Terapia adiuvante: quale futuro

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Unit of Investigative Clinical Oncology Istituto di Candiolo (IRCCS)

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

Filippo Montemurro

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Direzione Oncologia Clinica Investigativa, IRCC Candiolo

 Speaker’s Honoraria

 Astra Zeneca

 Novartis

 Roche

 Travel grants

 Astra Zeneca

 Roche

Disclosures

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 Discussing the rationale

 Overview 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

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

Cortazar et al, Lancet 384; 164, 2014

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Activity seen in the metastatic setting fully supports 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, 2016 Hortobagyi et al, NEJM 375;1738, 2017 Di Leo et al, ESMO 2017

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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

1:1

RANDOMIZATION

Primary endpoint: iDFS Secondary endpoints:

iDFS excluding second primary 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 B

Endocrine therapy (5–10 years)

Arm A Palbociclib

(2 years) Endocrine therapy+

(5–10 years)

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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

Primary endpoint: iDFS

Secondary endpoints:

OS, iDFS excluding second non-breast cancer, DDFS, LRFS, iDFS by commercially

available multigene assay subtyping, safety, PROs, biomarkers

Stratification factors:

lymph node status, age, biomarkers

(Ki67, pRb, Cyclin D), and region

N=800

1:1

RANDOMIZATION

PENELOPE

^a,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/score AKA Neo-Bioscore

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

8

Endocrine therapy^a+ 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

RANDOMIZATION

Primary endpoint:

iDFS

Secondary End points:

RFSDDFS QSQol

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

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Endocrine therapy^a+ Ribociclib

(600 mg/d, 3 weeks on/1 week off

× 26 cycles [24 mo])

•HR+, HER2– EBC

•Men and pre- and

•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

RANDOMIZATION ^Primaryendpoint:

iDFS

Secondary Endpoints RFSDDFS QSQol

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

Endocrine therapy^a+ Abemaciclib

[24 mo]

•HR+, HER2– EBC

•Men and pre- and

•N+ and at least one of the following

•≥4 metastatic lymph nodes

•T3

•G3

•Ki67 ≥20% (cohort B)

Endocrine therapy N = 3850

RANDOMIZATION

Primary endpoint:

iDFS

Secondary Endpoints:

IDFS according to Ki67 (cutoff 20%) OSPharmacokinetics Qol

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

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Trial Population Risk Neo/Adj

chemo CDKi

duration Accrual

target Early results expected*

Completion

PALLAS ^Pre-Post

menop Women, Men

IIA-III Allowed 2 y 4600 Sep 2020 Sep 2025

PENELOPE-B ^Pre-Post

menop women

CPS-EG≥3 Neoadj

Mandatory ~1y 800 Dec 2020 Nov 2023

EarLEE1 ^Pre-Post

menop Women, Men

Group** III or residual

disease after NACT

Allowed ~2y 2000 Sep 2023 Sep 2023

EarLEE2 ^Pre-Post

menop Women, Men

Group** III None

allowed ~2 y 2000 Sep 2023 Sep 2023

monarchE ^Pre-Post

menop Women, Men

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

Summary of key points

*Final data collection date for primary outcome measure

*AJCC 8^thEdition

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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

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Neoadjuvant palbociclib and letrozole vs chemotherapy

Cottu et al., Esmo 2017

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

Cottu et al., Esmo 2017

Ellis, JNCI 2008

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PEPI score is largely driven by residual Ki67 in surgical specimen

Dowsett et al. JNCI 100; 1380, 2008

Cottu et al., Esmo 2017

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For short treatment exposures, Ki67 raises sharply 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

AnastrozoleC0D1 +/-Goserelin

Ana. + Pal.C1D1 +/-Goserelin

4 weeks

(PIK3CA mutational analysis)

C1D15 Ana. + Pal.

+/-Goserelin

2 weeks

B

Ana. + Pal.C2D1 +/-Goserelin

B B

If ki67 >10% patients go off study

4 cycles

(5 in 8 patients)

PIK3CAwt 32 PIK3CAmut 16

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CDK 4/6 inhibition and prolonged G1 arrest may 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

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Senescence is capable of stimulating clearance by the immune system

Experimentally impaired immune surveillance

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

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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

Moderately Differentiated

Ki67: 20%

DifferentiatedWell Ki67: 3.4%

DifferentiatedWell Ki67: 0.2%

(Abemaciclib monotherapy)

(Abemaciclib & Anastrozole)

Suppressor/ Cytotoxic T cells

(CD8)

Hurvitz SABCS 2016

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CDK 4/6 inhibition triggers anti-tumour immunity

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

Goel et al, Nature; epub 2017

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 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

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Development in the Neoadjuvant setting

Criscitiello et al, Curr Opin Oncol, epub 2017

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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

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

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

1986-1992 2004-2008

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

Albain et al, Lancet Oncol 11;55, 2016