Terapia endocrina di associazione con inibitori di CDK 4/6: novità per la paziente in post-menopausa

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TERAPIA ENDOCRINA DI ASSOCIAZIONE CON INIBITORI DI CDK 4/6: NOVITÀ PER

LA PAZIENTE IN POST-MENOPAUSA

Dr. Marco Gunnellini Dirigente medico P.O. Gubbio – Gualdo Tadino – USL Umbria 1

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SEER (2010-2013) N= 7578 ER+/HER2- ER+/HER2+ ER-/HER2+ TNBC

Prevalence (%) 60,6 ^17,1 ^9,2 ^13,2

ER+/Her2- Metastatic Breast Cancer

Epidemiology

Gong Y et al., Sci Rep, 2017; 7: 45411

No curative intent of treatment

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AIOM guidelines 2018

Treatment

ET₁ ^response ET₂ ^response ET₃ ^response ET_n

CT₁ No response CT₂ No response CT₃ No response CT_n

Maintenance ET

No response or visceral crisis

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Triphaty D, et al., Clin Cancer Res, 2017; 23: 3251-62

CDK4/6 Inhibitors – mechanism of action

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CDK4/6 Inhibitors in ER+/Her2- Metastatic Breast Cancer

Agenda

Sequence

Concurrent RT Older patients

CDK4/6 inhibitors

Future directions

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ESMO annual meeting 2019

CDK4/6 Inhibitors

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CDK4/6 Inhibitors

Gao J, ASCO 2018

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CDK4/6 Inhibitors

Gao J, ASCO 2018

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First line treatment

Guo J et al., Targ Oncol, 2019; 14: 139-48

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CDK4/6 Inhibitors First line

Not first line overall survival advantage for

Palbociclib and Abemaciclib yet

Johnston S et al., npj Breast Cancer, 2019; 5:5 Slamon DJ et al., ESMO 2019

Subgroup of

Monaleesa 3

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CDK4/6 Inhibitors First line

Loibl S et al., ESMO 2019

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CDK4/6 Inhibitors Second or more lines

Slamon DJ et al., ESMO 2019

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Sleedge GW, et al., ESMO 2019

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Turner NC, et al. N. Engl. J. Med, 2018; 379: 1926–36

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Venous thromboembolic events 4.9% abemaciclib arm vs 0.6% placebo arm

CDK4/6 Inhibitors Toxicity

Cazzaniga ME, et al., Breast Cancer Res Treat, 2019; 176: 483–94

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CDK4/6 Inhibitors QoL

Verma S et al., Breast Cancer Res Treat, 2018; 170: 535-45 Harbeck N et al., Ann Oncol, 2016; 27: 1047-54

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Agenda

Sequence

New agents in mBC

Future directions

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There is no definitive evidence of the best choice of treatment in different patients

Crossover was not permitted in any of the PALOMA, MONALEESA or MONARCH trials,

→ it is impossible to definitively comment as to whether upfront or subsequent-line CDK4/6 inhibition offers the greatest benefit overall.

Slamon DJ et al., ESMO 2019 Rossi L., et al., Ther Adv Med Oncol ,2018; 10: 1–5

AI + CDKi 1° line → 33,6 m AI → ^{19,2 m}

FULVESTRANT ^{9.1 m} FULVESTRANT+CDKi 2° line → ^14,6m

Is there a best sequence?

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Slamon DJ et al., ESMO 2019 Sleedge GW, et al., ESMO 2019

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Sleedge GW, et al., ESMO 2019

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Slamon DJ et al., ESMO 2019

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XU L., et al., Oncotargets Ther, 2018; 11: 8389-98 Cediranib

Vandetanib

Everolimmus Pictilisib Buparlisib Buparlisib

Ganitinib Lapatinib Bortezomib Dovitinib

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Sayed RE, et al., Front Oncol, 2019; 9: 510

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Sayed RE, et al., Front Oncol, 2019; 9: 510

CDK4/6 inhibitor and ET is the choice in patients who have progressed on first-line ET monotherapy

Everolimus+ET may be superior to single-agent Fulvestrant (if first line CDK + ET)

(efficacy of these regimens after CDK4/6 inhibitors??)

Approximately 40% of patients with HR-positive, HER2-negative breast cancer have activating

mutations in the gene PIK3CA

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Andrè F et al., N Engl J Med, 2019; 380: 1929-40

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Andrè F et al., N Engl J Med, 2019; 380: 1929-40

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Agenda

Sequence

New agents in mBC

Future directions

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What timing of radiotherapy?

Palliative

Radiotherapy

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Hans S, et al., Radiother Oncol, 2018; 126: 181 Meattini I et al., Breast, 2018; 42: 1-2 Kawamoto T, et al, Radiother Oncol. 2019; 131: 240-1

A case report of severe enterocolitis (palbociclib plus bone pelvis RT)

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Ippolito E, et al., The Breast, 2019; 46: 70-4

No deteriorating trend of neutropenia during RT

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Figura NB et al., J Neuroncol, 2019; doi: 10.1007/s11060-019-03260-6

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Figura NB et al., J Neuroncol, 2019; doi: 10.1007/s11060-019-03260-6

Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

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Chowdhary et al., Adv Rad Oncol, 2019; 4: 453-7

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Agenda

Sequence

New agents in mBC

Future directions

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Does one size fit all?

Rugo HS et al., Eur J Cancer, 2018; 101: 123-33

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No safety concerns about palbociclib in older patients, quality of life was maintained, and no dose adjustment is required based solely on age.

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Battisti NML et al., Ther Adv Med Oncol, 2018; 10: 1–26

But….. How many CGA in our institution???

Same indication of young patients

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Agenda

Sequence

New agents in mBC

Future directions

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Palbociclib + Exemestane vs Capecitabine in primary refractory mBC PEARL TRIAL- NCT02028507 (Recruiting complete)

www.clinicaltrial.gov

Future directions

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Upfront aromatase inhibitors (AIs)+CDK4/6 inhibition followed by fulvestrant vs single-agent AIs followed by fulvestrant+CDK4/6 inhibitors

SONIA TRIAL - NCT03425838 (Recruiting)

Future directions

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CDK4/6 inhibition after progression on CDK4/6 Inhibition

Recruiting

Recruiting PALMIRA trial

MAINTAIN trial

Future directions

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Combination of

ribociclib, everolimus and exemestane after

previous progression on a CDK4/6 inhibitor TRINITI TRIAL - NCT02732119 (Active not recruiting)

Future directions

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Take-Home message

- Combining CDK 4/6 inhibitor with ET should be considered the standard therapy of ER+/HER2- mBC (what more do we want??)

- CDK inhibitors are safe also in elderly patients and concurrent to palliative RT (but beware to polifarmacology)

- Best treatment after CDK inhibitor is unclear

- Unclear if one agent is better then the others (different population and different subgroups definitions)

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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ESMO congress 2019

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Fogli S et al., Cancer Treat Rev, 2019; 74: 21–8

Drug-drug interactions?

Integratori inibitori enzimatici

Antifungini (fluconazolo, itraconazolo, posaconazolo,

voriconazolo)

Antivirali (inibitori proteasi, Efavirenz) Sostanze complementari

(erba di S. Giovanni, succo di pompelmo, cimicifuga racemosa,

curcumina, ginseng

Antidolorifici o adiuvanti (carbamazepina, fenobarbitale, fenitoina,

fentanyl, metadone, naloxegol, desametasone)

Antiemetici e gastroprotettori

(lansoprazolo, rabeprazolo, aprepitant, ondansetron,

domperidone) Antipertensivi,

antitrombotici, (losartan, ticlopidina,

bisoprololo, lercanidipina, amlodipina, nifedipina

amiodarone)

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Bellet M et al., Ther Adv Med Oncol, 2019,; 11: 1–43

Anticoagulanti (apixaban, rivaroxaban,

edoxaban, dabigatran)

Statine

(simvastatina, atorvastatina, rosuvastatina, pravastatina)

Ipoglicemizzanti

(metformina, rapaglinide, linagliptin, saxagliptin)

Antibiotici (ciprofloxacina, rifammpicina, macrolidi)

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Bellet M et al., Ther Adv Med Oncol, 2019,; 11: 1–43

Antidepressivi (trazodone, mirtazapina,

venlafaxina, citalopram, escitalopram)

Antipsicotici (Aloperidolo, clorpromazina,

quetiapina, olanzapina)