Nuovi pathways nuovi farmaci quali prospettive Angelo Di
- Slides: 29
Nuovi pathways nuovi farmaci: quali prospettive? Angelo Di Leo “Sandro Pitigliani” Medical Oncology Department Hospital of Prato Istituto Toscano Tumori, Prato, Italy
Conflict of Interest Disclosure Applicability Company Yes Astra. Zeneca, Bayer, Celgene, Lilly, Novartis, Pfizer, Roche (2) Stock ownership/profit None (3) Patent royalties/licensing fees None Yes Astra. Zeneca, Eisai, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche (5) Manuscript fees None (6) Scholarship fund None (7) Other remuneration None (1) Advisory role (4) Lecture fees
Focus on ER+ / HER-2 negative breast cancer • CDK 4 -6 inhibitors • PI 3 K inhibitors
Cooperation between ER and Cyclic D 1 pathways enhances proliferation in luminal breast cancer Cyclin D 1 ER Inhibitory control Cell Cycle: G 1 S proliferation p Rb Inhibitory control CDK 4 -6 Inhibitors: -Palbociclib -Abemaciclib -Ribociclib
Considerations on CDK 4/6 inhibitor activity PD 0332991 has shown activity preferentially on ER+, luminal breast cancer cell lines with or without HER 2 amplification. Non- luminal/post EMT Non- luminal IC 50 n. M Subtype Luminal HER 2 Amplified Immortalized • RB 1, cyclin D 1, and CDKN 2 A (p 16) were differentially expressed - with higher levels of RB 1 and cyclin D 1, and lower levels of p 16, in the sensitive group. • Resistance to PD in many of the nonluminal breast cancer cell lines may be explained by the absence of p. Rb. Recent publications highlighted the lack of p. Rb in basal-like breast cancer tissue and observed that p. Rb depletion can result in the characteristic epithelial-to- mesenchymal transition changes • The lack of activity of a CDK 4/6 inhibitor in cell lines and tumors that lack p. Rb can be explained by the fact that cyclin D 1 does not offer G 1 control in the absence of p. Rb. Finn et al, BCR 2011
We have results from two Phase III trials testing CDK 4 -6 inhibitors in the first-line treatment of HR+/HER-2 advanced breast cancer patients: - PALOMA 2 - MONA LEESA 2
MONA LEESA 2: Study design N= 668 • Postmenopausal 2 Ribociclib + Letrozole • ER+/HER-2 neg ABC • First-line • AI – resistant excluded 1 Placebo + Letrozole Hortobagyi GN et al, New Engl J Med, 2016 (published online on October 8)
PFS (investigator-assessed) – ITT population Hortobagyi GN et al, New Engl J Med, 2016 (published online on October 8)
MONA LEESA 2: Adverse events Hortobagyi GN et al, New Engl J Med, 2016 (published online on October 8)
Do we have strong evidence that the combination CDK 4 -6 inh. + endocrine therapy should be the upfront option? ?
(In my opinion) not yet … • Cross-over would have been important to address this question CDK 4 -6 inh + endocrine therapy • In addition, the clinical activity of endocrine therapy after PD to CDK 4 -6 inhibitors is not clear
First-line therapy for HR+/HER-2 negative advanced breast cancer: Back-home message (my personal view) • Life-threatening disease: chemotherapy • Visceral involvement and/or symptomatic disease: CDK 4 -6 inhibitor + endocrine therapy (HT) • Non visceral involvement and non symptomatic disease (previously treated or untreated with HT): Fulvestrant CDK 4 -6 inhibitor + aromatase inhibitor
Perspectives: Identifying patients with primary resistance to CDK 4 -6 inhibitors. The Rb Sig E 2 F 1 and E 2 F 2 high vs low breast cancers in the TCGA Expression data Differential gene expression analysis Functional RBsig • Correlation with palbociclib activity (in-vitro) • Prognostic value (in-silico analysis) Malorni L et al, Oncotarget, 13: 68012 -22, 2016
Functional RBsig discriminates sensitive vs resistant BC cell lines AUC = 0. 93 Malorni L et al, Oncotarget, 13: 68012 -22, 2016
RBsig is prognostic in patients with ER+ tumors Untreated ER+ Luminal A Luminal B Endocrine treated only Malorni L et al, Oncotarget, 13: 68012 -22, 2016
New agents currently tested in Phase III trials
PI 3 K Pathway Inhibitors in Clinical Development in Breast Cancer Drug Source Target(s) GDC-0032 MLN-1117 BYL 719 GS-1101 XL-147/SA 245408 BKM 120 GDC-0941 PF-05212384/PKI-587 GDC-0941 XL-765/SAR 245409 BEZ 235 GDC-0980 MLN-128/MLN 0128 OSI-027 AZD 2014 AZD 5363 MK 2206 GDC-0068 Genentech Millenium Novartis Gilead Exelixis/Sanofi Novartis Genentech Pfizer Genentech Exelixis/Sanofi Novartis Genentech Millenium OSI Pharma Astra. Zeneca Merck Genentech PI 3 Kα PI 3 Kd Pan-PI 3 K Pan-PI 3 K/m. TOR PI 3 K/m. TORC 1/2 AKT (catalytic) AKT (allosteric) AKT (catalytic) Clinical. Trials. gov. From: www. clinicaltrials. gov. Accessed August 2013.
Baselga J et al, proc. SABCS, 2015
Baselga J et al, proc. SABCS, 2015
Baselga J et al, proc. SABCS, 2015
Pre-clinical rationale for a PI 3 K inhibitor after progression to m. TORC 1 inhibitors • m. TORC 1 inhibition elicits AKT phosphorylation (feedback activation) IGFR 1 PI 3 K Phospho AKT IRS 1 Phospho Short loop Long loop m. TORC 2 m. TORC 1 S 6 inhibition • PI 3 K inhibitors abrogate or attenuate AKT phosphorylation elicited by m. TORC 1 inhibition • Any role for PI 3 K inhibitors after progression to Everolimus? Sun SY et al, Cancer Res 2005; O’Reilly KE et al, Cancer Res 2006; Breuleux M et al, Mol Canc Ther 2009; O’Brien NA et al, Clin Cancer Res 2014; Wander SA et al, J Clin Invest 2011; Mayer IA et al, Annu Rev Med 2016
BELLE-3 trial design and Endpoints Post menopausal women with HR+, HER 2 -, locally advanced or metastatic breast cancer, who received Everolimus + AIs as last line of therapy, N= 432 Primary Endpoint • PFS in the full population Key secondary Endpoint • OS in the full population Other Secondary Endpoints Randomization (2: 1) Stratification by visceral disease status Buparlisib (100 mg/day) + Fulvestrant (500 mg) n=289 • PFS by PIK 3 CA status based on ct. DNA • ORR and CBR in the full population and by PIK 3 CA status based on ct. DNA • Safety, Pharmacokinetics, Quality of Life Placebo + fulvestrant (500 mg) n=143 90% power to detect a 33% reduction in the risk of progression (α one-sided= 0. 025) (313 events required)
Primary tumor vs. Circulating Tumor Cells (CTC) vs. circulating tumor DNA (ct DNA) Analysis of single CTCs, ct DNA and primary tumor tissue from pt 11, pt 12, and pt 18 Pt 11 ct DNA Primary Pt 12 ct DNA Primary De Luca F et al, Oncotarget, 2016; 7: 26107 -119
Acknowledgments
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