Cdk 4-6 inhibitors in breast cancer with their unique features and trials due to which they received approvals.

Cdk 4/6 inhibitors are the most significant advancement for hormone positive breast cancers.They had started their role in metastatic setting and now have been sucfessfully useful in adjuvant setting as well. Mechanism of action and resistance have been simplified here. Key points about palbociclib,ribociclib and abemaciclib with their trials, doses, side effects,DLT have been shown.

1. CDK 4/6 INHIBITORS IN
BREAST CANCER
DR. AASTHA SHAH

2. Mechanism of action

3. ●Monophosphorylated Rb prevents G0 exit.

●Hyperphosphorylation by Cyclin E-CDK2 in late G1.

●Cancer cells activate CDK4/6 via increased of D-Cyclins: can be due to gene
amplification, can also be due to loss of expression of INK 4 proteins.

●Why HR+? 1.Increase incidence of Rb positivity
2.ER positive tumors depend on Cyclin D- CDK 4 for proliferation.

4. Generations
●First Third
Flavopiridol Palbociclib
Roscovitine Ribociclib
●Second Abemaciclib
Dinaciclib Trilaciclib
Fadraciclib
ATT519

5. PALBOCICLIB
●FDA approval in 2015 for metastatic breast cancer hormone positive for first
line therapy.
●Paloma 1:phase 2 study
Letrozole:PFS 10.2 months
Palbociclib +letrozole:PFS 10.2 months

6. ●PHASE 3 STUDY
●To verify PALOMA 1 findings.
●mPFS: 24.8 months vs 14.5 months(HR:
0.58)
●mOS: 53.9 months vs 51.2 months(
HR0.96)
●Prior adjuvant or neoadjuvant treatment
with a nonsteroidal aromatase inhibitor
was allowed unless disease had recurred
while the patient was receiving the therapy
or within 12 months after completing
therapy.
●Only post menopausal
PALOMA 2

7. PALOMA 3
●PHASE 3 STUDY
●mPFS:11.2 months vs 4.6months(HR:
0.50)
●mOS: 34.8 months vs 28 months(HR:
0.81)
●Eligible regardless of menopausal
status.
●Premenopausal or perimenopausal
patients received goserelin for the
duration of study treatment, starting at
least 4 weeks before randomization

8. PALOMA 4
●PHASE 3 STUDY
●Evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in
Asian women with ER+/HER2- ABC.
●mPFS was 21.5 months versus 13.9 months (HR 0.68)

9. DOSE: 125 mg 3 weeks on 1 week off , 28 day cycle.
Levels of dose reduction: 100mg and 75 mg.
DLT: Myelosuppression mainly neutropenia.Reversible and non cumulative
Asians are risk factor for myelosuppression.
Median time :15-28 days
No dose adjustment for renal dysfunction.
Hepatic dysfunction: Only in CP C 75 mg 3 weeks on 1 week off.
Diarrhea
Blurred vision and dry eyes
Palmar plantar erythrodysesthesia
Half life:29 hours
Hepatic metabolism

10. RIBOCICLIB
●FDA approval on March 13,2017 for use in
combination with AI for first line for MBC
postmenopausal female.
●MONALEESA 2: PHASE 3 STUDY
●mPFS:25.3 months versus 16 months(HR
0.56)
●mOS: 63.9 months vs 51.4 months(HR
0.76)
●Prior adjuvant or neoadjuvant treatment
with a nonsteroidal aromatase inhibitor was
allowed unless disease had recurred while
the patient was receiving the therapy or
within 12 months after completing therapy.
●Only post menopausal

11. MONALEESA 3
●PHASE 3 STUDY
●mPFS: 33.6 months vs 19.2
months (HR 0.55)
●mOS:67.6 months vs 51.8
months(HR 0.67)

12. MONALEESA 7
●PHASE 3 STUDY
●Compared ribociclib with
placebo, in addition to endocrine
therapy, in premenopausal or
perimenopausal women with
hormone-receptor–positive,
HER2-negative advanced breast
cancer.
●Both groups received goserelin
●mPFS: 23.8 months vs 13
months(HR 0.55)
●mOS:58.7 months vs 48
months(HR 0.76)

13. NATALEE
●PHASE 3 STUDY
●Stage II and III. Required 1 LN+ and if LN-
then grade2 with ki 67>=20% or grade 3 or
high genomic risk score.
● At 3 years, invasive disease–free survival
was 90.4% with ribociclib plus an NSAI and
87.1% with an NSAI alone(HR 0.75)
●Absolute iDFS benefit was 3.2%
●Both groups received goserelin (at a dose of
3.6 mg, administered subcutaneously on day
1 of each 28-day cycle). Patients also
received either a nonsteroidal aromatase
inhibitor (letrozole at a dose of 2.5 mg or
anastrozole at a dose of 1 mg) or tamoxifen
(at a dose of 20 mg), administered orally
once daily continuously

14. DOSE: 600 mg for MBC and 400 mg for EBC for 3 years
3 weeks on 1 week off 28 days cycle
Hematological: Mainly neutropenia.Median time to onset: 15 days
Renal dysfunction: if creat clearance< 15 ml/min dont give and 15-30 ml/min 200 mg OD
Hepatic dysfunction: CP B/C 400 mg
Check OTc before initiation.Give only if <450 msec
Hepatic metabolism
Half life:30-55 hours

15. ABEMACICLIB
●FDA approval on September 28,2017
●Approval as monotherapy based on MONARCH 1 study.
●A single-arm, open-label, multicenter study in women with measurable
HR-positive, HER2-negative metastatic breast cancer whose disease progressed
during or after endocrine therapy, had received a taxane in any setting, and who
received one or two prior chemotherapy regimens in the metastatic setting.

16. MONARCH 2
●PHASE 3 STUDY
●Patients were randomly assigned 2:1 to
receive abemaciclib or placebo (150 mg
twice daily) on a continuous schedule
and fulvestrant (500 mg, per label).
●mPFS: 16.4 months vs 9.3 months(HR
0.55)
●mOS:38.7 months vs 31.5 months

17. MONARCH 3
●PHASE 3 STUDY
●Abemaciclib +AI vs placebo +AI
●mPFS:28.18 months vs 14.76
months(HR 0.54)
●mOS:67.1 months vs 54.5
months(HR 0.73)

18. MonarchE
●PHASE 3 STUDY
●5,637 patients were randomly assigned 1:1
to receive either abemaciclib plus ET or ET
alone.
●Cohort 1 included patients with either at
least 4 positive pathologic axillary lymph
nodes (pALNs) or 1-3 pALNs with
additional high-risk features of either grade
3 disease or tumor ≥5 cm. Cohort 2
included patients with1-3 positive pALNs
and central Ki-67 ≥ 20%
●Exclusion:node-negative breast cancer, and,
patients with inflammatory breast cancer,

19. ●iDFS AT 5 years: 83.6% vs76%(HR 0.68) 7.6% points
●DRFS:86% vs 79.2(HR 0.73) 6.7% points

20. DOSE: 15O mg BD continuously and in adjuvant setting for 2 years and 200 mg BD when given as
monotherapy.
DLT: Fatigue
Renal impairment: No dose modification
Hepatic impairment: CP C:150 mg OD
Diarrhea most common, seen in 90% patients
Myelosuppression less common than other two.Median time to onset of neutropenia is 1 month.
Half life: 18 hours
Crosses BBB

21. RIGHT CHOICE TRIAL
●PHASE 2 STUDY
●Presented at SABCS 2022
●Head to head comparison between CDK4/6 inhibitor Ribociclib + ET vs chemotherapy in life
threatening visceral crisis
●Pre and perimenopausal female
●mPFS:24 months vs 12.3 months(HR 0.54)
●ORR:66.1% vs 61.8%
●Time to response: 4.9 months vs 3.2 months

22. MAINTAIN TRIAL
●PHASE 2 STUDY
●Presented at 2022 ASCO Annual meeting.
●Cdk 4/6 inhibitor after progression on Cdk4/6 inhibitor.
●84% patients had previously received palbociclib,11% had received ribociclib and 1.7% had
received abemaciclib.
●Ribociclib compared to placebo in addition to exemestane of fulvestrant.
●mPFS: 5.29 months vs 2.76 months

24. CDK 4/6 inhibitor + Anti HER2
●monarcHER: PHASE 2 STUDY
●Should have previously received 2 Her 2 targeted therapies for advanced disease


ARM mPFS mOS
●A. Abemaciclib+
Trastuzumab+
Fulvestrant
8.3 31.1
B. Abemaciclib+
Trastuzumab
5.7 29.2

C.Chemotherapy+Trastu
zumab
5.7 20.7

25. Mechanism of Resistance
●Loss of Rb
●Amplification of CDK 6
●Activation of CDK 2 due to decrease of p27 expression.
●Presence of BRK:Breast Tumor Related Kinase