III Sessione: La malattia in fase avanzata Il trattamento medico Emilio Bria Oncologia, Dipartimento di Medicina, Università di Verona, Azienda Ospedaliera Universitaria Integrata Verona emilio.bria@univr.it Padova, 21 Marzo 2016
Disclosures Advisory Boards/Honoraria/Speakers fee/consultant for: Astra-Zeneca, Celgene, Pfizer, Helsinn, MSD, Eli-Lilly, BMS, Novartis, Roche Research Support / Grants from: A.I.R.C. (Associazione Italiana Ricerca sul Cancro) I.A.S.L.C. (International Association for the Study of Lung Cancer) Fondazione Cariverona
Outcome of MBC: Real World Scenario 472 patients from 2004 to 2012 Bonotto M et al, The Oncologist 2014
Overall Strategy: AIOM Recommendation [1] [2] 1] Bone (Y/N) 2] Immunophenotype
Overall Strategy: ESO-ESMO Recommendation Expert opinion Treatment choice should take into account at least these factors: HR and HER-2 status, previous therapies and toxicities, DFI, tumour burden (defined as number and site of metastases), biological age, performance status, co-morbidities (including organ dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychological factors, available therapies in the patient's country and patient preference. A small but very important subset of patients with MBC, for example those with oligometastatic disease, can achieve complete remission and a long survival. A multimodal approach should be considered for these selected patients. A prospective clinical trial addressing this specific situation is needed. Cardoso F et al, The Breast 2014
Overall Strategy: AIOM Recommendation [1] [2] 1] Bone (Y/N) 2] Immunophenotype
Overall Strategy: AIOM Recommendation [3] [4] [5] 3] Disease Charachteristics 4] Menopausal Status 5] Horm. Exposure
Overall Strategy: ESO-ESMO Recommendation ER+/HER-2 negative ABC Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless: Concern or proof of endocrine resistance Disease needing a fast response Optimal post-aromatase inhibitor treatment is uncertain. Available options include, but are not limited to: Tamoxifen Another AI (with a different mechanism of action) Fulvestrant HD Megestrol acetate Everolimus + AI For pre-menopausal women, ovarian suppression/ablation combined with additional endocrine therapy is the first choice. IA IA IA Cardoso F et al, The Breast 2014
Endocrine Maintenance: ESO-ESMO Definition Resistance Setting Relapse (months) Hormonal treatment Primary Adjuvant < 24 During Advanced < 6 During Secondary Adjuvant 24 < 12 after adjuvant Advanced 6 During During After adjuvant Cardoso F et al, The Breast 2014
Treatment Alghorith according to AIOM
Evolution of Treatment for Luminal MBC Palbociclib + Fulvestrant Modified by Frassoldati A, 2015
Molecular Portrait of MBC: Which pathways are guilty? Cirello et al, BCRT 2013 Ignatiadis M et al, NRCO 2013
BOLERO-2: OS Mature Results Open Issues: No OS benefit in absence of cross-over Extremely refractory patients Toxicity Piccart M, AO 2014
PALOMA-3: Final Analysis for PFS Open Issues: Immature for OS Toxicity [ex.: G3-4 Neutropenia 60% vs. <1%] Cristofanilli M et al, Lancet Oncol 2016
Targeted Agents: Adding BEVA to Horm. Therapy LEA [380 pts] CALGB 40503 [352 pts] LET [80%] or FUL [10%] LET [100%] Both: No difference in OS Martin M, JCO 2015 Dickler M, ASCO 2015
Poly-endocrine Therapy: Fulvestrant + Anastrozole FUL + ANA vs. ANA FUL + ANA vs. ANA Pts: 707; PFS Pts: 514; TTP Different Pts Features Metha NEJM 2012 Bergh JCO 2012
Overall Strategy: Which role for Chemotherapy? Courtesy of Frassoldati A, 2015
Chemotherapy for MBC: ESO-ESMO Recommendation Expert opinion Visceral Crisis: Severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases, but implies: Important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since another treatment option at progression will probably not be possible. Cardoso F et al, The Breast 2014
Chemotherapy for MBC: ESO-ESMO Recommendation Sequential monotherapy is the preferred choice for MBC. Combination CT should be reserved for patients with: rapid clinical progression, lifethreatening visceral metastases need for rapid symptom and/or disease control. In patients pre-treated (in the adjuvant or metastatic setting) with an anthracycline and a taxane, and who do not need combination chemotherapy, single agent capecitabine, vinorelbine or eribulin are the preferred choices. Additional choices include gemcitabine, platinum agents, taxanes, and liposomal anthracyclines. The decision should be individualized and take into account different toxicity profiles, previous exposure, patient preferences, and country availability. IA IB Cardoso F et al, The Breast 2014
Overall Strategy: Comorbidities in the Real World Modified - Montemurro F, AIOM 2014
Overall Strategy: How choose (best) treatment?
Chemotherapy for MBC: ASCO Recommendation Recommendations Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor positive metastatic breast cancer unless improvement is medically necessary (eg, immediately life-threatening disease). Single agent is preferable to combination chemotherapy, and longer planned duration improves outcome but must be balanced against toxicity. There is no single optimal first-line or subsequent line chemotherapy, and choice of treatment will be determined by multiple factors including prior therapy, toxicity, performance status, comorbid conditions, and patient preference. The role of bevacizumab remains controversial.. not currently an approved indication for bevacizumab in the United States because the weight of evidence shows no significant survival benefit. Parthridge A et al JCO 2014
Chemotherapy for MBC: The role of Bevacizumab PFS OS Current International Recommendations:..Bevacizumab can only therefore be considered as an option in selected cases.. the role of bevacizumab is controversial, and this therapy should be considered (where available) with single-agent chemotherapy only when there is immediately life-threatening disease or severe symptoms, in view of improved response rates. Miles et al, Ann Oncol 2013 ESMO Cardoso et al, Ann Oncol 2014 ASCO Partridge et al, JCO 2014
Chemotherapy Maintenance: Modern Evidences N=94 N=287/360 planned N=185/360 planned N=91 Gligorov et al, Lancet Oncol 2014
Chemotherapy for MBC: Predictors of activity/efficacy TNBC: Differential Effect of CARBO according to BRCA Tutt SABCS 2014
Hormonal Maintenance: ESO-ESMO Recommendation
Hormonal Maintainace: Modern Evidences Tredan et al, Ann Oncol 2016
Hormonal Maintenance: Modern Evidences Multicenter study: patients non progressive after First Line Chemotherapy 1.0.9.8.7.6.5.4.3.2.1 0.0 0 p=0.01 6 12 OT maint (66 pts) No OT maint (66 pts) 33.9% 20.3% 18 24 1.0.9.8.7.6.5.4.3.2.1 0.0 0 p=0.03 6 12 18 24 OT maint (78 pts) No OT maint (54 pts) 62.3% 43.2% 30 36 PFS OS Curves adjusted for Propensity Score Carbognin L et al, AIOM 2015
Predictors of Efficacy: Are all Luminal BCs equal? Cirello et al, BCRT 2013
Predictors of Efficacy: Are all Luminal BCs equal? Ades et al, JCO 2014
Predictors of Efficacy: Are all Luminal BCs equal? Turner ESMO 2014
Overall Strategy: AIOM Recommendation [1] [2] 1] Bone (Y/N) 2] Immunophenotype
HER2 Positive MBC: Clinical Scenario Expected benefit in OS: > 24 months (additional 3-4 months) Expected benefit in PFS: > 7.5 months (additional 2.5-4 months) Michiels S et al, Ann Oncol 2016
Overview of improvements with Pertuzumab & T-DM1 CLEOPATRA OS PFS Increased ORR More FN EMILIA TH3RESA OS PFS OS PFS Increased ORR and CBR; Less G3 and 4 toxicity Increased ORR Less G3 and 4 toxicity Swain et al, NEJM 2015; Verma et al, NEJM 2012; Krop et al, Lancet Oncol 2014
Current treatment options for HER2-positive MBC Qualifying statement: Although clinicians may discuss using endocrine therapy with or without HER2-targeted therapy, the majority of patients will still receive chemotherapy plus HER2- targeted therapy. ASCO Panelists, 2014
Issues for Pertuzumab: Does previous Trastuzumab affect efficacy? Subgroup N Doce + T Doce + T + P HR Progression-Free Survival Prior adjuvant trastuzumab 88 10.4 16.9 0.62 Prior adjuvant chemo (no trast) 288 12.6 21.6 0.60 No prior chemo 432 - - 0.63 Swain S et al, NEJM 2015 Despite the inferior median PFS, T-based therapy was an effective first-line treatment for patients relapsing after previous T. TFI, type of 1st site of disease relapse, and HR status should be considered in the choice of the best 1st-line treatment option for HER2-positive MBC. Lambertini M et al, Oncologist 2015
Issues for Pertuzumab & TDM1: Does disease pattern affect outcome (PFS)? CLEOPATRA Baseline EMILIAcharacteristic Disease involvement Visceral Nonvisceral Total n 669 322 HR (95% CI) 0.55 (0.45, 0.67) 0.96 (0.71, 1.30) T DM1 better Cap + Lap better TH3RESA Swain et al, NEJM 2015; Verma et al, NEJM 2012; Krop et al, Lancet Oncol 2014
Issues for TDM1: Does long-term exposure to anti HER2 therapy cause loss of HER2 addiction? T-DM1 vs. TPC + Trast. T-DM1 vs. TPC TPS (198 pts) T-DM1 (404 pts) Prior Exposure to anti-her2 therapy Trastuzumab 198 (100%) 404 (100%) Duration (months) 23.7 24.3 Lapatinib 198 (100%) 404 (100%) Duration (months) 7.6 8.0 Krop et al, Lancet Oncol 2014
Could we further optimize First line anti HER2 treatment? Ellis P et al, ASCO 2015
MARIANNE: Primary End-Point (PFS) Ellis P et al, ASCO 2015
MARIANNE: Secondary End-Points Ellis P et al, ASCO 2015
CLEOPATRA & MARIANNE: New Clinical Scenario (OS) CLEOPATRA MARIANNE Expected benefit in OS: > 50 months (additional 10-12 months) Expected benefit in PFS: > 18 months (additional 6-7 months) Swain S et al, NEJM 2015 Ellis P et al, ASCO 2015
Evolution of Treatment of HER2 Positive MBC 2009 Lapatinib + trastuzumab 2001 Pivotal Trial Trastusuzmab Beyond Progression 2012 Emilia 2015 Marianne 1996 First Trial 2006 Lapatinib Capecitabine Anti HER2 therapy + endocrine therapy 2011 Cleopatra 2013 Th3resa Try to identify markers of resistance, sensitivity and to elaborate strategies to improve the efficacy of HER2 targeting in the clinic by newer molecules/approaches
EMILIA: PFS according to PIK3CA Baselga Jet al, CCR 2016
HER2 Positive MBC: The PI3K/Akt/mTOR axis Role of PI3K/Akt/PTEN alterations on Everolimus-related benefit (combined analysis of the Bolero 1 and 3 studies) Slamon D et al, ASCO 2014
Medical Treatment for MBC: Conclusions - 1 Luminal BC: the optimization of HT and targeted agents significantly lower the adoption of chemotherapy, preserving QoL without affecting survival. TNBC: chemotherapy according to genetic features may represent a future perspective. HER2 Positive: dramatic improvement in prognosis with the new drugs.
Medical Treatment for MBC: Conclusions - 2 Common Issue for Clinical Practice: Which one the best sequence? How to deal with costs? EMA dumps the responsibility to AIFA, AIFA dumps the responsibility to Local Governments. Common Principle: To identify markers of resistance, sensitivity to improve the efficacy of (any) treatment