inhibidores de la cdk 4/6: resultados y papel de la … · • bind within the atp-binding pocket...

Inhibidores de la CDK 4/6: Resultados y papel de la nueva

diana terapéutica en el CM metastásico RE+/HER2- S López-Tarruella, MD, PhD

a

b

c

d

Tumor Microenvironment

NR: ER: variants,

loss

ERβ

EER

AR

Coregulators

TKR/GF: EGFR/HER2

IGFR, FGFR,

VEGFR2

FGFR

Cellular Kinases: MEK/MAPK

PTEN/PI3K/Akt

P38/JNK

SRC/FAK

TF: AP1

SP1

NFkB

Stress

Responses: Treatments

Cytokines

Hypoxia

OS/ROS

Pathways: Cell Cycle (Cyclin D,

E) Survival (Bcl, BAD)

Proliferation (Myc)

F

T

AI

F AI

T +

Integrins

Osborne CK & Schiff R Ann Rev Med 2011, TCGA Nature 2012

ER SIGNALING &

ED_RESISTANCE

MECHANISMS

Killing 2nd messenger: targeting loss of cell cycle control

Lange & Yee End Relat Cancer 2011

Mitogenic signaling pathways

• Mitogenic or GFR signalling

pathways converge on the cyclin

D–CDK4 or CDK6–RB axis

• Activation of CDK4 or CDK6

RB phosphorylation

inactivation of Rb cell

progression from G1 to S…G2...M

(associated with resistance to ED

therapy)

Cell Cycle (Cyclin D1-CDK4/6 pathway)

RB “the master-regulator” of R-point

• Protein kinases control cell cycle

progression & depend on associating

regulatory subunits, cyclins

Cyclin Inhibitors Landscape

Malumbres & Barbacid. Nat Rev Cancer 2001, Asghar et al Nat Rev Drug Discov 2015

Sele

ctiv

ity

Agent Target

Alvociclib (flavopiridol) CDK 1/2/4/6/7/9

Seliciclib (Roscovitine) CDK 2/7/9

Dinaciclib (SCH 727965) CDK 1/2/5/9

SNS-032 CDK 1/2/4/9

Palbociclib (PD 0332991) CDK 4/6

Abemaciclib

(LY2835219)

CDK 4/6

Ribociclib (LEE 011) CDK 4/6

• 1G: pan-CDK inhibitors (relatively non-specific) (phase I/II)

• 2G: increasing selectivity for CDK1/2 and increasing overall potency (phase I/II)

Will improved selectivity for certain CDKs be the key to the successful development of

CDK inhibitors as therapeutic cancer agents? • CDK4/6 inhs: elicit cytostatic G0/G1 arrest & direct reflection of the engagement of RB to

suppress gene expression and proliferation

- lack of clear understanding of the mechanism of action

- lack of appropriate patient selection

- lack of a therapeutic window

Chemical structure of selective CDK4/6 inhibitors

O’Leary et al Nat Rev Clin Oncol 2016

• Orally-administered compounds are of similar structure

• Bind within the ATP-binding pocket of CDK4 and CDK6

• High degree of selectivity for CDK4 and CDK6, compared with CDK1 and CDK2

*

Preclinical PALBOCICLIB

• Identification of differentially expressed genes and sensitivity to PD 0332991: Rb and cyclin D1 expression and CDKN2A (p16) in sensitive cell lines

• PD 0332991 blocks Rb phosphorylation in sensitive cell lines

• PD 0332991 acts synergistically with TAM in inhibiting growth of ER-positive human BC cell lines

• PD 0332991 overcomes acquired resistance to tamoxifen: enhances the effects of TAM in an MCF7 tamoxifen-insensitive cell line

Finn et al Breast Cancer Res 2009

In vitro sensitivity to PD 0332991 across a panel of human BC cell lines

Early phases of PALBOCICLIB development

• First-in-human: Advanced solid tumors & NHL with intact Rb (N=33), 2wks

on/1wk off (2/1). DLTs: neutropenia & thrombocytopenia. RP2D 200 mg/d

• Phase 1: Rb-positive advanced solid tumors (N=41), 3wks on/1wk off

(3/1). DLT: neutropenia. RP2D 125 mg/d

Schwartz et al BJC 2011, Flaherty et al CCR 2012, DeMichele et al CCR 2015

Palbociclib Monotherapy

• 3wks on/1wk off (3/1) schedule

• N=37 (84% HR+, 5% HR+/HER2+, 11%

TN)

• CBR 19% (21% HR+ and 29% >2 prior

lines HT)

• Median PFS: 3.7 mo (longer in HR+ 4.5

mo & those progressed to HT 5 mo)

• Toxicity: neutropenia (51%),

thrombopenia (22%) and anemia (5%) – 24% treatment interruption

– 51% dose reduction

Phase II: Rb-positive advanced BC

HR+/HER2-

PALBO in 1L setting. PALOMA-1/TRIO 018

Finn et al SABCS 2009 (Abst 5069) and Finn et al Lancet Oncol 2015

PD 0332991 + Letrozole for 1L postM ER+/HER2- MBC (fase Ib/II)

• Phase 1 part (N=12): Palbo 125 mg/d (3/1 schedule)+Letrozole 2.5 mg/d (no DDI)

• AEs: neutropenia, leukopenia and fatigue

PD 0332991 125 mg QD 3/1 + Letrozole 2.5 mg QDx 4wk

Letrozole 2.5 mg QDx 4wk

Postmenopausal women

with ER-positive, HER2-negative

advanced BC (N= 66)

Stratified by disease site (visceral, bone only, or other); Disease-Free Interval (>12 vs ≤12 mo from

end of adjuvant to recurrence or de novo advanced disease)

Postmenopausal women

with ER-positive, HER2-negative advanced bc &

CCND1 amp, and/or p16 loss

(N= 99)

Part 1 Part 2

*All patients continued assigned treatment until disease progression, withdrawal of consent, or unacceptable toxicity with follow-up tumor assessment every 2 mo & accrual to cohort 2 stopped after interim analysis of cohort 1 amending statistical plan to combine both cohorts

Stratified by disease site (visceral, bone only, or other); Disease-Free Interval (>12 vs ≤12 mo from end

of adjuvant to recurrence or de novo advanced disease)

Exploratory study evaluating safety and efficacy of the combination in patients

selected based on HR status only

PD 0332991 125 mg QD 3/1 + Letrozole 2.5 mg QDx 4wk

Letrozole 2.5 mg QDx 4wk

1:1 1:1

• Primary Endpoint: PFS inv • Designed to detect a 50% improvement in median

PFS from 9 to 13.5 months (80% power, 1-sided α = 10%)

• Open label, randomized phase II study (2 cohorts sequentially enrolled)

• Postmen. ABC (1L)

• No prior AI or stopped adjuvant AI

at least 1 yr before relapse

• Measurable by RECIST or bone-only

disease


Finn et al Lancet Oncol 2015

N=165


Finn et al Lancet Oncol 2015

Median PFS 20.2 vs 10.2mo

HR 0.499*



• Response: ORR 36 vs 27% and CBR 68 vs 47% and DoR 20.3 vs 11.1mo

• OS (median FU 27.9 vs 29.6mo): 37.5 vs 33.3 mo (HR 0.81 NS)

• AEs: neutropenia, leucopenia and fatigue >> anemia, nausea, arthralgia, alopecia

• Dose interruptions bc AEs: 33% vs 4%

• 45% dose delay and 40% dose reduction (mean relative dose-intensity 94%)

• FDA grants breakthrough therapy

designation for Palbociclib in BC (11/APR/13)

• FDA grants accelerated approval (3/FEB/15)

in combination with LET for the treatment of postM ER+HER2-

advanced BC as initial endocrine-based therapy for MBC


Finn et al ASCO 2016 (Abst 507)

• Median FU: 23 mo Palbo/LET and 22.3mo Pbo/LET

PALBO in 1L ABC: PALOMA-2/TRIO 22


PALBO in 1L ABC. PALOMA-2/TRIO 22: efficacy

• Palbo/LET significantly improved median PFS vs Pbo/LET as 1L therapy in women with

ER+/HER2– advanced BC

- A >10 month improvement in median PFS was observed (24.8 vs 14.5 mo) HR =

0.58 (95% CI, 0.46–0.72; P<0.0001)

• Benefit from palbociclib demonstrated across prespecified subgroups and confirmed

by blinded independent review


PALBO in 1L ABC. PALOMA-2/TRIO 22: safety


• Overall incidence of SAEs higher in Palbo/LET 19.6% vs 12.6% in Pbo/LET arm • 9.7% pts in Palbo/LET vs 5.9% Pbo/LET permanently discontinue due to AEs • 2.3% vs 1.8% death due to AEs in both arms none due to treatment-related toxicity

PALBO after endocrine failure: PALOMA-3

Turner et al ASCO 2015

PALBO after endocrine failure. PALOMA-3: efficacy

• Response: ORR 10.4 vs 6.3% (NS) and CBR 34 vs19%*

• OS (median FU 5.6 mo) still inmature

* Update 8.9 mo FU (median PFS 9.5 vs 4.6 mo HR 0.46*) benefit in ORR and CBR confirmed (although it can take months to achieve)

• Median age (57 vs 56 yr): 21%

pre/periM

• 60% visceral metastasis & 29% 2

disease sites

• 79% documented sensitivity to

prior HT (relapsed after 24 mo of

adjuvant HT or clinical benefit to prior HT

in ABC)

• 86% prior AI and 60% prior TAM

+/- GnRH

Turner et al NEJM 2015, Cristofanilli et al Lancet Oncol 2016

17

PALBO after endocrine failure. PALOMA-3: efficacy

Turner et al NEJM 2015

• Overall incidence of SAEs was similar (9.6% vs 14.0%)

• Discontinuations due to AEs 2.6 vs 1.7%

• Incidence of febrile neutropenia was the same (0.6% vs 0.6%)

– Neutropenia most common AE leading dose reductions 21%

• Infections (any grade) were more common (34.2% vs 24.4%) mainly G1/2

Turner et al NEJM 2015

• FDA grants breakthrough therapy designation for Palbociclib in BC (11/APR/13)

• FDA grants accelerated approval (3/FEB/15)

in combination with LET for the treatment of postM ER+HER2- advanced BC as initial

endocrine-based therapy for MBC

• FDA grants regular approval (19/FEB/16)

in combination with FULV for the treatment of postM ER+HER2-

advanced or metastatic BC with disease progression following

endocrine therapy

PALBO after endocrine failure. PALOMA-3: safety

PALBOCICLIB ongoing phase III trials in ER+ BC

Finn et al BCR 2016

Trial Phase

(N)

Design Population Primary

Endpoint

PEARL

GEICAM 2013-02

III

(348*)

Palbo+EXE &

Palbo/FUL* vs

Capecitabine

with resistance to

NSAIs MBC postM

PFS

FLIPPER

GEICAM 2014-12

II

(190)

Palbo+FUL vs

Pbo+FUL

1L MBC postM

(after 5yr HT

>12mo DFS or

CMM de novo)

PFS

PENELOPE-B

GBG78/BIG1-13/NSABP-

B64

III

(800)

Palbo+ED vs

Pbo+ED

after NACT with

residual disease

(High Risk EBC)

pre/postM

iDFS

PALLAS

AFT-05, ABCSG 42, BIG 14-

03, 2014-005181-30

III (4600) Palbo (2yrs)+HT (>5yrs)

vs HT (>5yrs)

Stage II-III

pre/postM.

iDFS

NeoPAL

UC-0140/1404, 2014-

002560-33, CARMINA04

II

(132)

Palbo+LET vs FEC-3 –

Docex3

NA. Stage II-

IIIA.PostM. PAM50=

ROR

low/intermediate

RCB

PALLET

NSABP FB-11, WI180455

II

(306)

Palbo+LET vs LET vs

LET-LET/Palbo vs

Palbo-LET/Palbo

NA. T>2 cm. PostM Biomarker

cCR and Ki

67 change

Early phases of RIBOCICLIB development

20

• Specifically inhibits CDK4 and 6 in tumors with

full functional pRb (intact total pRb by IHC)

• Phase I recommended dose 600 mg/d 21-of-28

day dosing schedule

• Most common AE (G3/4): neutropenia (19%),

leukopenia (12%) and lymphopenia (14%)

Infante et al ASCO 2014 & O'Brien et al AACR 2014, Asghar et al Nat Rev Drug Discov 2015, Juric er al ASCO 2016

• 47 pts (dose escalation and dose expansion) had been treated with

Ribo 600 mg QD (3-weeks-on/1-week-off) + LET 2.5 mg QD

90% in dose escalation were

previously treated for aBC

96% in dose expansion treatment-naïve for aBC

46% ORR

79% CBR

RIBOCICLIB ongoing trials in BC

Trial Phase

(N)


Endpoint

MONALEESA-1 II

(120)

LEE011+LET (400 mg or 600

mg) vs LET

NA (resectable

BC)

Cell-cycle

RR (Ki 67)

MONALEESA-2

NCT01958021

III

(650)

LEE011600 mg+LET vs Pbo+LET 1L MBC postM PFS

MONALEESA-3

NCT02422615

III

(660)

LEE011600 mg+FUL

vs Pbo+FUL

>1L MBC postM PFS

MONALEESA-7

NCT02278180

III

(660)

LEE011600

mg+TAM/IA+goserelin vs

Pbo+TAM/IA+goserelin

1L MBC preM PFS

Finn et al BCR 2016

Is there a role for a triple HT+ CDK4/6 and PI3K

inhibitor combination ?

O’Leary et al NRCO 2016, Herrera-Abreu et al Cancer Res 2016, Hamilton et al Cancer Treat Rev 2016

• ER+ BC cells can adapt to CDK4/6 inhibition and evade cytostasis in part via non-

canonical cyclinD1-CDK2-mediated S-phase entry prevented by co-treatment

with PI3K inhs • PI3K inhs failed to re-sensistize cells once resistance is acquired (CDK2 inh role?)

Trial Phase Design

NCT02088684 Ib/II

(216)

Ribociclib+Buparlisib+FUL

Ribociclib+Alpelisib+FUL

Ribociclib+FUL

NCT01872260

Juric et al SABCS

2015

Ib/II

(200)

Ribociclib+Alpelisib+LET

* RP2D for the triplet ribociclib 300 mg/day (3-weeks-on/1-

week-off) + alpelisib 200 mg/day (continuous) + letrozole 2.5

mg/day (continuous)

NCT01857193

Bardia et al

SABCS 2015

Ib

(142)

Ribociblib+EVE+EXE

* RP2D for the triplet 300 mg/day ribociclib (3-weeks-on/1-

week-off) + 2.5 mg/day EVE (continuous) + 25 mg/day EXE

(continuous) with food

Early phases of ABEMACICLIB

development • Specifically inhibits CDK4 (more potent in vitro) and 6

but also reduces CDK9 activity

• Recommended dose 200 milligrams mg LY2835219 given

orally once every 12 hours in 28 day cycles (continuous

dosing)

• Crosses the blood brain barrier (JPBO phase II study)

Infante et al AACR 2012 & Patnaik et al Cancer Discov 2016 & Tolaney et al ASCO 2015, Sahebjan et al ASCO 2016

Phase I dose escalation followed by a tumor-specific cohort trial

• N=225 (33 in dose

escalation and 192

tumor-specific)

• DLT: G3 fatigue

• MTD 200 mg Q12h

• Dose reductions:

• 21% @150mgq12h

• 43% @200mgq12h

Early phases of ABEMACICLIB

development

ER+HER2-hBC xenograft (T47D)

Patnaik et al Cancer Discov 2016

ER+HER2+ responders

• Overall BC (N=47):

ORR 23% and CBR 49% and disease CR 70%

Median DoR 13.4 mo

Median PFS 5.8 mo

• HR+ BC (N=36):

ORR 31% & CBR 61.1% and DCR 81%

Median DoR 13.4 mo

Median PFS 8.8 mo

• MBC cohort (N=47) mixed

intrinsic subtypes

• Median 7 prior regimens

(highly pre-treated)

• 77% visceral involvement

*Non-responding breast tumors were more likely to harbor

TP53 mutations, all in the region encoding the p53 DNA-binding

domain

Phase I Breast Cancer cohort

ABEMA in HR+/HER2- pretreated: MONARCH-1

Dickler et al ASCO 2016 (Abst 510)

Characteristics of the population

ABEMA in HR+/HER2- pretreated: MONARCH-1: efficacy


ABEMA in HR+/HER2- pretreated: MONARCH-1: safety


• Overall incidence of SAEs 24.2% • 7.6% of patients permanently discontinue due to AEs • 2.3% death due to AEs

ABEMACICLIB ongoing trials

Trial Phase

(N)


Endpoint

MONARCH 1

NCT02102490 II

(128)

LY2835219 200mg/12hx28d MBC ORR

MONARCH 2

NCT02107703 III

(630)

LY2835219150mg/12h+FULvs

Pbo+FUL MBC PFS

MONARCH 3

NCT02246621 III

(450)

LY2835219150mg/12h+NSAIs vs

Pbo+NSAIS MBC

PFS

neoMONARCH

NCT02441946 II

(220)

LY2835219150mg/12h+ANA vs ANA vs

LY2835219150mg/12h

LY2835219150mg/12h+ANA

NA early

BC

Changes in

Ki 67

• Abemaciclib demonstrates single agent activity in heavily pre-treated pts

with HR+/HER2-MBC (ORR 19.7%, DoR 8.9 mo, CBR 42.4% and median PFS 6

mo OS 17.7 mo)


• FDA grants breakthrough therapy designation

for Abemaciclib in BC (8/OCT/2015)

HR+ BC most promising agents & TOXICITY

Rugo et al ASCO Educational book 2016

CDK4/6 inhibition and BIOMARKERS

• A number of biologically plausible biomarkers of sensitivity to CDK4/6

inhibition are available, for example cyclin D, CDKN2A and/or RB1 status;

however, ER-positivity in BC is the only selection marker currently

confirmed for use in the clinical setting

O’Leary et al NRCO 2016


• PALOMA-1: ER+ in BC (very dependent on cyclin D1 and CDK4/6 to drive

proliferation) and cyclin D1 amp and/or p16 loss NOT correlated with

palbo benefit

• PALOMA-3: palbo benefit NOT related to degree of endocrine sensitivity

(clinically assessed previous endocrine response), pathologically assessed

(levels of ER/PR expression) or PI3K mut status (cfDNA exon 9 and 20

muts BEAMing tech)

O’Leary et al NRCO 2016, Cristofanilli et al Lancet Oncol 2016

PIK3CA wt PIK3CA mut


• PALOMA-3: ESR1 muts were detected in 27% of baseline cfDNA and were

strongly associated with acquired resistance to prior AIs & palbo offers

high efficacy regardless of ESR1 mut status.

Turner et al ASCO 2016 (Abst 512)

Post-Menopausal Pre-Menopausal

• Patient: age, menopausal status, comorbidities, PS, expectations and

preferences, toxicities to previous treatments, adherence and compliance

• Tumor: histological subtype, HR expression, HER2 amp, intrinsic subtype,

predictive biomarkers*

• Disease: site of metastasis, tumor burden, symptoms/need rapid response,

previous HT, DFI on adjuvant setting, response to previous HT, DoR to

previous HT

• Agent: mechanism of action, expected toxicities, pharmacological

interactions, availability, cost, route of administration

• Availability of clinical research, existing guidelines, financial issues, social

support

Rugo et al JCO 2016, Reinert et al Ther Adv Med Oncoll 2015

CONCLUSIONES

Explosión actual de datos sobre la eficacia de Inhs CDK4/6 en CMM:

• Palbociclib es “first in class” queda apoyado por los datos del fase II (PALOMA1) y dos

fase III (PALOMA 2&3) con beneficio en términos de SLP (FDA breakthrough

designation regular approval)

• Ribocliclib acaba de anunciar datos positivos en su fase III en combinación con LET

en SLP (MONALEESA2) y abre la posibilidad de triples combinaciones con inhs PI3K

• Abemaciclib aporta datos en monoterapia de tasa de respuestas aprox 20% (fase II

MONARCH1) con un perfil de toxicidad algo diferente al resto (diarrea vs

neutropenia)

El descubrimiento y validación de BIOMARCADORES de respuesta para la

combinación de Inhs CDK4/6 & HT representa un reto, la re-biopsia de

lesiones metastásicas o la biopsia líquida son herramientas que pueden

ayudarnos a caracterizar molecularmente la dinámica de la enfermedad en

cada paciente y avanzar en la individualización del tratamiento (value in

cancer care context)

El panorama de la terapia hormonal para el CMM está cambiando

rápidamente y es preciso integrar los resultados de los estudios con el

balance riesgo/beneficio individual de cada alternativa para ofrecer el

mejor tratamiento a nuestras pacientes

[email protected]

Muchas Gracias

inhibidores de la cdk 4/6: resultados y papel de la … · • bind within the atp-binding pocket...

Documents