1. Cyclin Kinases inhibitors and beyond
Patrizia Vici

2. Cooperation between ER and Cyclin D1 pathways enhances proliferation in “luminal”breast cancer

4. 165 pts
Amplif cyclin D1, loss p16 or both

5. Hypothesis: Can the Amplification of Cyclin D1 Predict Sensitivity?

6. (No differences between cohorts)
PFS (ITT)
Palbo+Letroz better
(No differences between cohorts)
20.2 vs 10.2mo
closed

7. Clinical benefit: 81% vs 58% p 0.0009
trend in ORR: 43% vs 33% p 0.13 OS
Clinical benefit: 81% vs 58% p

8. Palbo+letrozole as first-line:
No neutropenic fever
Palbo+letrozole as first-line:
longer PFS,
safety predictable and manageable

9. Phase III
1°-line

10. PALOMA 2: Baseline Characteristics (ITT)
Palbociclib + Letrozole
(n = 444)
Placebo + Letrozole
(n = 222)
Median age, yrs (range)
65 yrs or older, %
62 (30-89) 41
61 (28-88) 36
Race, %
White/Black/Asian/other
77/2/15/6
77/1/14/8
ECOG PS, %
0/1/2
58/40/2
46/53/1
Disease site, %
Visceral
Nonvisceral
Bone only 48 52 23 50 22
Disease-free interval, %
> 12 mos
≤ 12 mos
De novo advanced disease 40 38 42
Prior (neo)adjuvant hormonal therapy, % 56 57
ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status.
Finn R, et al. ASCO Abstract 507.

11. PFS 24.8 vs 14.5mo Primary objective M f up duration 23 mo

12. PALOMA 2

13. Confirmed phase II trial results

14. Neutropenia any grade: 79.5%
Febrile neutropenia 1.8% vs none

15. PALOMA 2: Conclusions
First-line palbociclib + letrozole significantly improved median PFS vs placebo + letrozole in women with ER+/HER2- advanced breast cancer
Median PFS improved by > 10 mos compared to placebo
24.8 mos vs 14.5 mos, HR: 0.58 (95% CI: ; P < .0001)
Palbociclib clinical benefit observed in all prespecified subgroups
Palbociclib well tolerated with neutropenia, leukopenia the most frequently reported Aes
PALOMA-2[1] data confirm PALOMA-1[2] results and constitute the longest median PFS improvement to date in the front-line setting in advanced ER+ breast cancer
AE, adverse event; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.
1. Finn R, et al. ASCO Abstract 507.
2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.
OS: too early

16. Qualitative analysis
Quantitative analysis
Finn R, San Antonio 2016

18. 521 pretreat pts
PALOMA-3: Interim anal.
Premenopausal + goserelin
Fulv+palbo vs
Fulv+plac

19. Response Rate 10.4% vs 6.3% (p=0.16)
Clin Benefit % vs 19.0% (p<0.001)

20. ITT
Previous adj/neoadjuvant only
Previous CT/ET for advanced disease

23. PALOMA-3 Final Analysis: Effect by ER and PR Expression Level in Patients With HR-Positive MBC

24. PIK3CA Mutation and Resistance to CDK4/6 Inhibitors

25. ESR1 Mutations and Resistance to CDK4/6 Inhibitors

26. from PALOMA 3:
5 months advantage with palbociclib
ESR1 status

27. 1° line MONALEESA 2 Letrozole+ ribociclib vs Letrozole+placebo
Phase III
668 pts
1° line
Letrozole+ ribociclib vs
Letrozole+placebo
Stopped at pre-planned interim analysis
(m fup 15.3mo)

28. ITT-Investigators assessment
Not reached
14.7mo

31. Nausea, elevated liver transaminases, QTc prolongation

32. MONALEESA: Biomarkers analysis (AACR 2017)
Exploratory endpoint
Archival/fresh tumor samples (>400 pts):
Rb expression
P16
CDKN2A, CCND1, ESR1
Ki 67
PIK3CA
No differences in PFS: the benefit with ribociclib was seen in all subgroups

33. >9 months advantage with ribociclib

34. Less neutropenia, more diarrhea, cross blood-brain barrier, single-agent active

35. Abemaciclib: Breast Cancer Clinical Program (1 of 2)
Study1
Clinicaltrials.gov #
Disease
Treatment Groups
JPBA2
Phase 1
NCT
Metastatic breast cancera
abemaciclib (Cohort D)
abemaciclib + fulvestrant (Cohort G)
JPBH3
NCT
Metastatic breast cancer
abemaciclib + letrozole
abemaciclib + anastrozole
abemaciclib + tamoxifen
abemaciclib + exemestane
abemaciclib + exemestane + everolimus
abemaciclib + trastuzumab
JPBO4 Phase 2
NCT
HR+ breast cancer with brain metastasesa
abemaciclib
JPBN5 MONARCH 1 Phase 2
NCT
Recurrent metastatic breast cancer after progression on hormone and chemotherapy treatment
JPBL: MONARCH 2 Phase 3
NCT
HR+, HER2- locally advanced or metastatic breast cancer after progression on endocrine therapy
abemaciclib + fulvestrant
placebo + fulvestrant
Abbreviations:
HER2=human epidermal growth factor receptor 2; HR+=hormone receptor positive
Key Points:
JPBA1
Abemaciclib in combination with hormone therapies for metastatic breast cancer.
JPBH1
A study of abemaciclib in combination with hormone therapies for breast cancer that has spread.
JPBO1
Phase 2 study of abemaciclib in patients with brain metastases secondary to hormone receptor positive breast cancer, non-small cell lung cancer, or melanoma.
JPBN1 (MONARCH 1)1
Phase 2, open-label study of abemaciclib to assess the efficacy of abemaciclib in patients with recurrent metastatic breast cancer that have previously progressed on hormone and chemotherapy treatments.
JPBL1 (MONARCH 2)1
Phase 3, randomized, double-blind, placebo-controlled, study of fulvestrant with or without abemaciclib in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer.
I3Y-MC-JPBA, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPBH, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPBN, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPBL, Clinicaltrials.gov identifier: NCT
References:
Last accessed: March 22, 2016.
Last accessed: March 22, 2016.
Last accessed: March 22, 2016.
Last accessed: March 22, 2016.
Last accessed: March 22, 2016.
Patnaik A, Rosen LS, et al. Efficacy and safety of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discovery 2016;(Ahead of print).
Tolaney SM, Beeram M, et al. A phase Ib study of abemaciclib with therapies for metastatic breast cancer. Poster presented at American Society of Clinical Oncology; Abstract 522.
Sahebjam S, Le Run E, et al. Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer. Poster presented at ASCO Abstract 526.
Dickler MN, Tolaney SM, et al. Results from a Phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for metastatic disease. Presented at ASCO Annual Meeting 2016, Chicago, IL; Abstract 510.
Abem
aMultiple-cohort study with disease indications in addition to breast cancer
Sahebjam S et al. Poster presented at ASCO Abstract 526
Patnaik A et al. Cancer Discovery 2016;(Ahead of print)
Dickler MN et al. Presented at ASCO 2016
Tolaney SM et al. Poster presented at ASCO Abstract 522
© 2016 Eli Lilly and Company

36. Abemaciclib: Breast Cancer Clinical Program (2 of 2)
Study
Clinicaltrials.gov #
Disease
Treatment Groups
JPBM: MONARCH 3 Phase 3
NCT
HR+, HER2 negative locally advanced or metastatic breast cancer initial therapy in PMP women
abemaciclib + anastrozole or letrozole
placebo + anastrozole or letrozole
JPBY: neoMONARCH Phase 2
NCT
HR+, HER2 negative, early stage breast cancer in PMP women
abemaciclib + anastrozole
anastrozole
abemaciclib
JPBZ: monarcHER Phase 2
NCT
HR+, HER2 positive, locally advanced or metastatic breast cancer in PMP women
abemaciclib + fulvestrant + trastuzumab
abemaciclib + trastuzumab
trastuzumab + single-agent chemotherapy
JPCG: nextMONARCH1 Phase 2
NCT
HR+, HER2 negative, metastatic breast cancer in women
abemaciclib + tamoxifen
abemaciclib + prophylatic loperamide
JPCE: Phase 2
NCT
HR+, HER2 negative breast cancera
abemaciclib + pembrolizumab
Abbreviations:
HER2=human epidermal growth factor receptor 2; HR+=hormone receptor positive; NSCLC=non-small cell lung cancer; PMP=postmenopausal
Key Points:
JPBM1 (MONARCH 3)1
Phase 3, randomized, double-blind, placebo-controlled study of nonsteroidal aromatase inhibitors (anastrozole or letrozole) plus abemaciclib or placebo in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer.
JPBY1 (neoMONARCH)1
Phase 2 neoadjuvant trial comparing the biological effects of 2 weeks of abemaciclib (ly ) in combination with anastrozole to those of abemaciclib monotherapy and anastrozole monotherapy in postmenopausal women with hormone receptor positive, HER2 negative breast cancer.
JPBZ1 (monarcHER)1
Phase 2, randomized, multicenter, 3-arm, open-label study to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant to standard-of-care chemotherapy of physician's choice plus trastuzumab in women with HR+, HER2+ locally advanced or metastatic breast cancer.
JPCG1: nextMONARCH1
Phase 2, randomized, open-label, study of abemaciclib plus tamoxifen or abemaciclib alone, in women with previously treated HR+, HER2-, metastatic breast cancer.
JPCE1
Phase 2 study of abemaciclib in combination with pembrolizumab for patients with Stage IV NSCLC or HR+, HER2- breast cancer.
I3Y-MC-JPBN, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPBY, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPBZ, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPCG, Clinicaltrials.gov identifier: NCT ; I3Y-MC-JPCE, Clinicaltrials.gov identifier: NCT
References:
Last accessed: March 22, 2016.
Last accessed: March 22, 2016.
Last accessed: March 22, 2016.
Last accessed: June 6, 2016.
Last accessed: June 6, 2016.
Abem
aStudy with NSCLC cohorts in addition to breast cancer
© 2016 Eli Lilly and Company

37. Perspectives: Identifying patients with primary resistance to CDK 4-6 inhibitors. The Rb Sig
E2F1 and E2F2 high vs low
breast cancers in the TCGA
Expression data
Differential gene expression analysis (METABRIC)
Functional Rbsig loss of function
Correlation with palbociclib activity (in-vitro)
Prognostic value (in-silico analysis)
Malorni L et al, Oncotarget 2016

38. Functional RBsig discriminates palbociclib sensitive vs resistant BC cell lines
AUC = 0.93
Malorni L et al, Oncotarget 2016

39. RFS: RBsig loss of function is prognostic in pts with ER+ tumors
Untreated
LOW expression-> better RFS
ER+
Luminal A
Luminal B
Endocrine treated only
Malorni L et al, Oncotarget 2016

40. CDK4/6 inhibitors may overcome resistance to HER-2 blocking agents
Not only ER+/Her2neg….
CDK4/6 inhibitors may overcome resistance to HER-2 blocking agents
Rbsig predictive of resistance in neoadjuvant CT/Trast Her2+
Studies ongoing

42. TAMRAD Ph II: TAM +/- everolimus
CB 61% vs 42%
TTP vs 4.5mo

43. >12mo previous adjuvant NSAI allowed

46. buparlisib
2° line (after AIs)
Baselga J et al, proc. SABCS, 2015

47. Primary tumor archival tissue (mutations exons 7,9,20, PTEN loss)
Baselga J et al, proc. SABCS, 2015

48. Fulvestrant alone doesn’t work in ctDNA PIK3CA mut pts
Baselga J et al, Proc. SABCS, 2015

58. Phase 3 SANDPIPER trial (fulvestrant +/- taselisib) ONGOING
alpelisib
Phase 3 SANDPIPER trial (fulvestrant +/- taselisib) ONGOING

59. PI3K Pathway Inhibitors in Clinical Development in Breast Cancer
Drug
Source
Target(s)
GDC-0032
Genentech
PI3Kα
MLN-1117
Millenium
BYL719
Novartis
GS-1101
Gilead
PI3Kd
XL-147/SA245408
Exelixis/Sanofi
Pan-PI3K
BKM120
GDC-0941
PF /PKI-587
Pfizer
XL-765/SAR245409
PI3K/mTOR
BEZ235
GDC-0980
MLN-128/MLN0128
TORC1/2
OSI-027
OSI Pharma
AZD2014
AstraZeneca
AZD5363
AKT (catalytic)
MK2206
Merck
AKT (allosteric)
GDC-0068
ClinicalTrials.gov. From: Accessed August 2013. 59

60. more and more…… “Targetable” genomic alterations
Growth-factors receptor TK inhibitors:
sorafenib/letrozole; vandetanib/fulvestrant; dovitinib/fulvestrant, lucitinib, fulv +/-pictilisib
Src inhibitors: dasatinib/letrozole
PD-1 inhibitors: pembrolizumab + vorinostat
Proteasome inhibitors: bortezomib/fulvestrant
Epigenetic modifiers: azacitidine/fulvestrant; entinostat/exemestane; azacitidine/entinostat; decitabine/panobinostat/TAM
“Targetable” genomic alterations

62. Conclusions Thanks for your attention ! CDK 4/6 inhibitors
- New standard first/second line in HR positive advanced breast cancer
- Efficacy and manageable toxicity
No predictive biomarkers
Many trials ongoing
How endocrine therapy or chemotherapy work after CDK 4/6 inhibitors ?
PI3K/mTOR pathway inhibitors
-Everolimus in combination with AI other than exe, as 1°line, independently on previous PD to adjuvant NSAIs
Buparlisib: efficacy, high toxicity; efficacy in PIK3CA mutated and visceral disease
Studies with more selective agents ongoing
“Targetable” genomic alteration…..
Thanks for your attention !