Terapia adiuvante con inibitori delle Kinasi Cliclina...

Unit of Investigative Clinical OncologyIstituto di Candiolo (IRCCS)

Terapia adiuvante con inibitori delle Kinasi CliclinaDipendenti 4/6: quale futuro?

Filippo Montemurro

Direzione Oncologia Clinica Investigativa, IRCC Candiolo

Speaker’s HonorariaAstra Zeneca

Novartis

Roche

Travel grantsAstra Zeneca

Roche

Disclosures


Discussing the rationaleOverview of the most important ongoing Phase

III trial evaluating the addition of CDK 4/6 inhibitors to endocrine therapy

Some speculation on what to expect Conclusions

Presentation outline


Long-term prognosis of HR+/PgR-breast cancer

Cortazar et al, Lancet 384; 164, 2014


Activity seen in the metastatic setting fullysupports studies in operable breast cancer

Study Treatment ORR CBR Median DFS (m) Median OS (m)

PALOMA 2 Letrozole+Placebo 34.7% 70.3% 14.5 N.A.

Letrozole+ Palbociclib 42.1% 84.9% 24.8 N.A.

MONNALEESA 2 Letrozole+Plac 27.5% 72.8% 14.7 33

Letrozole+Ribociclib 40.7% 79.2% 25.3 N.R.*

MONARCH 3 Let. or Ana. + Placebo 34.5% 71.5% 14.7 N.A

Let or Ana + Abemaciclib 48.2% 78.0% N.R. N.A.

0.58

0.56

0.54

Finn et al, NEJM 375;1925, 2016Hortobagyi et al, NEJM 375;1738, 2017Di Leo et al, ESMO 2017


Randomized, Open-label Phase III Study of Palbociclib + Adjuvant Endocrine Therapy vs. Adjuvant Endocrine Therapy Alone in

HR+/HER2– Early Breast Cancer: PALLAS

1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02513394 (Accessed April 28 2016)

2. Meyer E, et al. Presented at SABCS 2015; San Antonio, Texas, USA (Oral presentation OT1-03-21)

N=4600 Histologically confirmed

HR+/HER2– early invasive breast cancer

Stage IIA or III

Pre- or postmenopausal women

Men are eligible

≤12 months since initial pathologic diagnosis

Prior chemotherapy allowed

1:1RA

NDO

MIZ

ATIO

N

Primary endpoint: iDFS

Secondary endpoints: iDFS excluding secondprimary cancers of non-breast origin; DRFS; LLRFS; OS; PROs; safety

Stratification factors: Pathologic stage (IIA vs. IIB/III) or clinical stage (if preoperative therapy was given with the higher stage determining eligibility);neo/adjuvant chemotherapy (yes vs. no); age (<50 vs. ≥50 years); geographic region (North America vs. Europe vs. Asia)

Arm BEndocrine therapy

(5–10 years)

Arm APalbociclib

(2 years) +

Endocrine therapy(5–10 years)


Phase III Study of Palbociclib in High-risk Early Breast Cancer: PENELOPE

1. ClinicalTrials.gov NCT01864746 2. Data on file, Pfizer

Early ER+ breast cancer “high risk” (CPS-EG ≥3*)

Premenopausal/postmenopausal

Completed taxane-based neoadjuvant therapy, surgery, radiotherapy


Secondary endpoints: OS, iDFS excluding second non-breast cancer, DDFS, LRFS, iDFSby commercially available multigene assay subtyping, safety, PROs, biomarkers

Stratification factors: lymph node status, age, biomarkers(Ki67, pRb, Cyclin D), andregion

N=800

1:1

RAN

DOM

IZAT

ION

PENELOPEa,1,2

Non-study adjuvant endocrine therapies being taken for 5–10 years after surgery were permitted during the study:

tamoxifen (pre- and postmenopausal women)

goserelin agonists (premenopausal)

AIs: anastrozole, letrozole (postmenopausal)

Placebo X 13 cycles (3/1 schedule)

+ SOC

Palbociclib X 13 cycles

(125 mg QD, 3/1 schedule)

+ SOC

CPS-EG; clinical –patologic stage estrogen/scoreAKA Neo-Bioscore


EarLEE-1: adjuvant therapy for high-risk early breast cancer

8

Endocrine therapya + Ribociclib

(600 mg/d, 3 weeks on/1 week off × 26 cycles [24 mo])

• HR+, HER2– EBC• Men and pre- and

postmenopausal women• High risk of recurrence

- AJCC 8th ed, Prognostic Stage Group III

- Residual disease in LN(s) and breast tissue after neoadjuvant chemotherapy

Endocrine therapy + Placebo

(3 weeks on/1 week off× 26 cycles [24 mo])

AJCC, American Joint Committee on Cancer; EBC, early breast cancer; DDFS, distant disease-free survival; HER2–, human epidermal growth factor receptor-2–negative; HR+, hormone receptor-positive; iDFS, invasive disease-free survival; LN, lymph node; NACT, neoadjuvant chemotherapy; OS, overall survival; QoL, quality of life; RFS, recurrence-free survival.

EarLEE-1 Clinical Trial Protocol

https://clinicaltrials.gov/ct2/show/NCT03078751

a Endocrine therapy can be started up to 12 weeks before randomization and continue for at least 60 months.

N=2000

RAN

DOM

IZAT

ION


SecondaryEnd points:RFSDDFSQSQol


EarLEE-2: adjuvant therapy for moderate risk early breast cancer

9

Endocrine therapya + Ribociclib

(600 mg/d, 3 weeks on/1 week off × 26 cycles [24 mo])

• HR+, HER2– EBC• Men and pre- and

postmenopausal women• Intermediate risk of

recurrence- AJCC 8th ed, Prognostic Stage

Group II- No neoadjuvant chemotherapy

and/or endocrine therapy

Endocrine therapy + Placebo

(3 weeks on/1 week off× 26 cycles [24 mo])

AJCC, American Joint Committee on Cancer; EBC, early breast cancer; DDFS, distant disease-free survival; HER2–, human epidermal growth factor receptor-2–negative; HR+, hormone receptor-positive; iDFS, invasive disease-free survival; LN, lymph node; NACT, neoadjuvant chemotherapy; OS, overall survival; QoL, quality of life; RFS, recurrence-free survival.

EarLEE-1 Clinical Trial Protocol

https://clinicaltrials.gov/ct2/show/NCT03078751

a Endocrine therapy can be started up to 12 weeks before randomization and continue for at least 60 months.

N=2000

RAN

DOM

IZAT

ION Primary

endpoint: iDFS

SecondaryEndpointsRFSDDFSQSQol


monarchE: adjuvant treatment for HR+/HER2-, high risk operable breast cancer

Endocrine therapya + Abemaciclib

[24 mo]• HR+, HER2– EBC• Men and pre- and

postmenopausal women• N+ and at least one of the following

• ≥4 metastatic lymph nodes• T3• G3• Ki67 ≥20% (cohort B)

Endocrine therapy

N = 3850

RAN

DOM

IZAT

ION Primary endpoint:

iDFS

SecondaryEndpoints:IDFS according to Ki67 (cutoff 20%)OSPharmacokineticsQol

https://clinicaltrials.gov/ct2/show/NCT03155997?term=abemaciclib&cond=breast&draw=1&rank=2


Trial Population Risk Neo/Adjchemo

CDKiduration

Accrualtarget

Earlyresults

expected*

Completion

PALLAS Pre-Post menop

Women, Men

IIA-III Allowed 2 y 4600 Sep 2020 Sep 2025

PENELOPE-B Pre-Postmenopwomen

CPS-EG≥3 NeoadjMandatory

~1y 800 Dec 2020 Nov 2023

EarLEE1 Pre-Postmenop

Women, Men

Group** III or residual

diseaseafter NACT

Allowed ~2y 2000 Sep 2023 Sep 2023

EarLEE2 Pre-Postmenop

Women, Men

Group** III None allowed

~2 y 2000 Sep 2023 Sep 2023

monarchE Pre-Postmenop

Women, Men

High-risk N+ Allowed ? 3850 June 2022 Jun 2027

Summary of key points

*Final data collection date for primary outcome measure*AJCC 8th Edition


What to expect

Could we expect increased cure rate due to a sort of "pCR in micrometastatic sites" effect?

Cortazar et al, Lancet 384; 164, 2014


Neoadjuvant palbociclib and letrozole vs chemotherapy

Cottu et al., Esmo 2017


pCR rates remain globally low, but PEPI scores is better with palbo and letrozole

Cottu et al., Esmo 2017Ellis, JNCI 2008


PEPI score is largely driven by residual Ki67 in surgical specimen

Dowsett et al. JNCI 100; 1380, 2008

Cottu et al., Esmo 2017


For short treatment exposures, Ki67 raisessharply upon CDK 4/6 treatment interruption

Neoadjuvant palbociclib and anastrozole (NEOPALANA study).

Ma et al, Clin Cancer Res, epub 2017

ER+ (Allred 6-8)HER2-

Surgery

C0D1Anastrozole+/-Goserelin

C1D1Ana. + Pal.

+/-Goserelin

4 weeks(PIK3CA mutational

analysis)

C1D15Ana. + Pal.

+/-Goserelin

2 weeksB

C2D1Ana. + Pal.

+/-Goserelin

B BIf ki67 >10% patients go off study

4 cycles(5 in 8 patients)PIK3CAwt 32

PIK3CAmut 16


CDK 4/6 inhibition and prolonged G1 arrestmay induce cancer cell senescence

Kovatcheva et al, Oncotarget 6;8226, 2015

Evidence that this occurs in: Vemurafenib-resistant melanoma (PMID 26988987), Sarcoma (PMID 26528855), Neuroblastoma (PIMD 24045179 ), Breast (PIMD 28813415), Glioblastoma multiforme (PMID 20354191), Hepatocellular carcinoma (PIMD 27849562), Leukemia (PMID 28286417) and others


Senescence is capable of stimulatingclearance by the immune system

Experimentally impaired immune surveillance

Wong-Kang et al, Nature 479; 547, 2011


Changes occurring in the tumor bed in the neoadjuvant setting with abemaciclib

C1D15

T Regulatory cells(FOXP3)

Total T cells(CD3)

C5D28

Baseline

H&E

ModeratelyDifferentiated

Ki67: 20%

WellDifferentiated

Ki67: 3.4%

WellDifferentiated

Ki67: 0.2%

(Abemaciclib monotherapy)

(Abemaciclib & Anastrozole)

Suppressor/ Cytotoxic T cells(CD8)

Hurvitz SABCS 2016


CDK 4/6 inhibition triggers anti-tumourimmunity

Collectively, these results establish that CDK4/6 inhibitors induce breast cancer cellcytostasis without directly causing their apoptosis, and enhance their capacity to present antigen and stimulate cytotoxic T cells

Goel et al, Nature; epub 2017


Adding CDK 4/6 inhibitors to adjuvant endocrine in high-risk, ER+/HER2- breast cancer patients has a strong rationale

Biology suggests a potential eradicating effect based on induction of senescence and clearance by the immune system

Safety in patients who have been recently exposed to cytotoxic chemotherapy needs to be addressed

Potential effects of senescence on normal cells need to be clarified

Which type of tumors will be faced with upon progression?

Conclusions


Development in the Neoadjuvant setting

Criscitiello et al, Curr Opin Oncol, epub 2017


Toxicity, dose adjustments and discontinuation without progression

Paloma 2 Monnaleesa 2* Monarch 3

Item (% any grade/% G3-4) Palbociclib Placebo Ribociclib Placebo Abemaciclib Placebo

Any 99/76 96/24 98/81 97/33 98/55 90/22

Neutropenia 80/66 6/1 74/59 5/1 41/21 2/1

Febrile Neutropenia 1.8 0 1.5 0 - -

Anemia 24/24 11/1 19/1 4/1 28/6 5/1

Diarrhea 26/1 19/1 35/1 22/1 81/37 30/1

Nausea 35/0 26/2 52/3 28/1 38/12 20/2

Vomiting 16/1 17/1 29/4 16/1 28/9 12/4

Alopecia 33/0 16/0 33/0 16/0 27/0 11/0

Need for dose interruption 67% 41% 77% 41% 43% 6%

Need for dose adjustment 36 1 54 7 43 6

Discontinuation for adv. ev. 10 6 8 2 20 2


Rationale for using CDK 4/6 in the adjuvanttreatment of HR positive breast cancer

Cossetti et al. J Clin Oncol 33; 65, 2017

1986-1992 2004-2008


SWOG 8814: Disease-free survival according to Recurrence Score and treatment arm

Albain et al, Lancet Oncol 11;55, 2016

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