1. CDK 4/6 Inhibitors in Breast Cancer
Expert Perspectives on New Data
Faculty
Javier Cortes, MD, PhD Head
Breast Cancer Program Oncology Department Ramon y Cajal University Hospital Madrid, Spain
Fabrice André, MD, PhD
Professor
Chairman, Inserm Unit U981
Institut Gustave Roussy
Villejuif, France
CKD = cyclin-dependent kinase

2. Program Overview In this program, we will discuss
The evolution of the treatment of HR+, HER2- MBC
The role of CDK 4/6 inhibitors, including recently presented data on their efficacy, safety, and use in clinical practice
HER2- = HER2-negative
HR+ = hormone receptor-positive
MBC = metastatic breast cancer

3. CDK 4/6 Inhibitors: Consistency of Response
Palbociclib
With LET for HR+, HER2- ABC as initial ET in postmenopausal women
PFS = 10.2 months (PBO + LET) vs 20.2 months (PAL + LET); HR (95% CI): (0.319, 0.748); P = .0004
PALOMA-1[a]
With FUL for HR+, HER2- ABC/MBC with PD following ET
PFS = 9.2 months (PAL + FUL) vs 3.8 months (PBO + FUL); HR (95% CI): 0.42 (0.32, 0.56); P < .001
PALOMA-3[b]
HR+, HER2- ABC/MBC with AI as initial ET in postmenopausal women
PFS = 24.8 months (PAL) vs 14.5 months (PBO); HR (95% CI): 0.58 (0.46, 0.72); P < .001
PALOMA-2[c]
HR+, HER2- ABC/MBC in combination with an AI as initial ET or in combination with FUL following prior ET[b,c]
Ribociclib
With an AI as initial ET for postmenopausal women with HR+, HER2- ABC/MBC
PFS = 14.7 months (RIB) vs NR (PBO); HR (95% CI): 0.56 (0.43, 0.72); P < 3.29 × 10−6
MONALEESA-2[d]
With an AI as initial ET for pre- or perimenopausal women with HR+, HER2- ABC/MBC
PFS: 23.8 months (RIB) vs 13.0 months(PBO); HR (95% CI): (0.44, 0.69); P < .0001
MONALEESA-7[e]
With FUL for postmenopausal women with HR+, HER2- ABC/MBC as initial ET or following PD on ET
Estimated median PFS = months (RIB) vs 12.8 months (PBO); HR (95% CI): 0.593; (0.480, 0.732); P < .0001
MONALEESA-3[f]
With an AI as initial ET for postmenopausal women with HR+, HER2- ABC/MBC[d]
Abemaciclib
With FUL in HR+, HER2- ABC/MBC with PD following ET
PFS = 16.4 months (ABE) vs 9.3 months (PBO); HR (95% CI): (0.449, 0.681) P < .001
MONARCH-2[g]
As monotherapy for HR+, HER2- ABC/MBC with PD following ET and prior CT
PFS = 6.0 months (95% CI: 4.2, 7.5)
MONARCH-1[h]
With an AI as initial ET for postmenopausal women with HR+, HER2- ABC/MBC
PFS = NR (ABE) vs 14.7 months (PBO); HR (95% CI): (0.409, 0.723); P =
MONARCH-3[i]
With an AI or FUL as initial ET or in women who have received prior ET[g,i]
ABC = advanced breast cancer
ABE = abemaciclib
AI = aromatase inhibitor
CI = confidence interval
CT = chemotherapy
ET = endocrine-based therapy
FUL = fulvestrant
HR = hazard ratio
LET = letrozole
NR = not reached
PAL = palbociclib
PBO = placebo
PD = progression of disease
PFS = progression-free survival
a. Finn RS, et al. Lancet Oncol. 2015;16:25-35; b. Turner NC, et al. N Engl J Med. 2015;373: ; c. Finn RS, et al. N Engl J Med. 2016;375: ; d. Hortobagyi GN, et al. Ann Oncol. 2018;29: ; e. Tripathy D, et al. Lancet Oncol. 2018;19: ; f. Slamon DJ, et al. J Clin Oncol. 2018;36: ; g. Sledge GW Jr, et al. J Clin Oncol. 2017;35: ; h. Dickler MN, et al. Clin Cancer Res. 2017;23: ; i. Goetz MP, et al. J Clin Oncol. 2017;35:

4. PALOMA-3: OS (ITT)
ITT = intention to treat
OS = overall survival
N = 521 patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy. Absolute improvement in median OS in the palbociclib arm vs the placebo arm was 6.9 months.
From N Engl J Med, Nicholas C. Turner, M.D, et al., Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

5. PALOMA-3: OS by Sensitivity to Prior ET
Patients With Sensitivity to Previous ET
Patients Without Sensitivity to Previous ET
From N Engl J Med, Nicholas C. Turner, M.D, et al., Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

6. Clinical Outcomes in Patients With or Without OR: Results From PALOMA-2
DOR = duration of response
OR = objective response
In patients who achieved an OR, median DOR was longer with palbociclib plus letrozole (27.7 months; 95% CI: 24.7, 36.1) vs placebo plus letrozole (20.9 months; 95% CI: 16.5, 27.6).
Rugo HS, et al ESMO Congress. Poster 332P.

7. SOLAR-1: Alpelisib + Fulvestrant for HR+, HER2- ABC
Phase 3 randomized, double-blind, placebo-controlled trial evaluating the safety/efficacy of alpelisib in addition to fluvestrant in men and postmenopausal women with HR+, HER2- ABC, who received prior treatment with an AI, with or without a CDK 4/6 inhibitor[a]
Approximately 40% of patients with HR+ ABC have PIK3CA mutations[b,c]
The PI3K pathway is the most commonly mutated pathway associated with tumor progression in HR+ ABC
a. André F, et al ESMO Congress. Abstract LBA3; b. Sabine VS, et al. J Clin Oncol. 2014;32: ; c. Lee JJ, et al. Cancer Biol Med. 2015;12:

8. SOLAR-1: Median PFS in Patients With PIK3CA Mutations
HR (95% CI): 0.65 (0.50, 0.85)
P =
PFS determined by local assessment. There was no advantage to alpelisib on median PFS in patients without a PIK3CA mutation.
André F, et al ESMO Congress. Abstract LBA3.

9. Implications of SOLAR-1 Trial Results
In the future, may consider different treatment options based on genomic testing results, as well as estrogen- receptor positivity
Genomic testing is used in other fields of cancer medicine
It is expected that other drugs will show efficacy according to genomic segments in the future

10. Risk of VTE in Patients Receiving CDK 4/6 Inhibitors: Updated Meta-Analysis
Homogeneity existed between RCTs
Patients receiving CDK 4/6 inhibitors experienced an increase in VTE risk vs control group
Pooled RR: 3.56 (95% CI: 1.57, 8.06; P = .002)
RCT = randomized clinical trials
RR = risk ratio
VTE = venous thromboembolism
6 studies (PALOMA-1, PALOMA-2, PALOMA-3, MONARCH-2, MONARCH-3, MONALEESA-2) with a total of 3159 eligible patients.
Thein KZ, et al ESMO Congress. Poster 1691P.

11. CDK 4/6 Inhibitors and the Risk for VTE: Implications of Meta-Analysis
Although the risk of VTE was higher in patients who received a CDK 4/6 inhibitor, overall incidence was low
Evaluate other factors, which may contribute to increased VTE risk in patients receiving CDK 4/6 inhibitors

12. Importance of Real-World Data in Oncology
Support active pharmacovigilance
Develop external control arms
Enable evidence generation based on pragmatic clinical trials
Support randomized study designs
Expand clinical research to point of care
May help increase access to experimental therapies
Increase patient participation in clinical trials
Importance of Real-World Data in Oncology
Khozin S, et al. J Natl Cancer Inst. 2017;109.

13. Real-World Use of Palbociclib in Patients With HR+, HER2- ABC: Results From POLARIS
Disease-Free Interval, Patients Who Received Palbociclib as First-Line ABC Therapy
A heterogeneous population received palbociclib
Older, premenopausal, black, Latino/Hispanic, and male patients not commonly represented in clinical trials
69.9% of patients received palbociclib combination as first-line ABC therapy
56.6% received palbociclib in combination with letrozole or anastrozole, 39.5% with fulvestrant, and 3.9% with exemestane
This interim analysis includes the first 402 patients (target enrollment 1500 patients) with completed baseline case report forms from 86 sites in the United States (data cutoff, August 13, 2018).
Blum JL, et al ESMO Congress. Poster 344P.

14. Real-World Treatment With Palbociclib Therapy in Germany: Results From IRIS
Reasons for Discontinuation
Overall
PAL + AI
PAL + FUL
Total, n
257
194 63
PD following initial control/response, n (%)
5 (13.2)
3 (10.0)
2 (25.0)
PD without initial control/response, n (%)
3 (7.9)
2 (6.7)
1 (12.5)
Pill burden/compliance, n (%)
1 (2.6)
1 (3.3)
0 (0)
Side effects/toxicity, n (%)
13 (34.2)
12 (40.0)
Patient request, n (%)
7 (18.4)
5 (16.7)
Other, n (%)
7 (23.3)
EMA = European Medicines Agency
Evaluation of treatment patterns in patients with HR+, HER2- ABC/MBC in Germany who received palbociclib combinations (palbociclib + an AI or palbociclib + fulvestrant) in line with EMA labeled indications.
Mitra D, et al ESMO Congress. Poster 338P.

15. Treatment Landscape of HR+, HER2- MBC
Evolving with recent positive advances
In the past 3 years, CDK 4/6 inhibitors, a novel class of targeted therapy, have been approved for patients with HR+, HER2- MBC
Palbociclib, ribociclib, abemaciclib
Fernandes MT, et al. Drugs Context. 2018;7:

16. Treatment Landscape of HR+, HER2- MBC (cont)
Demonstrated benefit of CDK 4/6 inhibitors
All agents exhibit PFS benefit vs standard of care
Benefits also demonstrated in terms of OS
CKD 4/6 inhibitors for all patients?
CDK 4/6 inhibitors are efficacious among different patient subgroups
Further studies are needed to select patients who will receive the greatest benefit
CDK 4/6 inhibitors generally have fewer AEs vs traditional chemotherapeutic options
AE = adverse event
Fernandes MT, et al. Drugs Context. 2018;7:

17. HR+, HER2- MBC Treatment: Challenges for the Future
Optimizing the role of biomarkers to select patient populations that would receive the greatest benefit from CDK 4/6 inhibitors
While the use of biomarkers for patient selection may not be achievable in the short term, clinicians can work to determine which patients are not receiving adequate benefit from a CKD 4/6 inhibitor
Consider dynamic biomarkers

18. HR+, HER2- MBC Treatment: Challenges for the Future (cont)
Determining the role of continued treatment with CDK 4/6 inhibitors after treatment progression
Exploring mechanisms of resistance
Majority of mechanisms of resistance are to ET vs CDK 4/6 inhibitors, specifically[a]
a. Turner N. ASCO® Oral presentation 1001.

19. HR+, HER2- MBC Treatment: Challenges for the Future (cont)
Clarifying the role of CDK 4/6 inhibitors for patients with important visceral metastases, but not in visceral crisis
Guidelines recommend ET for patients with HR+ disease, even in the presence of visceral disease, unless there is a visceral crisis[a]
However, a group of patients with high disease burden, but not yet in visceral crisis exist
There is a role for CKD 4/6 inhibition in this group of patients
Exploring the role of CDK 4/6 inhibitors vs chemotherapy in patients with visceral crisis
a. Cardoso F, et al. Ann Oncol. 2017;28:16-33.

20. Summary
CDK 4/6 inhibitors are promising agents for the treatment of HR+, HER2- MBC
Efficacy is similar between agents
Different AE profiles between agents, but with better overall tolerability profile vs traditional chemotherapeutic agents
Several unanswered questions remain regarding the use of CDK 4/6 inhibitors
Optimal treatment sequence
Ideal patient population

21. Abbreviations
ABC = advanced breast cancer ABE = abemaciclib AE = adverse event AI = aromatase inhibitor CI = confidence interval CKD = cyclin-dependent kinase CT = chemotherapy DOR = duration of response EMA = European Medicines Agency ET = endocrine-based therapy FUL = fulvestrant HR+ = hormone receptor-positive HR = hazard ratio ITT = intention to treat LET = letrozole MBC = metastatic breast cancer NR = not reached OR = objective response OS = overall survival

22. Abbreviations (cont)
PAL = palbociclib PBO = placebo PD = progression of disease PFS = progression-free survival RCT = randomized clinical trials RR = risk ratio VTE = venous thromboembolism