MCO 2011 - Slide 9 - G. Curigliano - Joint medics and nurses spotlight session - New drugs in subsets of breast cancerPresentation Transcript
New drugs in subsets of breast cancer Giuseppe Curigliano MD PhD Division of Medical Oncology European Institute of Oncology
Breast Cancer Molecular Classification Each molecular segment is very rare and presents a specific biological feature Triple negative Her2 Luminal luminal Her2 Triple negative
Gene expression arrays identify five molecular subtypes
Overlap with clinical-pathologic characteristics
Could drive current medical treatments
Molecular classes could be re-divided according to
Disease is being segmented in rare molecular entities according to molecular alterations
Implication: Optimal development of targeted agent requires the enrichment of trials in patients presenting the candidate molecular alteration, ie a molecular selection needs to be done before inclusion in phase I/II trial
Drug Development One drug for the whole Angiogenesis inhibitors Biphosphonates Stroma-targeting drugs New chemotherapies Modulation of drug sensitvity (incl IGF1r Iinh) Cancer vaccines Low benefit for the whole Second-in class In a specific subtype: To do better To reverse resistance Molecular Niche Global trials Expected effect mTOR inhibitors small TKI Pertuzumab/trast CHK1 inh ? Trastuzumab T-DM1 PARP inh ? Cisplatin? Subtype-specific First-in class AI + everolimus? TKI ? or new subdivision according to molecular events TAM Small population High sensitivity
… .. Trastuzumab
Neratinib in MBC – Study 201
Open label, multicenter
Neratinib 240 mg orally QD with food, preferably in the morning
Targeting HER2/neu: Overcome resistance to trastuzumab
Dual HER2 blockade in neoadjuvant trials NEOSPHERE TRASTUZUMAB + PERTUZUMAB N = 417 Europe, Asia, N + S America Median age ~ 50 Operable ~ 60% Inflammatory 6 to 9% N = 450 Europe, Asia, Canada, South America Median age ~ 50 Operable 100% Inflammatory 0% HR+ 47% HR- 53% HR+ 48% HR- 52% NEOALTTO TRASTUZUMAB + LAPATINIB
Trastuzumab + Pertuzumab without chemotherapy Courtesy L. Gianni
Bevacizumab (BV), a monoclonal antibody, inhibits
vascular endothelial growth factor (VEGF), a key
mediator of angiogenesis.
3 randomized trials (E2100, AVADO, RIBBON-1) have
demonstrated significantly improved progression-free survivial (PFS) for BV combined with different
chemotherapies as first-line metastatic breast cacner
PFS improved when BV combined with chemotherapy
regardless of hormone receptor status, sites of
metastases, disease-free interval (DFI), or prior adjuvant
General Study Designs Optional Second-line Chemo + BV ( AVADO and RIBBON-1 only ) Chemo + No BV Chemo + BV Treat until PD RANDOMIZE Previously Untreated MBC RIBBON-1 Capecitabine, Taxane, or Anthracycline AVADO Docetaxel E2100 Paclitaxel
Progression-Free Survival, Pooled Population Non-BV (n=1008) BV (n=1439) Median, mo 6.7 9.2 HR (95% CI) 0.64 (0.57–0.71)
Objective Response Rate* *Includes only patients with measurable disease at baseline. Non-BV (n=788) BV (n=1105) 50 0 45 40 35 30 25 20 15 10 5 32 49
Overall Survival, Pooled Population Non-BV (n=1008) BV (n=1439) Median, mo 26.4 26.7 HR (95% CI) 0.97 (0.86–1.08) 1-yr survival rate (%) 77 82
New therapeutic approaches…
Patients with locally advanced breast cancer
(and/or with distant metastases) with
lymphangitic spread to the chest wall are
Excluded patients with deep venous thrombosis and documented brain metastases.
To assess activity in of bevacizumab in combination with capecitabine and oral vinorelbine (sequential and concurrent administration). Response assessed according to RECIST criteria
To gain insight into the mechanisms of action of bevacizumab assessing CECs and CEPs.
To identify a gene signature predictive of response to bevacizumab
ARM A: Bevacizumab for 2 cycles BEVIX
ARM B: BEVIX
Drug Dose Day 1 3 14 21 Bevacizumab 15 mg x Kg Oral Vinorelbine 55 mg/m2 Capecitabine 2000 mg/m2
From July 2007 to December 2009 enrolled 46 patients.
Results ARM A (Bevacizumab alone) ARM A BEVIX ARM B BEVIX N % N % N % Activity 18 18 28 CR/PR 2 11 7 39 13 46 SD 4 22 5 27 14 50 PD 12 67 6 33 1 4
Results 19.07.2007 18.10.2007
Results Expression pattern of approximately 160 genes correlates with response to bevacizumab
Endocrine Resistance : Who will be the First-in-class?
ER Function Growth Growth Factors HER-3 HER-2 T EGFR T ERK1,2 AKT ER ER ER ER AIB1 N-COR AIB1 N-COR ER
Overcoming Endocrine Resistance
Develop more effective ways to antagonize estrogen.
Understand mechanisms of resistance and develop strategies to overcome them.
Develop better biomarkers to predict estrogen dependence (response to therapy).
Will require serial tumor biopsies.
Understand genetic makeup of the patient and tumor.
Clinical Clues to Mechanisms of Resistance
Loss of ER expression.
Multiple responses to sequential endocrine therapies over time; “drug” resistance but not loss of E dependence.
Tumors with high HER2 or EGFR have lower ER and PR and less responsiveness to endo therapy.
Eventual loss of E dependence even though ER is still present.
Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology, 2011 ER Liver biopsy Primary Negative Positive Total Negative 43 (74.1%) 15 (25.9%) 58 (100%) Positive 22 (11.2%) 175 (88.8%) 197 (100%) Total 67 188 255
Clinical Clues to Mechanisms of Resistance G. Curigliano et al., Annals of Oncology, 2011
L. Ding,et al, Nature 464, 2010 Genome Remodeling in Breast Cancer Primary xenograft Brain metastasis breast primary
New drugs in Luminal B Breast cancers: two scenarios Scenario I: First-in-class drug for the whole luminal B breast cancer: Intracellular kinase inhibitors: mTOR inhibitors (everolimus) Tyrosine kinase inhibitors: EGFR, IGF1R inhibitors Retrospective identification of predictors
New drugs in Luminal B Breast cancers: two scenarios PI3KCA mutations FGFR1 amplification Orphan molecular diseases (ATK amp, JAK2 amp, FGFR2 amp) IGF1R expression Scenario II: biology-driven trials in small segments drugs specific to biologically-defined subsets of ER+ breast cancer: FGFR1 inhibitors in FGFR1 amplified breast cancers PI3K inhibitors in PI3KCA mutated breast cancers
Basal-like Breast Cancer: A Disease of DNA Repair?
PARP Inhibition With Chemotherapy for TN Breast Cancer: Where Are We?
Striking early results; phase III negative
Presumption is that PARP inhibition interferes
with chemo-induced DNA repair
Will PARP inhibition work in non-TN populations,
or is genomic instability of TN disease part of the
Is there single agent activity of PARP inhibition in TN disease?
Back to the future ….
Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive.
Daniel P. S. et al. J Clin Oncol; 28:1145-1153 2010
Neo-adjuvant chemotherapy with platinum-compounds: Phase II trials Garber JE 2006 CDDP N = 28 Gronwald J 2009 CDDP N = 25 Torrisi R 2008 ECF -> P N = 30 Ryan PD 2009 CDDP + BEV N = 51 22 15 40 72 triple negative triple negative triple negative BRCA-1 mutation % pCR
Phase II Study of Weekly Cisplatin and Metronomic Cyclophosphamide and Methotrexate in Second Line Triple-negative Metastatic Breast Cancer G. S. Bhattacharyya, et al. ESMO/ECCO 2009 Metastatic Ca Breast - ER/PR/HER-2neu negative Post anthracycline and taxanes No brain metastases Cisplatin 20mg/m 2 + Cyclophosphamide 50mg per day + Methotrexate 2.5 mg twice a day on day 1 and 2 of every week CM
Weekly Cisplatin and Metronomic Dosing of Cyclophosphamide and Methotrexate G. S. Bhattacharyya, et al. ESMO/ECCO 2009 A (66) B (60) CR 8% (5) 5% (3) PR 55% (36) 28% (17) SD 27% (18) 30% (18) Time to progression 13mo 7mo (9mo to 24mo) (6mo to 14mo) Median overall survival 16mo 12mo Survival at the end of 3 years 10 4
Weekly Cisplatin and Metronomic Dosing of Cyclophosphamide and Methotrexate
The average cost of this regimen is $60.00 per month for costs of drugs
Targeting hallmarks of cancer
Oncogenic events can be shared across molecular
Overcoming therapy resistance may require inhibition of multiple escape pathways for optimal treatment.
Biopsies of endocrine resistant tumors from patients are needed to confirm mechanisms of resistance.