the spinning of cdk4/6 inhibitors in hormone-positive ... · las ciclinas d1 y cdk4 son...

Ana LluchHospital Clínic Universitari de València

The spinning of CDK4/6 inhibitors in Hormone-PositiveBreast Cancer Care

Potential Conflicts of Interests

• Clinical Research: Amgen, Astra Zeneca, Boehringer-Ingelheim, Novartis, Pfizer, Roche/Genentech, Eisai, Celgene. Lilly

• Academic Research Projects: GEICAM, SOLTI. MINISTERIO SANIDAD, AECC.

• Advisory Boards and Consulting: Novartis, Pfizer, Roche/Genentech,Lilly. Celgene.

• No financial conflicts to declare.

Index

• Endocrine therapy plus CDK 4-6 inhibitors as a new standardtreatment for advanced breast cancer HR + / HER2-

• Hormonosensitive and Resistant Endocrine Disease• Programme trials PALOMA, MONARCH and MONALEESA• Positioning CDK 4-6 inhibitors in standard clinical practice

Introduction

Metastatic breast cancer

• More than 2/3 of breast cancers are positive hormone receptor

• The treatment of choice for these patients is endocrine treatment

• Over time, the tumors become endocrine-resistant

New effective treatments

are needed in endocrine-

resistant tumors

Luminal Disease

2018 → change of standard in the systemic treatment of luminal disease New systemic therapies

• Fulvestrant superior to IA in Novo patients • Combination with Cyclin Inhibitors as "new standard" in first - second lines • New PI3K inhibitors

Traceable and actionable resistance mechanisms

• PI3K mutations • ESR1 mutations

Advanced Breast Cancer TreatmentWe must offer the best treatment with the least toxicity

The best option for hormonesensitivepatients is

HORMONOTHERAPY

International Treatment Guidelines Emphasise Endocrine Therapy

for HR+/HER2– ABCASCO recommendations1

Endocrine therapy, rather than chemotherapy, should be offered as the standard first-line treatment for patients with hormone

receptor–positive advanced/metastatic breast cancer, except for immediately life threatening disease or if there is concern regarding

endocrine resistance.

•The main benefit is less toxicity and better quality of life for the patient associated with endocrine therapy compared with

chemotherapy (potential benefit: high). The harm is that metastatic disease could progress rapidly and prove fatal if there is no response,

but the risk of this is low (potential harm: low).

ESMO/ABC2 recommendations2

ESMO guidelines reinforce the preferential use of endocrine therapy, even in the presence of visceral metastases, for

ER-positive, HER-2-negative advanced breast cancer. Chemotherapy should be reserved for cases of rapidly progressive disease or

proven endocrine-resistance.

NCCN recommendations3

Women with recurrent or metastatic disease characterized by tumors that are ER- and/or PR-positive are appropriate candidates

for initial endocrine therapy.

✓ Less toxic

✓ Better QoL

1. Partridge AH, et al. J Clin Oncol 2014;32:3307–3329;2. Cardoso F, et al. The Breast 2014;23:489–502; 3. NCCN Guidelines: Breast Cancer. Version 3.2017.

Cyclin Inhibitors

They are potent selective inhibitors of CDK 4/6

kinase activity, which inhibit cell proliferationby blocking the progression of the cell cycle from the G1 to S phase.

Las ciclinas y la regulación del ciclo celularLas ciclinas D1 y CDK4 son “drivers” de la oncogenesis en CM

La inhibición de CDK4/6 reduce la proliferación

celular en cáncer de mama resistente a HT

• Las ciclinas son las principales proteínas encargadasde la regulación del ciclo celular y actúan regulandola actividad de las quinasas dependientes de ciclinaso CKDS

• CD1, que activa CDK4 y CDK6, está amplificada en un15-20% de los casos de cáncer de mama

• La interacción de la ciclina D1 con la CDK4 y 6, facilitala hiperfosforilación de la proteína delretinoblastoma que promueve la progresión de laFase G1 del ciclo celular a Fase S

CDK4-6 están sobreactivadas ennumerosos cánceres produciendo

pérdida del control de la proliferación.

CDK4 / 6 on the first line RH + HER2- Phase III Registration Studies

New Combinations with cell cycle inhibitors

Palbociclib + Letrozole

n = 444

Placebo + Letrozole

n = 222

Postmenopausal women with HR+, HER2– advanced breast cancer (N =

666)

No prior therapy for advanced disease

Randomization (2:1)

Primary endpointPFSSecondary endpointsOS, ORR, safety, PRO

Primary endpoint

PFS

Secondary endpoints

OS, DoR, DCR, CBR,

ORR, PRO, safety,

tolerability

Abemaciclib + NSAIPostmenopausal women with HR+, HER2– advanced breast

cancer (N = 450)


Randomization (2:1)

Placebo + NSAI

Ribociclib + Letrozole

n = 334

Placebo + Letrozole

n = 334

Primary endpointPFS

Secondary endpointsOS (key), ORR, CBR,Safety, PRO, TTD for ECOG PS

Postmenopausal women with HR+, HER2– advanced breast

cancer (N = 668)


Randomization (1:1)

MO

NA

LEES

A-2

PA

LOM

A-2

PALOMA 3: PALBOCICLIB ESMO 2018

OS 34.9 months

OS 28.0 months

PALOMA 3: PALBOCICLIB ESMO 2018

OS 39.7 months

OS 29.7 months

MONALEESA-2 Fase III ribociclib + letrozol en CMA HR+, HER2-1,2

Estratificado por la presencia/ausenciade metástasishepáticas y/o pulmonares

R 1:1

Main goal• SLP (local evaluation local

according to RECIST v.1.1)

Secondary goals• SG (fundamental)• TRG• TBC• Security and tolerance• CdV

PATIENES (N=668)

• Postemenopausalwomen with CMA HR+, HER2-

•No pretreatment foradvanced disease

RIBOCICLIB600 mg/day, 3 weeks of

treatment/1 week without treatment+

letrozol 2,5 mg/day, continuous pattern(n=334)

Placebo3 weeks of treatment / 1 week

without treatment + letrozol 2,5 mg/day in continuous

pattern(n=334)

• Tumor evaluations were performed every 8 weeks for the first 18 months, and then every 12 weeks

• The final analysis was planned after 302 SLP-93.5% power events to detect a risk reduction of 33% (hazard ratio 0.67) with α = 2.5% unilateral

• On the cut-off date of the data for the intermediate analysis (January 29, 2016), there were 243 SLP events (80% fraction of information)

1. Hortobagyi GN et al. N Engl J Med 2016;375:1738-48. 2. Hortobagyi GN et al. Ann Oncol 2016;27(Suppl

6): abstr LBA 3552 (oral).

No. at Risk

Ribociclib + Letrozole

334 294 277 257 240 227 207 196 188 176 164 132 97 46 17 11 1 0

Placebo + Letrozole

334 279 265 239 219 196 179 156 138 124 110 93 63 34 10 7 2 0

Ribociclib + Letrozole n=334

Placebo + Letrozole n=334

Number of events, n (%) 140 (41.9) 205 (61.4)

Median PFS, months(95% CI)

25.3 (23.0–30.3)

16.0 (13.4–18.2)

Hazard ratio (95% CI) 0.568 (0.457–0.704)

p value 9.63 x 10-8

ASCO 2017

In a subsequent analysis with an additional 11 months of follow-up, the median PFS was 25.3 months with RIBOCICLIB + letrozole versus 16.0 months with placebo + letrozole (HR = 0.568 [95% CI: 0.457-0.704], P <0.0001)1

0 342 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Time (Months)

0

20

40

60

80

100

Pro

ba

bilit

y o

f P

FS

(%

)

1. Hortobagyi GN et al. American Society de Clinical Oncology Annual Meeting; 2017; Poster 1038.

MONALEESA-2: Eficacia1

• 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

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

37ECOG 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.http://ascopubs.org/doi/abs/10.1200/JCO.2018.78.9909 DOI:

10.1200/JCO.2018.78.9909

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

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

Primary endpoint: PFS (investigator-assessed)

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

Pro

babilit

yof

PFS

(%)

100

80

60

40

20

0

No. at risk

Ribociclib + fulvestrant

Placebo + fulvestrant

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

484 403 365 347 324 305 282 259 235 155 78 52 13 0

242 195 168 156 144 134 116 106 95 53 27 14 4 0

CI, confidence interval.

• The hazard ratio of 0.593 corresponds to a 41% reduction in risk of

progression in the ribociclib vs placebo arm

aNo prior endocrine therapy for ABC;bUp to one line of prior endocrine therapy for ABC or relapse on/within 12 months of (neo)adjuvant endocrine therapy; cInvestigator assessed.

1. Slamon DJ et al. ASCO 2018;abst 1000 (oral); 2. Slamon DJ et al. J Clin Oncol 2018;36:2465–2472.

PFS BENEFIT CONSISTENT ACROSS TREATMENT SETTINGS

First linea Second line + early relapseb

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

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

Pro

bab

ility

of

PFS

(%

)

26181614121086420 20 22 24

0

20

40

60

80

100

Time (months)

Pro

bab

ility

of

PFS

(%

)

26222016121086420 1814 24

0

20

40

60

80

100

Time (months)No. at risk



No. at risk



PFSc,1,2Ribociclib +fulvestrant

n=238


n=129Median PFS, months

NR 18.3

HR (95% CI) 0.58 (0.42–0.80)

PFSc,1,2Ribociclib +fulvestrant

n=236


n=109Median PFS, months

14.6 9.1

HR (95% CI) 0.57 (0.43–0.74)

1810

0619

67

ESMO 2018

First Line MBC CDK4/6i +ET vs ET monotherapy

Forest plot of HRs for PFS in trials of CDKi + ET compared ET alonefor endocrine-sensitive disease

Messina C et al. Breast Cancer Res Treat 2018

Five phase III trials (PALOMA-2, MONALEESA-2, MONARCH-3, MONALEESA-7, MONALEESA-3) One phase II trial (PALOMA-1) and assessed the efficacy of CDK inhibitor plus ET versus ETalone in endocrine sensitive setting.(MONALEESA 3 included women ET naïve or who progressed to one prior line of ET)

A total of 2009 patients were enrolled in the CDKi plus ET arm and 1381 in the ET arm. The addition of CDKi to ET was associated

with a statistically significant PFS benefit (HR 0.55, 95% CI 0.50–0.62) for metastatic HR+/HER2− breast cancer patients in endocrine-sensitive setting.

Second Line MBC CDK4/6i + ET vs ET

monotherapy

Are CDK 4-6 inhibitors plus endocrine therapy the new standard for advanced breast cancer ER + / HER2- sensitive and

resistant?

Endocrine therapy in 2018:Conclusions

➢ CDK4 / 6 inhibitors introduce a "revolutionary" change in the clinical management of patients with advanced luminal disease.



➢ High clinical benefit against "classical" endocrine therapy (HR PFS 0.56) is not conditioned by a different toxicity profile or a compromise in quality of life




➢ In patients with a high hormonal sensitivity profile, the combination of letrozole with cyclin inhibitors in the first line, offers a control of disease superior to any other hormonal option and a better global control of the disease against delaying the introduction of cyclin inhibitors to the second line





➢ In patients with aggressive profile (visceral disease, symptomatic) and without criteria of visceral crisis the option of Cyclin Inhibitors offers response rates in line with the best option of chemotherapy with a longer control of the disease





➢ In patients with aggressive profile (visceral disease, symptomatic) and without criteria of visceral crisis the option of Cyclin Inhibitors offers response rates in line with the best option of chemotherapy with a longer control of the disease

➢ In the absence of mature global survival data that would allow cyclin inhibitors to be established as standard first-line therapy, the relevant question in clinical practice is which patient with advanced luminal disease does not require therapy with initial Cyclin Inhibitors.

Next Directions for CDK4/6 Inhibitors

- Biomarkers that can predict response to a CDK4 / 6 inhibitor- Determine if a CDK4 / 6 inhibitor should be continued or changed after progression- CDK4 / 6 inhibitors can be combined with other non-endocrine therapies- Role in early breast cancer and in breast cancer HR + / HER2 +

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