Carcinoma mammario e i
CDK4/6 Inhibitors
SINTESI DEI DATI DELLA LETTERATURA
Anna Maria Mosconi Oncologia Medica Perugia
• The first major breakthrough in endocrine therapy occurred in the 1970s with the introduction of
tamoxifen, a selective estrogen receptor modulator (SERM)
• Over the next 4 decades, the development of several new endocrine-based therapies helped improve
outcome and QoL in patients with HR+ BC
• However, most patients eventually relapse as the tumors became endocrine resistant again
Endocrine therapy
• Alteration or nonexpression of the estrogen receptor
• Amplification/overexpression of growth factor receptor pathways (e.g., HER2, EGFR)
• Dysregulation of the PI3K/AKT/mTOR pathway
• Dysregulation of the cyclin/CDK pathways
Mechanisms of Endocrine Resistance
ER-Signaling and Cellular Signaling Network
CDK4/6 in Breast Cancer
Cooperation between ER and Cyclin D1 Pathways Enhances Proliferation in Luminal Breast Cancer
Synergistic blockade of ER and CDK4/6
Classification of CDK Inhibitors
CDK 4-6 Inhibitors
Paloma-1:Phase IIR Study Design
Paloma-1: PFS
February 2015
Phase III Trials Testing CDK4/6 Inhibitors
We have results from three phase III trials testing CDK4/6 inhibitors in the first-line treatment of
HER+/HER-2 advanced breast cancer patients:
• PALOMA-2
• MONALEESA-2
• MONARCH-3
ER+ Endocrine Sensitive MBC
CDK4/6 Inhibitors Trials: Design
AI=letrozole
AI=letrozole
AI=anastrozole or letrozole
ER+ Endocrine Sensitive MBC CDK4/6 Inhibitors Trials: PFS
All subgroups equally benefit from a CDK4/6
MONARCH-3
First-line CDK4/6 Inhibitors Trials in MBC:
Safety Data
Febrile neutropenia in 1.8% of patients in PALOMA-2
First-line CDK4/6 Inhibitors Trials in MBC:
Safety Data
First-line CDK4/6 Inhibitors Trials in MBC:
Safety Data
Evolution of Therapy for Endocrine- Sensitive Metastatic Breast Cancer
Phase III Trials Testing CDK4/6 Inhibitors
We have results from two phase III trials testing CDK4/6 inhibitors in HER+/HER-2 advanced breast cancer patients who progressed on prior endocrine therapy:
• PALOMA-3
• MONALEESA-3 (no data yet)
• MONARCH-2
ER+ Endocrine Resistant MBC
CDK4/6 Inhibitors Trials: Design
No more than one ET or any prior CT for MBC Prior CT for MBC in 1/3 of pts
ER+ Endocrine Resistant MBC CDK4/6 Inhibitors Trials: PFS
9.5 vs 4.6 months 16.4 vs 9.3 months
Monarch-2
All subgroups equally benefit from a CDK4/6
PALOMA-3: No PFS difference in patients who had a dose reduction because of an AE
Evolution of Therapy for Endocrine- Resistant Metastatic Breast Cancer
9.5- / 16.4months
Palbociclib in ER+/HER2- Metastatic Breast Cancer
• 10.3 months median PFS improvement in
hormone-sensitive mBC (HR 0.58)- PALOMA-2
• 4.9 months median PFS improvement in
hormone-resistant mBC (HR 0.49)- PALOMA-3
Palbociclib
November 25, 2016
Palbociclib can be used for the treatment of
patients with advanced or metastatic , hormone receptor-positive, HER2-negative breast cancer
In combination with an AI as initial therapy (+LHRH agonistig pre o
perimenopausal patients)
Rimborsabilità AIFA
In combination with Fulvestrant after prior endocrine therapy (+LHRH agonistig pre o
perimenopausal patients)
The recommended dose of palbociclib is 125 mg orally taken once daily with food for 21
consecutive days followed by 7 days off treatment
Ribociclib
August 24, 2017
In combination with an AI as initial therapy
In attesa della Rimborsabilità AIFA
Ribociclib can be used for the treatment of postmenopausal patients with advanced or metastatic , hormone receptor-positive, HER2- negative breast cancer
The recommended dose of ribociclib is 600 mg orally (three 200 mg tablets) taken once daily with or without food for 21 consecutive days followed by 7 days off treatment
Main challenge
• Identification of the patients to be treated biomarker of the response/resistance
Do we have strong evidence that the combination CDK4/6 inhibitors + endocrine therapy should be the up-front option ?
Yes, but perhaps not
necessarily in all patients
Benefit of palbociclib is irrespective of CCD1 and p16 status
PALOMA-3: ESR1 Mutation in ctDNA
Benefit of palbociclib is irrespective of Rb status
Benefit of palbociclib is irrespective of ER status
Mechanisms of resistance and predictivity of response
No validated predictive factors yet
Selecting patients who don’t
need a CDK4-6 Inhibitor
• Can these agents be used interchangeably ?
– An advantage of abemaciclib is that continous dosing may be simpler for patients
– In addition abemaciclib is suggested to have CNS penetration – The minor differences in their toxicity profiles may lead to a
switch from one drug in the class to another
• Impact on OS ?
• What therapy do we use after progression on CDK4/6i ?
Some Questions about CDK 4/6 Inhibitors
Influence of palbociclib + AI on the effect of subsequent therapies
Treatments after palbociclib plus ET- Insights from a real word observation
Palbociclib
Current ET+
Palboclib HR+ HER2- mBC
Postmenopausal who progressed on 1-2 prior ET
Addition of palbociclib to previous ET A phase IIR TREnd trial
CBR (primary endpoint): 54 % (95% CI 42-67%) with P+ET vs 60% (95% CI 48-73%) with P alone
ORR. 11 % (95% CI 3-19%) with P+ET vs 7% (95% CI 0.4-13%) with P alone mPFS: 10.8 mo (95% CI 5.6-12.7%) with P+ET vs 6.5 mo (95% CI 5.4-8.5) with P alone
N=115 pts
Addition of palbociclib to previous ET
(mPFS 10.8 with P+ET vs 6,5 months with P)
48
ER and HER2 pathways interact to activate CDK-dependent transcription
THE FUTURE
49
Co-targeting of ER, HER2 and CDK4/6 Co-targeting of ER, HER2 and CDK4/6
50
NA-PHER2 Phase II trial of neo-
adjuvant treatment with palbociclib
51
NA-PHER2: Ki67 levels decreased following treatment
52
NA-PHER2: Patological and
clinical response
• CDK4/6 inhibitors are a new standard for
ER+/HER2- MBC, to be considered for first or second line
• The optimal sequence of treatments awaits for further evidences
• No validate predictive factors yet
• Ongoing trials in adjuvant and neoadjuvant setting (also including men)
CONCLUSIONS
Some Answers, Many New Questions
