity to abemaciclib monotherapy, based on this small subset of tumors from
neoMONARCH
♦ Gene expression analysis revealed that tumors intrinsically resistant to any therapy
displayed higher levels of cell cycle and immune related genes at baseline compared to
sensitive tumors
♦ Together, these data suggest that the early changes in CCAG gene expression and baseline gene expression pathways might be used to predict response to abemaciclib and endocrine therapy in early-stage HR+, HER2- breast cancer
Conclusiones
• Los inhibidores de CDK 4/6 en combinación con hormonas aumentan de
forma estadísticamente significativa y clínicamente relevante el PFS en
mujeres metastásicas con tumores HR+/HER2-.
• No existe ningún subgrupo de enfermas que no se beneficie de la
combinación en primera o segunda línea
• Es muy probable que el beneficio se traslade a un aumento de
supervivencia, aunque de menor magnitud
• La mayoría de las enfermas HR+/HER2- metastásicas deberían recibir
inhibidores de CDK 4/6 en primera o segunda línea.
• No hay evidencias de que un fármaco sea superior a otro(s) dentro del
grupo.
• Estos fármacos se están actualmente desarrollando en adyuvancia.
Table 2. Prior Therapies
Endocrine Therapy for
ABC (# of regimens), n (%)a
1 21 (26.9) 24 (30.4) 26 (33.8)
2 23 (29.5) 26 (32.9) 16 (20.8)
>3 16 (20.5) 16 (20.3) 15 (19.5)
Chemotherapy
by setting, n (%)
1 regimen for ABC 43 (55.1) 36 (45.6) 40 (51.9)
2 regimens for ABC 30 (38.5) 39 (49.4) 33 (42.9)
3 regimens for ABC 3 (3.8) 0 0
Chemotherapy
in any setting, n (%)
Taxanes 68 (87.2) 71 (89.9) 66 (85.7)
Capecitabine 30 (38.5) 43 (54.4) 27 (35.1)
aprior fulvestrant in metastatic setting: 22 (28.2%) in arm A; 20 (25.3%) in arm B; 18 (23.4%) in arm C
abemaciclib 150 mg + tamoxifen
N = 78
abemaciclib 150 mgN = 79
abemaciclib 200 mg N = 77
Figure 1. Primary Endpoint: Investigator-assessed Progression-free Survival
HRa 95% CI p value
A vs Cb .815 .556, 1.193 .293
B vs C 1.045 .711, 1.535 .811
A vs B .805 .551, 1.177 .256
astratified HRbprimary endpoint was A vs C
Median PFS
Arm A (abemaciclib 150 mg + tamoxifen): 9.1 monthsArm B (abemaciclib 150 mg): 6.5 monthsArm C (abemaciclib 200 mg): 7.4 months
Figure 2. Change in Tumor Size from BaselineC
hange f
rom
Baselin
e (
%)
20% Increase
30% Decrease
20% Increase
30% Decrease
20% Increase
30% Decrease
ARM A
ARM C
ARM B
N = 78 ORRa CBRa
Investigator-assessed 34.6% 61.5%
Confirmed 25.6% 57.7%
N= 77 ORRa CBRa
Investigator-assessed 32.5% 51.9%
Confirmed 28.6% 49.4%
N= 79 ORRa CBRa
Investigator-assessed 24.1% 49.4%
Confirmed 19.0% 46.8%
aORR and CBR were not statistically significant between any arm
Table 4. Treatment-emergent Adverse Events(Safety Population)
Grade (≥15 % occurrence in any arm), n (%)
Any Grade 3 Any Grade 3 Any Grade 3
Any Adverse Event 73 (93.6)a 33 (42.3) 77 (97.5)d 34 (43.0) 76 (98.7)h 46 (59.7)
Diarrhea 42 (53.8) 1 (1.3) 53 (67.1) 3 (3.8) 48 (62.3) 6 (7.8)
Neutropenia 32 (41.0)b 14 (17.9) 40 (50.6)e 21 (26.6) 40 (51.9)i 26 (33.8)
Anemia 31 (39.7) 9 (11.5) 25 (31.6) 6 (7.6) 32 (41.6) 8 (10.4)
Nausea 24 (30.8) 2 (2.6) 26 (32.9)f 2 (2.5) 33 (42.9) 2 (2.6)
Leukopenia 21 (26.9) 8 (10.3) 27 (34.2) 10 (12.7) 21 (27.3) 9 (11.7)
Fatigue 23 (29.5) 3 (3.8) 20 (25.3) 2 (2.5) 22 (28.6) 5 (6.5)
Abdominal Pain 21 (26.9) 0 17 (21.5) 1 (1.3) 25 (32.5) 0
Thrombocytopenia 15 (19.2)c 2 (2.6) 12 (15.2)g 3 (3.8) 27 (35.1)j 2 (2.6)
Vomiting 14 (17.9) 2 (2.6) 20 (25.3) 3 (3.8) 20 (26.0) 4 (5.2)
Decreased Appetite 20 (25.6) 4 (5.1) 12 (15.2) 1 (1.3) 17 (22.1) 2 (2.6)
Constipation 10 (12.8) 0 9 (11.4) 0 25 (32.5) 1 (1.3)
Muscular Weakness 14 (17.9) 2 (2.6) 12 (15.2) 1 (1.3) 7 (9.1) 2 (2.6)
Blood Creatinine Increased 14 (17.9) 1 (1.3) 8 (10.1) 0 8 (10.4) 0
Dyspnea 9 (11.5) 2 (2.6) 13 (16.5) 3 (3.8) 5 (6.5) 0
abemaciclib 150 mg+ tamoxifen
N = 78
abemaciclib 150 mgN = 79
abemaciclib 200 mgN = 77
Grade 4 events, n (%): a 6 (7.7)b 2 (2.6)c 1 (1.3)
d 4 (5.1)e 1 (1.3)f 1 (1.3)g1 (1.3)
h 8 (10.4)i 3 (3.9)j 3 (3.9)
Table 5. Overview of Treatment-emergent Diarrhea (Safety Population)
Median Time to First Onset, days (range) 14.0 (1-219) 11.0 (1-596) 10.5 (2-351)
Duration of Grade 2/3 Diarrhea, daysa
4.5/3.0 7.0/4.0 3.5/4.5
Patients with ≥1 Diarrhea Event, n 42 53 48
Use of Antidiarrheal Medication, n (%)b
Loperamide 20 (47.6) 30 (56.6) 15 (31.3)c
Other 9 (21.4) 8 (15.1) 8 (16.7)
Dose Omission of abemaciclib, n (%)b
2 (4.8) 6 (11.3) 6 (12.5)
Dose Reduction of abemaciclib, n (%)b
1 (2.4) 4 (7.5) 7 (14.6)
a1 patient across study arms discontinued study treatment due to diarrheabpercentage was calculated based on the number of patients with ≥1 diarrhea eventcloperamide was administered as supportive therapy and does not include prophylactic doses administered during cycle 1
abemaciclib 150 mg+ tamoxifen
N = 78
abemaciclib 150 mgN = 79
abemaciclib 200 mgN = 77
Table 6. Occurrence of Venous Thromboembolism
Preferred terma
Total, n (%) 7 (9.0) 4 (5.1) 3 (3.9)
Venous
DVT, n (%) 3 (3.8) 2 (2.5) 1 (1.3)
PE, n (%) 4 (5.1) 2 (2.5) 2 (2.6)b
Death 0 0 0
Discontinued Treatment 0 0 0
SAE, n (%) 3 (3.8) 2 (2.5) 1 (1.3)
amapped from AE verbatim (i.e. reported term)b1 DVT and 1 PE event occurred in the same patient on the same day; reported here as PE
1 patient in each arm had an arterial thromboembolism event
abemaciclib 150 mg+ tamoxifen
N = 78
abemaciclib 150 mgN = 79
abemaciclib 200 mgN = 77
Conclusions
68
♦ nextMONARCH 1 confirmed the single-agent activity of abemaciclib in HR+,
HER2- MBC patients who experienced progression after prior chemotherapy and
ET
♦ Combining tamoxifen with abemaciclib resulted in numerically higher PFS but did
not demonstrate a statistically significant improvement in PFS compared to
abemaciclib 200 mg monotherapy. Efficacy of abemaciclib monotherapy was
similar at both 150 mg and 200 mg dose levels
♦ Addition of prophylactic loperamide to abemaciclib 200 mg resulted in treatment-
emergent diarrhea similar to abemaciclib 150 mg without prophylaxis
♦ Compared to the MONARCH 1 study, rates of grade 2 and 3 diarrhea were lower
across all arms. Early onset of treatment-emergent diarrhea is dose-dependent
and best managed with antidiarrheal medication and dose omissions/reductions
References
69
Abbreviations: ABC, advanced breast cancer; AEs, adverse events; CBR,
clinical benefit rate; CDK, cyclin-dependent kinase; CI, confidence interval;
DVT; deep vein thrombosis; ECOG PS, Eastern Cooperative Oncology
Group performance status; ET, endocrine therapy; HER2-, human
epidermal growth factor receptor 2 negative; HR, hazard ratio; HR+,
hormone receptor-positive; MBC, metastatic breast cancer; ORR, objective
response rate; OS, overall survival; PE, pulmonary embolism; PFS,
progression-free survival; PgR, progesterone receptor; QD, every day;
Q12H, every 12 hours; SAEs, serious adverse events; TAM, tamoxifen
1. Cardoso F, et al. Breast 2017;31:244-59
2. Cardoso F, et al. Ann Oncol 2017;28(1):16-333. Milani A, et al. World J Clin Oncol 2014;5(5):990-10014. Dickler MN, et al. Clin Cancer Res 2017;23(17):5218-245. Sledge GW Jr, et al. J Clin Oncol 2017;35(25):2875-846. Goetz MP, et al. J Clin Oncol 2017 Nov 10;35(32):3638-467. Cristofanilli M, et al. Eur J Cancer 2018;104:21-318. Slamon DJ, et al. J Clin Oncol 2018;36(24):2465-729. Patnaik A, et al. Cancer Discov 2016;6(7):740-53
MONARCH ·: ORR and CBR
All patients, n 328 165
Objective Response Rate, % (95% CI) 48.2 (42.8, 53.6) 34.5 (27.3, 41.8) 0.002
Complete Response, n (%) 5 (1.5) 0
Clinical Benefit Rate, % (95% CI) 78.0 (73.6, 82.5) 71.5 (64.6, 78.4) 0.101
Patients with measurable disease at baseline, n
267 130
Objective Response Rate, % (95% CI) 59.2 (53.3, 65.1) 43.8 (35.3, 52.4) 0.004
Complete Response, n (%) 5 (1.9) 0
Clinical Benefit Rate, % (95% CI) 79.4 (74.5, 84.3) 69.2 (61.3, 77.2) 0.024
p valueplacebo + NSAIabemaciclib + NSAIResponse
MONARCH ·: ORR and CBR
All patients, n 328 165
Objective Response Rate, % (95% CI) 48.2 (42.8, 53.6) 34.5 (27.3, 41.8) 0.002
Complete Response, n (%) 5 (1.5) 0
Clinical Benefit Rate, % (95% CI) 78.0 (73.6, 82.5) 71.5 (64.6, 78.4) 0.101
Patients with measurable disease at baseline, n
267 130
Objective Response Rate, % (95% CI) 59.2 (53.3, 65.1) 43.8 (35.3, 52.4) 0.004
Complete Response, n (%) 5 (1.9) 0
Clinical Benefit Rate, % (95% CI) 79.4 (74.5, 84.3) 69.2 (61.3, 77.2) 0.024
p valueplacebo + NSAIabemaciclib + NSAIResponse
MONARCH 3: side effects
Phase III study in women with HR+, HER2– with locally advanced or mBC1
• Postmenopausal
women with HR+,
HER2–
locoregionally
recurrent or
metastatic BC
• No prior systemic
therapy for
advanced disease
Placebo +anastrozole or letrozole*
Abemaciclib + anastrozole or letrozole*
Ran
do
miz
ati
on
2:1
Primary endpoint PFS
Secondary endpoints OS
ORR
DCR
DOR
CBR
QoL
PK
MONARCH-3
Abemaciclib in combination with NSAIs in HR+, HER2– mBC
1. NCT02246621. Clinicaltrials.gov: http://www.clinicaltrials.gov. Accessed May 2015.
*150 mg of oral abemaciclib or matching placebo given once every 12 hours in 28 day cycles. 1 mg anastrozole given once daily in 28-day cycles.
2.5 mg letrozole given once daily in 28-day cycles.
BC, breast cancer; CBR, clinical benefit rate; DCR, disease control rate; DOR, duration of response;
HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; NSAI, non-steroidal aromatase inhibitor;
ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QoL, quality of life.
Abemaciclib Phase III trials
Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer (PALOMA 3 trial)
Turner N et al, N Engl J Med 2018;379:1926.
Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer (PALOMA 3 trial)
Turner N et al,
Among 521 patients who underwent randomization, the median overall survival
was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–
fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulves-
trant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute
difference, 6.9 months).
Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer (PALOMA 3 trial)
Turner N et al, N Engl J Med 2018;379:1926.
LEE011 development in BC
Specifically inhibits CDK4 and 6 in tumors with full functional pRb (intact total pRbby IHC)
Phase I recommended dose 600 mg/d 21-of-28 day dosing schedule
AEs: neutropenia (19%), leukopenia (12%) and lymphopenia (14%)
Infante et al AACR 2012 & O'Brien et al AACR 2014
Trial Phase(N)
Design Population PrimaryEndpoint
MONALEESA-1 II(120)
LEE011+LET (400
mg or 600 mg) vs LETNA (resectable BC)
Cell-cycleRR (Ki 67)
MONALEESA-2 III(550)
LEE011600 mg+LETvs Pbo+LET
1L MBC PFS
* Other combinations with EVE+EXE, BYL719+LET or FULV+BYL719 or BKM120 being tested in phase I CTs (preclinical in vivo/in vitro evidence of potential efficacy of triple-combination)
LY2835219 development in BCSpecifically inhibits CDK4 and 6
Recommended dose 200 mg /12 h in 28d cycles
Phase I trial:AEs: diarrhea (5% G3-4), nausea (3% G3-4), fatigue (2%
G3-4) and neutropenia (11% G3-4)
MBC cohort (N=47) median 7 prior regimens (highly pre-treated)
ORR 25% in HR+ confirmed BC and 56% SD rate
Disease control rate: 70% all MBC and 81% HR+ MBC
Median PFS: 5.8 mo all MBC and 9.1 mo HR+ MBC
NCT02107703
Infante et al AACR 2012 & Patniak et al AACR 2014
Trial Phase(N)
Design Population PrimaryEndpoint
NCT02057133 I(81)
LY2835219+HT(LET, ANA, TAM, EXE or EXE+EVE)
MBC Drug-related AEs
NCT02102490 II(128)
LY2835219 200mg/12hx28d
MBC ORR
NCT02107703 III(550)
LY2835219+FULvs Pbo+FUL
MBC PFS
P276-00Selectively inhibits CDK4/cyclin D1, CDK1/cyclin B and CDK9/cyclin T1
Preclinical data: induces G1-G2 arrest and shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models
Phase I/II in TN-MBC pts testing GEM 1000 mg/m2 + CARBO AUC2 d1, 8 q 21d vs P276-00 100mg starting dose d1-5 with CT
Joshi et al Mol Cancer Ther 2007
Other CDK/cyclin inhibitors in BC
Dinaciclib (SCH 727965)
• Selectively inhibits CDK1, CDK2, CDK5 and CDK9
• Preclinical data: inhibition of CDK1 and CDK2 may result in cell cycle repression and tumor cell apoptosis
• Phase I in TN-MBC pts testing dinaciclib + epirubicin
MONALEESA 2
• Postmenopausal
women with
HR+/HER2–
advanced breast
cancer
• No prior therapy
for advanced
disease
• N=668
(1:1)
RANDOMIZATION
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
Hortobagyi G et al, NEJM 2017
MONALEESA 2: PFS
Hortobagyi G et al, NEJM 2016
MONALEESA 2: PFS
Hortobagyi G et al, NEJM 2016
MONALEESA 2: ORR and CBR
Hortobagyi G et al, NEJM 2016
MONALEESA 2: Side effects
0
Median TTP/PFS (months)
12 246 18
Evolution of therapy for endocrine sensitive metastatic breast cancer
PFS, progression-free survival; TTP, time-to-progression1.Ellis M, et al. ESMO 2016, LBA14_PR; 2. Finn RS, et al. N Engl J Med 2016;375:1925–36; 3.Hortobagyi G, et al. N Engl J Med 2016;375:1738–48
Letrozole + palbociclib or ribociclib or abemaciclib24.8 months7
Fulvestrant 500 mg16.6 months1
Aromatase inhibitors13–15 months1-3
HR+/HER2- MBC: Objective Response Rate to First Line withDifferent Therapies
0 10 20 30 40 50 60
AROMATASE INHIBITORS*
FULVESTRANT 500MG (1)
AI PLUS RIBOCICLIB (2)
AI PLUS PALBOCICLIB (3)
AI PLUS ABEMACICLIB (4)
%ORR
39%
48.2%
42.1%
34.8%
40.7%
Data from: 1) Robertson JFR et al. Lancet 2016; 2) Hortobagyi G et al, NEJM 2017; 3) Finn R et al, NEJM 2016; 4). Goetz MP et al, J Clin Oncol. 2017; * pooled data
of the control arm of the trials
AE, %
First-Line (grade 3-4)
Palbo + AI1 Ribo + AI2 Abema + AI3
Neutropenia 56 + 10 50 + 10 20 + 2
Diarrhea 1 + 0 1 + 0 9 + 0
Liver enzymes* <1* 16* 13*
QTc prol NR <1 NR
TEP/VE NR + <1 <1 + <1 5 (grade?)
4Turner NC, et al. N Engl J Med 2015; 5Cristofanilli M, et al. Lancet Oncol 2016; 6Sledge G, et al. J Clin Oncol 2017
1Finn RS, et al. N Engl J Med 2016; 2Hortobagyi G, et al. N Engl J Med 2016; 3di Leo A, et al. J Clin Oncol 2017
Main toxicities of CDK 4-6 inhibitors
*all grades
CDK 4-6 inhibitors in patients with prior AIs
MONARCH 2 Median PFS 1
abemaciclib + fulvestrant: 16.44 months (N = 446)placebo + fulvestrant: 9.27 months (N = 223)
HR, 0.553 (95% CI, 0.449 to 0.681)
p <.0000001
0
PFS (months)
12 246 18
Sequence of therapies in hormone-sensitibe MBC
PFS, progression-free survival; TTP, time-to-progression1.Ellis M, et al. ESMO 2016, LBA14_PR; 2. Finn RS, et al. N Engl J Med 2016;375:1925–36; 3.Hortobagyi G, et al. N Engl J Med 2016;375:1738–48
Letrozole plus palbociclib or ribociclib or abemaciclib
24.8 months7
Fulvestrant 500 mg16.6 months1
Aromatase inhibitors13–15 months1-3
30 36 42
Fulvestrant plus abemaciclib
16.5 mo
Fulvestrant 500 mg4-9 mo
Aromatase inhibitors
plus CDK 4-6 inh
?
0
PFS (months)
12 246 18
Sequence of therapies in hormone-sensitibe MBC
PFS, progression-free survival; TTP, time-to-progression1.Ellis M, et al. ESMO 2016, LBA14_PR; 2. Finn RS, et al. N Engl J Med 2016;375:1925–36; 3.Hortobagyi G, et al. N Engl J Med 2016;375:1738–48
Letrozole plus palbociclib or ribociclib or abemaciclib
24.8 months7
Fulvestrant 500 mg16.6 months1
Aromatase inhibitors13–15 months1-3
30 36 42
Fulvestrant plus abemaciclib
16.5 mo
Fulvestrant 500 mg4-9 mo
Aromatase inhibitors
plus CDK 4-6 inh
?
Combination Trials