Aggiornamenti tra ricerca e clinica: il carcinoma della mammella Filippo Montemurro Unit of (INCO) Fondazione del Piemonte per l Oncologia Candiolo Cancer Institute (IRCCs)
Research Needs in Breast Cancer De-escalate breast cancer therapies in early breast cancer without sacrificing outcomes Explore optimal adjuvant treatment durations Develop better tools to identify patients with genetic predisposition Improve care in young patients with breast cancer Develop tools to speed up drug development in biomarkerdefined populations Identify and validate targets that mediate resistance to chemotherapy, endocrine therapy or anti-her2 therapies Cardoso et al, Ann Oncol, Epub 9 th Nov 2016
Research Needs in Breast Cancer: 2016 Evaluate the efficacy of local-regional treatments for metastatic disease Better define the optimal sequence of treatments in the metastatic setting Evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity) Better understand the biology and identify new targets in triplenegative breast cancer Better understand immune surveillance in breast cancer and further develop immunotherapies Increase survivorship research efforts including supportive care and quality of life Cardoso et al, Ann Oncol, Epub 9 th Nov 2016
My problem. Altough many of these aims are being pursued by innovative clinical trial designing, most of the recent practice changing treatments come from "traditional" randomized phase III trials, where meeting the "primary end-point" provides evidence for registration (almost always)
Not always a problem: CLEOPATRA trial First-line HER2 positive MBC
PALOMA 2: Study Design Slamon R, et al. ASCO 2016. Abstract 507.
CDK 4/6 inhibitors added to endocrine therapy Paloma 2: primary end-point analysis First-line HR+ HER2- MBC Finn et al, NEJM 375;1925, 2016
CDK 4/6 inhibitors added to endocrine therapy Monnaleesa 2: primary end-point analysis First-line HR+ HER2- MBC Hortobagyi et al. NEJM, epub Oct 2016
Cyclin Dependent Kinase (CDK) 4/6 Inhibitors
Palbocliclib: CDK 4/6 Inhibitor Breast Panel Finn RS. Breast Cancer Res 2009
Potential biomarkers of palbociclib activity
Clinical evaluation of biomarkers of Palbociclib Activity Rb Protein CCDN1 P16 ER status (central review) Finn et al, ESMO 2016
Two-component tumor growth model Cytotoxic model: fast response and highly resistance tumor burden model Cytostatic model: slow response and highly resistance tumor burden model Filleron et al, Ann Oncol 27; 1981, 2016
How frequency of restaging influences TTP Cytotoxic Citostatic Filleron et al, Ann Oncol 27; 1981, 2016
Different estimates of TTP according to assessment schedule Filleron et al, Ann Oncol 27; 1981, 2016
Paloma 2: primary end-point analysis Finn et al, NEJM 375;1925, 2016
BOLERO-2 (NCT00863655) Study design and results Assessment Arms Events/N PFS (mo) HR (95% CI) P-value Local EVE+EXE 310/485 7.8 0.45 (0.38- PBO+EXE 3200/239 3.2 0.54) P<0.0001 Baselga J, NEYM 2012 Yardley DA, Adv Ther. 2013
BOLERO-2 (NCT00863655) Efficacy and safety according to visceral vs non-visceral metastases Visceral Non-visceral Campone M. EJC 2013
BOLERO-2 (NCT00863655) 39 months follow-up: OS analysis Piccart M, Ann Oncol 2014
Should we abandon single agent Author (Year) Setting ET alone endocrine therapy? ET+ biologic RR ( CBR) a Months PFS a Months OS a Months Turner (2016) 1st Line metastatic Letroz. Letroz.+Palbo 10.9% (14.6%)* 10.3* N.R. Hortobagyi (2016) 1st Line metastatic Letroz. Letroz.+Palbo 15.6% (9.3%)* >10* N.R. Finn (2015) 1st Line metastatic Letroz. Letroz.+Palbo 9% (21%)* 10* 4.2 Turner (2015) Failing prior ET Fulv. Fulv+Palbo. 4.1% (15%)* 5.4* - Piccart (2015) Failing prior NSAIs Exem. Exem.+ Everolimus 9.1%* (25%)* 4.1* 4.4 Bachelot (2012) Failing prior AIs Tam. Tam.+Everolimus 1% (19%)* 4.1* 0.45 (HR)* Dickler 2015 1st line metastatic Letroz. Letroz.+ Bevacizumab 20%* b (18%)* b 4* 3 Martin 2015 1st line metastatic Letroz. Letroz.+Bevacizumab 18.9%* (9.4%)* 4.9* N.S. a Increase in response rate (RR), clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS) of combined therapy vs endocrine therapy alone. b Calculated in patients with measurable disease. *Increase is statistically significant Abbreviations: ET, endocrine therapy; NSAIs, non-steroidal aromatase inhibitors; AIs, aromatase inhibitors; HR, hazard ratio. Fulv, fulvestrant; Letroz., letrozole; Exem., exemestane; Tam., tamoxifen. Tiurner et al, NEJM 375;1925, 2016 Hortobagyi et al, NEJM 375;1738, 2016 Finn et al, Lancet Oncol 16; 25, 2015 Turner et al, NEJM 373; 209, 2015 Piccart et al, Ann Oncol 25; 2357, 2014 Bachelot et al, JClin Oncol 30;2718, 2012 Dickler et al, ASCO 2015 Martin et al, J Clin Oncol, epub feb 2015