Clinical

Evidences of First-Line CDK 4/6 Inhibitors in

Postmenopausal Women with Advanced Breast Cancer

Denni Joko Purwanto

Dharmais National Cancer Hospital
Indonesia
 Disclaimer
No conflict of interest with companies that support this event and some
information in this presentation may include inappropriate indication or
dosage, please follow approved product information by BPOM

Denni Joko Purwanto

Dharmais National Cancer Hospital
Indonesia
 Human breast cancer is highly heterogeneous
On the level of histopathology On the molecular level

Stage (in situ/invasive)

Differentiation
Nuclear Grade
Lymphovascular invasion
Nodal involvement Shift to A New Approach Based on the
HR Biology of the Disease
HER2

Sorlie T et al, PNAS 2001; Sotiriou C et al, Proc Natl Acad Sci USA, 100; 2003
Estrogen Pathway is a Key Driver of Growth in Luminal
Breast Cancer
• Multiple compounds for estrogen
suppression have been
developed as treatment for
luminal (HR+) breast cancer

• Endocrine monotherapy
improves survival rates1 and was
established as first-line standard
of care in HR+, HER2- breast
cancer for over a decade

• Fulvestrant, a selective estrogen

receptor downregulator (ERD),
was the last endocrine
monotherapy agent receiving
approval from US FDA for HR+
postmenopausal women in 2nd
line setting (2002) and in 1st line
setting (2017)2
Year of compound 1. Yamamoto-Ibusuki M, et al. BMC Med. 2015;13:137
development 2. https://www.cancer.gov/news-events/cancer-currents-
blog/2017/fda-fulvestrant-breast-cancer
CDK4/6 Inhibitors in Breast Cancer

Hamilton E, et al. Cancer Treatment Reviews. 2016;45:129–138.

The Three CDK4/6 Inhibitors are Different

• CDK4 plays a vital role in breast cancer tumorigenesis

and tumor cell proliferation, while CDK6 has a smaller
impact on tumor cell growth

• The average differential for CDK4 versus CDK6

dependent lines for ribociclib, palbociclib, and
abemaciclib is 8.0-, 1.3-, and 5.5-fold, respectively

• Ribociclib has a greater concentration of free drug

available to penetrate tumor cells and contribute to in
vivo CDK4 inhibition, with a free drug concentration
that is 22 times more than either palbociclib or
abemaciclib
Yu et al. Cancer Cell 2006;9:23–32; Chen et al. Mol Cancer Ther. 2016;15(10);2273–81; Kim et al. Oncotarget 2018;9(81):35226-40.
 Ribociclib Selectivity:
Ribociclib had the fewest interactions with off-target kinases1

KRYXANA

Oncotarget, 2018, Vol. 9, (No. 81), pp: 35226-35240

7
EVIDENCE OF KRYXANA (RIBOCICLIB)
 Regulatory Approval Was Based on MONALEESA-2, a Pivotal
Phase III, First-Line Trial of Ribociclib + Letrozole in HR+/HER2–
Advanced Breast Cancer Patients1

KRYXANA Primary endpoint1-4

PATIENTS (N=668) 600 mg/day, 3 weeks on/1 week off + • PFS (locally assessed per

1:1 Randomization
letrozole 2.5 mg/day continuous dosing RECIST v1.1)
Postmenopausal HR+/HER2–
(n=334) 1-4
advanced breast cancer
Secondary endpoints
No prior therapy for advanced
• OS (key)
disease
• ORR
(de novo§ or >12 months
since completion
Placebo • CBR
3 weeks on/1 week off + letrozole • Safety
of adjuvant therapy)1-4 2.5 mg/day continuous dosing • QOL
(n=334) 1-4

CBR, clinical benefit rate; ORR, overall response rate; OS, overall survival; QOL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors.

10
1. KISQALI [Summary of Product Characteristics]. Novartis Pharma AG; 2017. 2. Data on file. Novartis Pharma AG. KISQALI [Core Data Sheet]. 3. Novartis Pharma AG; 2017. 4. Hortobagyi GN, Stemmer SM, Burris HA, et al.
Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748.
 MONALEESA-2 enrolled multiple patients types1
Baseline characteristics KRYXANA + letrozole (N=334) Placebo + letrozole (N=334)

Median age, years (range) 62 (23-91) 63 (29-88)

Race, n (%)*
Caucasian 269 (80.5) 280 (83.8)
Asian 28 (8.4) 23 (6.9)
Black 10 (3.0) 7 (2.1)
Other/unknown 27 (8.1) 24 (7.2)
ECOG performance status - n (%)
0 205 (61.4) 202 (60.5)
1 129 (38.6) 132 (39.5)
Metastatic sites, n (%)
†
Visceral disease 197 (59.0) 196 (58.7)
Bone-only disease 69 (20.7) 78 (23.4)
De novo metastatic disease, n (%) 114 (34.1) 113 (33.8)
‡
Disease-free interval since end of (neo)adjuvant therapy, n (%)

≤12 months 4 (1.2) 10 (3.0)

>12 months 216 (64.7) 210 (62.9)
Prior (neo)adjuvant systemic therapy, n (%)
Chemotherapy and endocrine therapy 123 (36.8) 120 (35.9)
Endocrine therapy only 52 (15.6) 51 (15.3)
Chemotherapy only 23 (6.9) 25 (7.5)

*Race was self-reported.

†Visceral involvement included liver, lung, and other visceral metastases.
‡1 patient in the placebo + letrozole arm had an unknown disease-free interval.

ECOG, Eastern Cooperative Group

1. Hortobagyi GN et al. N Engl J Med 2016;375:1738–1748.

11
KRYXANA (ribociclib) + letrozole demonstrated
a median PFS of 25.3 months1,2
EFFICACY PER INVESTIGATOR
ASSESSMENT1,2

HR 0.568
(95% CI: 0.457-0.704)
P<0.0001

KRYXANA + letrozole
EARLY separation of Median PFS: 25.3 months
(95% CI: 23.0-30.3)
PFS curves seen as
early as 8 weeks
Placebo + letrozole
Median PFS: 16.0 months
(95% CI: 13.4-18.2)

Number of patients still at risk

KRYXANA 334 294 277 257 240 227 207 196 188 176 164 132 97 46 17 11 1 0
Placebo 334 279 265 239 219 196 179 156 138 124 110 93 63 34 10 7 2 0

12
1. Kisqali [Summary Product Characteristic]. Novartis Pharma AG;2017. 2. Janni W et al. Presented at: European Society for Medical Oncology Congress;
September 8–12, 2017; Madrid, Spain. Poster 245PD.
13
 Efficacy & safety of KRYXANA (ribociclib) + letrozole
were consistent for Asian patients1Asian region (n=68) 100

80
• PFS was prolonged in the

Probability of PFS, %
ribociclib + letrozole vs 60

placebo + letrozole arm both 40

in patients treated in Asia R + L
n=35
P + L
n=33
(hazard ratio=0.298) and 20 Median PFS, months
(95% CI)
NR
(14.9–NR)
11.0
(9.1–16.4)
those treated outside of Asia 0 Hazard ratio (95% CI) 0.298 (0.134–0.662)

(hazard ratio = 0.602) 0 2 4 6 8 10 12 14

Time (Months)
16 18 20

100 Non-Asian region (n=600)

• Ribociclib + letrozole resulted
in a similar safety profile in

Probability of PFS, %
80

patients treated in Asia to 60

that observed in the full 40 R + L P + L
population Median PFS, months
n=299
NR
n=301
15.2
20 (95% CI) (19.3–NR) (13.4–19.2)
Hazard ratio (95% CI) 0.602 (0.457–0.792)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (Months)
AE, adverse event; CI, confidence interval; L, letrozole; NR not reached; P, placebo; PFS, progression-free survival; R, ribociclib.

1. Yap Y-S et al. ESMO Asia 2016; abstr LBA1 (oral).

15
At 8 Weeks, 3 out of 4 Patients With KRYXANA (ribociclib) +
Letrozole Had a Reduction in Tumor Size
CHANGE IN TUMOR SIZE AT 8 WEEKS PER INVESTIGATOR ASSESSMENT
1
1

76% of Patients Receiving KRYXANA + Letrozole

BEST CHANGE FROM BASELINE
(MEASURABLE LESION) (%)
Had Tumor Reduction

KRYXANA + letrozole
(n=238)

Each line on the graph represents an individual patient; the length of each line demonstrates
the best percent change from baseline in measurable lesions for that patient.

Rapid reduction in tumor size in patients with measurable disease was

demonstrated with KRYXANA + letrozole1

1. Janni W, Alba E, Bachelot T, et al. Duration of response and tumor shrinkage with first-line ribociclib + letrozole in postmenopausal women with HR+, HER2– advanced 16
breast cancer. Poster presented at: European Society for Medical Oncology Congress; September 8-12, 2017; Madrid, Spain. Poster 245PD.
 At 8 Weeks, Median Reduction in Tumor Size With
Ribociclib + Letrozole Was 29%1

Tumor size at baseline Tumor size at 8 weeks

Scans are for illustration only and represent a 29% median reduction in tumor size at 8 weeks for KRYXANA + letrozole.1

17
1. Data on file. Novartis Pharma AG.
CDK inhibitors-related “class-effect” adverse events
• Blockade of cells in G1 phase by
CDK4/6 inhibitors induces reversible
pharmacologic quiescence of early
hematopoietic stem/progenitor cells.1

• CDK4/6 inhibitors arrest the cell cycle

in the G1 phase and thereby halt cell
proliferation, having a pronounced
effect on metabolically active organs
and tissues such as gastrointestinal
tract and bone marrow.2

• CDK4/6 inhibition has caused

reversible/transient bone marrow
suppression, differentiating it from
apoptotic cell death caused by
cytotoxic chemotherapeutic agents.3-5

1. Finn RS, et al. Breast Cancer Res. 2009;11(5):R77; 2. Roberts PJ, et al. J Natl Cancer Inst. 2012;104(6):476-487; 3. Hu W, et al. Clin Cancer Res. 2016;22(8):2000-2008;
4. Roberts PJ, et al. ASCO 2015. Abstract 2529 [poster]; 5. Bisi JE, et al. AACR 2015. Abstract 1784 [poster].
 Ribociclib safety profile is well established and
Predictable based on MONALEESA-2 data % Increased in
ribociclib + AI vs.
AI alone

Neutropenia 69

Leukopenia 29

Nausea 23

Alopecia 18
Anemia 14
Grade 1
Vomiting 14
Grade 2
Diarrhea 13
Grade 3
ALT increased 12
Grade 4
AST increased
11
10 20 30 40 50 60 70 80
0 % of Patients

• And they are manageable and reversible

Hortobagyi G, et al. N Engl J Med. 2016;375(18):1738-1748. 19

 Current Guidelines Recommend Baseline and
Routine Monitoring in Breast Cancer Patients1
Monitoring and Follow-up in Metastatic Breast Cancer Patients1

Baseline Prior to New Therapy During Chemotherapy During Endocrine Therapy

Symptom Assessment Yes Yes Yes

Physical Exam Yes Yes Yes

Performance Status Yes Yes Yes

Weight Yes Yes Yes

LFTs, CBC Yes Yes Yes

CT Scan Chest/Abd/Pelvis Yes Yes Yes

Bone Scan Yes Yes Yes

PET/CT Optional Unknown Unknown

1. NCCN Clinical practice guidelines in oncology—breast cancer version 1.2018.

20
 Monitoring Schedule for Ribociclib Ensures That
Adverse Events Are Identified Early and Managed
Appropriately1
QTc prolongation identified via ECG1
Neutropenia identified via CBC1
Reversible with Grade ≥3 ALT/AST elevation identified via LFT1
! Median onset: dose interruption
15 days and/or dose
reduction

0 1 2 3 4 5 6 7 8
0 0 0 0 0 0 0 0
! Median onset: Resolved in ! Median onset: Resolved in
16 days 15 days 57 days 24 days

* A central analysis of ECG data showed 11 of 334 patients (3.3%) and 1 of 330 patients (0.3%) with at least 1 post-baseline QTcF >480 msec for the KISQALI + letrozole
arm and the placebo + letrozole arm, respectively

1. KISQALI [summary of product characteristics]; 2018.

21
 Early Monitoring Recommendations Optimize
Treatment With Ribociclib1
MONITORING SCHEDULE1

CYCLE 1 CYCLE 2 CYCLE 3-6 BEYOND CYCLE 6

Beginning Beginning
Baseline Mid-cycle Mid-cycle Mid-cycle
of Cycle of Cycle

CBC, LFTs

Electrolytes NONE

ECG for QT

No scheduled ECGs required beyond Cycle 2.1

No scheduled blood tests required beyond Cycle 6.1

1. KISQALI [summary of product characteristics]; 2018.

22
 Clear guidance for dose modification to manage AEs1,2
RECOMMENDED DOSE MODIFICATIONS FOR SPECIFIC AEs 1

‡ If dose reduction below 2 0 0 mg is required, discontinuetreatment. 1

§ Grade 3 neutropenia with single episode of fever >38.3°C or above 38°C for more than 1hour and/or concurrent infection. 1
||Without total bilirubin increase >2 x ULN.1
¶ Baseline=prior to initiation of treatment. 1

# Excluding neutropenia, hepatotoxicity, and QT interval prolongation. 1

**Initiate appropriate medical therapy and monitor as clinically indicated. 1

AEs, Adverse Events; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; QTcF, QT prolongation corrected by Fridericia’s formula; ULN, Upper Limit of Normal

Monitoring and dose modification recommendations

provide clear guidance on A E management1,13

For use by Novartis speakers and appropriate Novartis associates when delivering approved content. Not for distribution.

1. KISQALI [Summary of Product Characteristics]. Novartis Pharma AG; 2017. 2. Chen P, Lee NV, Hu W, et al. Spectrum and degree of CDK drug interactions predicts clinical
performance. Mol Cancer Ther. 2016;15(10):2273-2281.
 CASE SHARING

Hormonal Postive Advance Breast Cancer

Treatment
Female, 39 Years old.

Cancer Center Hospital di Jakarta (Sep 28, 2019)

Post Partum (P3A0H3), , Breast Lump Susp
Malignant & Susp Liver Metastatic (T1N0M1)
RADIOLOGY
 CASE REPORT

Hormonal Postive Advance Breast Cancer

Treatment
Female, 39 Years old.
Post Partum, Liver Metastatic Breast Cancer
Gleanagles Hospital (Oct 10, 2019)
T4A, N1, M1 (PET Scan), Core Biopsi
Inviltrating Ductal Carcinoma grade 2
ER + (50%), PR + (50%), Her2 – (+1)
PET AND CARDIAC IMAGING
HISTOPATOLOGY REPORT
 CASE REPORT

Hormonal Postive Advance & Metastatic Breast Cancer

Treatment
Female, 39 Years old.
Post Partum, Liver Metastatic Breast Cancer
Guangzhou Huayin Hospital (Oct 24, 2019)
Liver Biopsi :
Infiltrating Carcinoma
ER + (10%), PR + (10%), Her2 – (+1), KI67 +(15%)
PATHOLOGIC REPORT - GUANGZHOU
 CASE REPORT

Hormonal Positive Advance & Metastatic Breast

Cancer Treatment
Female, 39 Years old.
Post Partum, Liver Metastatic Breast Cancer
(Oct 24, 2019 – Marc, 2020)
Ghangzhuo Huayin Hospital :
Chemoterapy 8 Cycles (AC-T_ continued with
TACE for breast lump.
 CASE REPORT

Hormonal Postive Advance Breast Cancer

Treatment
Female, 39 Years old.
Post Partum, Liver Metastatic Breast Cancer
Cancer Center Hospitals di Jakarta (April 27, 2020)
Radical Mastectomy + (Lap) Bil. Salphino Oophorectomy
(Patholigic Rep: Invasif Carcinoma, NST grade 3, Invasif
limfovascular, Free Margine, 14 Metastatic Limfnode)
ANATOMIC PATHOLOGY REPORT
 CASE REPORT

Hormonal Postive Advance & Metastatic Breast

Cancer Treatment
Female, 39 Years old.
Post Partum, Liver Metastatic Breast Cancer
Radical Matectomy + BSO
Cancer Center Hospital di Jakarta (June 5, 2020)
External Beam Radiotherapy
5000 cGy (200 cGy, fraction)
 CASE REPORT

Hormonal Postive Advance & Metastatic Breast Cancer

Treatment
Female, 39 Years old.
Post Partum, Liver Metastatic Breast Cancer
Cancer Center Hospital di Jakarta (April 27, 2020)
Radical Mastectomy + BSO + External Beam Radiotherapy
Continued
Femara 2.5 mg + Ribociclib 600 mg -> 400 mg
LABORATORY REPORT – JUNE 2020
 CASE REPORT

Hormonal Postive Advance & Metastatic Breast Cancer

Treatment

Female, 39 Years old.

Post Partum, Liver Metastatic Breast Cancer
Radical Mastectomy + BSO + Externa Beam Radiotherapy
Continued :
Letrozole 2.5 mg + Ribocclib 600 mg -> 400 mg
PFS -, Netrophenia (gr1), ALT/AST Increased (gr 1)
(Managable)
 Conclusions
• Current guidelines support the use of endocrine-based combination
therapeutic approaches in HR+, HER2– advanced BC
• Endocrine plus CDK4/6 inhibitor became a new standard of care in
post-menopausal HR+, HER2- advanced BC with a significant PFS
improvement over endocrine monotherapy approaches (eg., median
PFS 25.3 vs 16 months in MONALEESA-2 trial) and with the
expectable, manageable, and reversible “class-effect” AEs
• Kryxana (Ribociclib) has well established and predictable safety
profile
• Adverse event can be managed by following a clear guidance on dose
modification