1. Vincenzo Adamo Luminal Metastatic Breast Cancer:
role of CDK4/6 inhibitors from preclinical data to clinical practice
Vincenzo Adamo
Oncologia Medica AO Papardo &
Università degli Studi di Messina

2. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
Final Remarkers

3. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
Final Remarkers

4. “Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC”
“Treatment recommendations should be based on type of adjuvant treatment, disease-free interval and organ function”
“Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women”
Rugo H, et al. JCO 2016;34:

5. Top Line recomendations from ESO-ESMO ABC4 panel (Lisbona 2017)
“Endocrine therapy plus a CDK4-6 inhibitor, is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance”
courtesy by A. Prat

6. Evolution of therapy for Endocrine-sensitive Metastatic Breast Cancer

7. Evolution of therapy for Endocrine Resistant Metastatic Breast Cancer

8. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
Final Remarkers

9. Cyclin-dependent protein kinase (CDK) 4/6 Inhibitors
Palbociclib
Abemaciclib
Ribociclib
Lange CA, et al. Endocr Relat Cancer 2011

10. ER and CDK4/6 are two distinct target for controlling cancer cell growth

11. Palbociclib preferentially inhibits proliferation of luminal ER+ human breast cancer cell lines in vitro

12. Palbociclib Acts Synergistically with Tamoxifen in ER+ Breast Cancer Cell Lines
Finn R, Breast Cancer Res 2009

13. Tumour Growth Inhibition: Synergy Between Palbociclib and Letrozole in ER+ Xenograft Model
Lee, AACR 2014

14. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
Final Remarkers

15. Selective CDK4/6 Inhibitors
IC50
Palbociclib
Ribociclib
Abemaciclib
CDK4
9–11 nM
10 nM
2 nM
CDK6
15 nM
39 nM
5 nM
CDK2
>10 µM
>50 µM
>500 nM
CDK9 ND
57 nM
Kinase selectivity tree: Bigger circles = more inhibition
Chen P, et al. Mol Cancer Ther 2016.
Asghar U, et al. Nat Rev Drug Discov 2015

16. Clinical data for CDK4/6 inhibitors in HR+/HER2-MBC
Palbociclib: NCT , NCT , NCT
Abemaciclib: NCT ,
Ribociclib: NCT ,
NCT , NCT
NCT
PALOMA-1
PALOMA-2
MONALEESA-2
MONARCH 3
1L ER+, HER2– mBC
Palbociclib + AI (letrozole)
1L ER+, HER2– mBC
Palbociclib + AI (letrozole)
1L ER+, HER2– ABC
Ribociclib + letrozole
1L ER+, HER2– mBC
Abemaciclib + NSAI
2014
2015
2016
2017
Data read-out dates
PALOMA-3
MONARCH 1
MONARCH 2
MONALEESA-7
2L Recurrent HR+, HER2– mBC
Palbociclib + fulvestrant
3L Recurrent ER+, HER2– mBC
Abemaciclib
ET resistant
Or ER+, HER2– 1LmBC
Abemaciclib + fulvestrant
1L ER+ HER2– pre/peri- menopausal ABC
Ribociclib + goserelin + tamoxifen / NSAI 16 16

17. Endocrine Sensitive Disease

19. RCTs of 1st Line Endocrine Therapy with CDK4/6 inhibitors for HR+/HER2-ve ABC
PALOMA-2
MONALEESA-2
MONARCH-3
Let+ Palbo
Let + Plac
Let + Ribo
NSAI+ Abema
NSAI + Plac
Pts
444
222
334
328
165
mPFSmo
24.8
(HR 0.58)
14.5
25.3
(HR 0.56) 16 NR
(HR 0.54)
14.7
mOS mo NA
ORR% 42 35 41 28 48
CBR% 85 70 80 72 78

20. All subgroups equally benefit from a CDK4/6i

21. MONARCH 3: exploratory analyses
Treatment-free interval <36 mos vs. ≥36 mos
“...Our exploratory subgroup analyses suggest that patients with indicators of poor prognosis had substantial benefit from the addition of abemaciclib, while in patients with a long treatment-free interval or bone-only disease, single agent endocrine therapy may be an appropriate initial therapy...”
Patients with/without bone only disease
Patients with/without liver metastases
Di Leo A, et al. ESMO 2017; Goetz MP, et al. JCO 2017

22. Endocrine Resistant Disease

23. Endocrine Resistant Disease

24. RCTs with CDK4/6 i in Endocrine Resistant Disease
PALOMA-3
MONARCH-2
Fulv +Palbo
Fulv + Plac
Fulv+ Abema
Fulv+ Plac
Pts#
347
174
446
223
Prior Chemo for ABC %
30.8
36.2
Median PFS mo
9.2
(HR 0.42)
3.8
16.4
(HR 0.55)
Median OS mo NA
ORR%
10.4
6.2
35.2
16.1
CBR% 34 19
72.2
56.1

25. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
Final Remarkers

26. Different Safety Profile of CDK4/6 inhibitors
Barros-Sousa, et al. Breast Care 2016

27. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
Final Remarkers

28. Premenopausal women and clinical trials
Premenopausal women generally excluded from large registrational trials HR+ ABC.
Clinical data limited to only a few small phase 2 trials.
PALOMA-3 included 108 premenopausal women ad is the only phase 3 study to date to report outcomes data for fulvestrant 500 mg with ovarian suppression in premenopausal patients.
MONALEESA-7 is the only phase 3 trial conducted in premenopausal women and is the only phase 3 trial to date report outcomes data in this populations.

29. Palbociclib + Fulvestrant in premenopausal women:
a subset analysis of PALOMA-3 trial
108 premenopausal women HER2-/HR+ MBC
ORR: 25.0% vs. 11.1%
CBR: 69.4% vs. 44.4%
“...These findings show that the addition of palbociclib had no impact on the concentration of fulvestrant, complete ovarian suppression was maintained, and no additional toxicities were evident with the addition of a LHRH agonist, all factors important for the investigation of palbociclib in early stage breast cancer. The results support the use of palbociclib in combination with fulvestrant and goserelin for women with HR+ ABC, and these findings have expanded the treatment options for premenopausal women...”
Loibl S, et al. Oncologist 2017

30. Placebo + tamoxifen/NSAI + goserelin* n=337
MONALEESA-7: Phase III placebo-controlled study of ribociclib and tamoxifen/NSAI + goserelin
Pre/perimenopausal women with HR+, HER2– ABC
No prior endocrine therapy for advanced disease
≤1 line of chemotherapy for advanced disease
N=672
Ribociclib (600 mg/day; 3-weeks-on/1-week- off) + tamoxifen/NSAI + goserelin* n=335
Primary endpoint
PFS (locally assessed per RECIST v1.1)‡
Secondary endpoints
Overall survival (key)
Overall response rate
Clinical benefit rate
Safety
Patient-reported outcomes
Randomization (1:1)
Placebo + tamoxifen/NSAI + goserelin* n=337
Stratified by:
Presence/absence of liver/lung metastases
Prior chemotherapy for advanced disease
Endocrine therapy partner (tamoxifen vs NSAI)
Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter
Primary analysis planned after ~329 PFS events
95% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%, corresponding to an increase in median PFS to 13.4 months (median PFS of 9 months for the placebo arm1,2), and a sample size of 660 patients
Triphaty D, SABCS 2017

31. MONALEESA-7: Primary Endpoint: PFS
100 90 80 70 60
Probability of PFS (%) 50 40 30
PFS (investigator assessment)
Ribociclib + tamoxifen/NSAI n=335
Placebo + tamoxifen/NSAI n=337
Number of events, n (%)
131 (39.1)
187 (55.5)
Median PFS, months (95% CI)
23.8 (19.2–NR)
13.0 (11.0–16.4)
Hazard ratio (95% CI)
0.553 (0.441–0.694)
One-sided p value 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
No. at risk
Time (months)
Ribociclib + tamoxifen/NSAI
335
301
284
264
245
235
219
178
136 90 54 40 20 3 1
Placebo + tamoxifen/NSAI
337
273
248
230
207
183
165
124 94 62 31 24 13 3 1
Triphaty D, SABCS 2017

32. MONALEESA-7: PFS by Endocrine Therapy Partner (investigator-assessed)
PFS (investigator assessment)
Tamoxifen
NSAI
Ribociclib arm
n=87
Placebo arm n=90
Ribociclib arm n=248
Placebo arm n=247
Number of events, n 39 55 92
132
Median PFS, months (95% CI)
22.1 (16.6–24.7)
11.0 (9.1–16.4)
27.5 (19.1–NR)
13.8 (12.6–17.4)
Hazard ratio (95% CI)
0.585 (0.387–0.884)
0.569 (0.436–0.743)
Triphaty D, SABCS 2017

33. MONALEESA-7: Secondary Endpoints
All patients
Rate (%)
Patients with measurable disease
Rate (%) p= p=
Ribociclib + tamoxifen/NSAI
Placebo + tamoxifen/NSAI
The CBR in patients with measurable disease was 79.9% for ribociclib + tamoxifen/NSAI vs 67.3% for placebo + tamoxifen/NSAI (p= )
Overall survival data were immature at the cut-off date
Triphaty D, SABCS 2017

34. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
The Future
Final Remarkers

35. ABC 4 guidelines (Lisbona 2017): Postmenopausal patients with ER+/HER2‒ ABC
courtesy by A. Prat

36. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
The Future
Final Remarkers

37. The Future
Integration of CDK 4/6 inhibitors in EBC setting, in HER2 positive disease and beyond second line setting

38. OUTLINE Therapeutic landscape of HR+HER2-MBC
Endocrine therapy plus CDK4/6 inhibitors as a new standard of care on HR+ advanced breast cancer-preclinical data
The CDK 4/6 inhibitors program
Toxicity
Premenopausal women
Positioning of CDK4/6 inhibitors in standard clinical practice
The Future
Final Remarkers

39. Final Remarkers
Are there clinical factors that may influence treatment decisions? DFI, tumor burden, metastatic site, menopausal status and endocrine resistance type should be included in the decision making.
Are all CDK4/6 inhibitors created equal? No, but they are similar and present different safety profile.
Do we have to use CDK4/6 inhibition + AI in 1st line in all pts? No, unless the OS results of PALOMA-2, MONALEESA-2, and MONARCH-3 state otherwise.
CDK4/6 inhibitors induce a meaningful benefit? Yes, in 1st and 2nd line
Are there predictive biomarkers? No, predictive biomarkers, all patients equally benefit from CDK4/6.
Should we incorporate CDK4/6 inhibitors plus endocrine therapy at some point in the treatment of ER+ MBC? Absolutely yes! The relatively good safety profile, the long duration of clinical benefit and the delay in chemotherapy start support it !

40. Grazie per l’attenzione

41. Do we need predictive markers for targeted agents
Do we need predictive markers for targeted agents? Yes, but…not yet identified and/or validated
BOLERO-2
PALOMA-2
PALOMA-3
MONALEESA-2
1. Baselga J, NEJM 2012; 2. Finn RS NEJM 2016; Cristofanilli M, Lancet 2016; 4. Hortobagyi G. NEJM 2016

42. PALOMA-3: PI3KCA Mutation in ctDNA
PFS in PIK3CA WT pts
PFS All population
PFS in PIK3CA mutated pts
“…Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo , irrespective of hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy…”
Cristofanilli M, et al. Lancet 2016

43. PALOMA-2: Subgroup Analysis of PFS by Biomarker
“…These exploratory analyses did not identify a subgroup of ER+ pts that did not benefit from the addition of Palbociclib to Letrozole…”
Finn RS, ESMO 2016

44. MONALEESA-2: Subgroup Analysis of PFS by Biomarker
Andre et al, AACR 2017

45. CDK4/6 in Breast Cancer o
The growth of HR+ breast cancer is dependent on Cyclin D1, a direct transcriptional target of ER
Cyclin D1 activates CDK4/6 resulting in G1–S phase transition and entry into the cell cycle1
Adapted from Asghar U, Nat Rev Drug Discov 2015

46. Luminal MBC: Treatment Guidelineso
NCCN/ASCO
Pts whose tumors express any level of ER and/or PgR. Treatment recommendations should be offered on the basis of type of adjuvant treatment, disease-free interval, and extent of disease at the time of recurrence.
Endocrine therapy should be recommended as initial treatment for patients with HR-positive MBC, except for patients with immediately life-threatening disease or for those experiencing rapid visceral recurrence during adjuvant endocrine therapy
Sequential hormone therapy should be offered to patients with endocrine-responsive disease
Treatment should be administered until there is unequivocal evidence of disease progression.
ESMO/ABC3
the preferential use of endocrine therapy, even in the presence of visceral metastases, until clear evidence of endocrine resistance.
Chemotherapy should be reserved for cases of rapidly progressive disease or proven endocrine resistance.
Endocrine treatment after CT (maintenance ET) to maintain benefit is a reasonable option, although this approach has not been assessed in randomized trials.
AIOM
Tumori ormonosensibili HER2 negativi, in assenza di malattia aggressiva e crisi viscerale.
Il trattamento ormonale dovrebbe essere proseguito (anche con linee di terapia successive) fino a quando è possibile considerare la malattia ormonosensibile.
la scelta della terapia, sia per la prima linea che per quelle successive, si basa soprattutto sullo stato menopausale della paziente e sulle terapie precedentemente eseguite in fase adiuvante o metastatica.
Rugo HS, et al. JCO 2017
Cardoso F, et al. Ann Oncol 2016
Linee Guida AIOM 2016

47. Treatment for HR+HER2neg MBC
CDK 4/6 inhibitors
+ AI
Breast Cancer o
ER+/HER2- 7%
CDK4/6 + fulvestrant
Toremifene
Everolimus + exemestane
Exemestane
Letrozolo
Buparlisib + fulvestrant
Fulvestrant
Tamoxifene
30%
Anastrozolo
70%
1975
1980
1985
1990
1995
2000
2005
2010
2015
2016

48. RCTs of 1st Line Endocrine Therapy with CDK4/6 inhibitors for HR+/HER2-ve ABC
Da togliere
Trial
Study Design
Study Size
Target Population
Partner ET
Primary Endpoint
PALOMA-1
Phase 2
Open label
165 pts
AI sensitive
Treatment naïve for mBC
Postmenopausal
Letrozole
PFS
PALOMA-2
Phase 3
Placebo
control
666 pts
MONALEESA-2
Placebo control
668 pts
MONARCH-3
Placebocontrol
496 pts
NSAI
(Letrozole or Anastrozole)

49. TOXICITY o

50. ASCO guidelines 2016: Endocrine therapy for patients with HR+ mBC
Da togliere?
Adapted from Rugo HS, J Clin Oncol 2016