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La malattia oligometastastica a livello encefalico:
il parere dell’oncologo
Lorenza Landi
Istituto Toscano Tumori
Ospedale Civile
Livorno-Italy
Istituto Toscano Tumori –Livorno, Italy
Critical issues in brain mets (BMs)
•
Brain is one of the preferred site of metastatic spread for breast cancer, lung
cancer, melanoma and kidney cancer
•
Increasing incidence of BMs
•
Sanctuary site of metastases
Blood-brain barrier
Necrotic areas within the tumor mass
•
Lack of activity of conventional chemotherapeutics
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Radiation therapy and surgery are the cornerstone of therapy in selected cases
•
Oligometastatic disease is a heterogeneous entity, existing mainly in “real life
world” than in literature
No ad hoc trials
Mainly retrospective series including different types of cancer
Istituto Toscano Tumori – Livorno, Italy
Factors to consider when treatening BMs
1- Patient related
•
Age
• ECOG PS
• Presence of symptoms
• Comorbidity/concomitant medications
2- Tumor related
• Type of tumor
•
3- Treatment related
• End point
(Histology/molecular portrait)
Short- vs long-term perspectives
Presence of extracranial disease
• Treatment AEs
• Size/location of brain lesions
• Benefit achievable
• Phase of disease
• Risk of disability
Istituto Toscano Tumori – Livorno, Italy
Limited impact of chemotherapy in BMs
Lombardi G, et al. Cancer Treat Rev 2014
Istituto Toscano Tumori – Livorno, Italy
BMs as the only site of metastases
Metastatic cancer unsuitable for target-oriented therapy
• Define the aim of treatment
• Consider patient for local ablative therapy
•
Systemic therapy according to
Patient characteristics
Tumor histology
Previuos therapies received
Previous AEs
•
Avoid unnecessary approaches if very-short life expectancy
Istituto Toscano Tumori –Livorno, Italy
The molecular revolution and the paradigm of
personalized therapy
A case of BRAFV660E melanoma successfully treated with BRAF inhibitor
Murrell J, et al. Cancer Treat Rev 2013
Istituto Toscano Tumori – Livorno, Italy
The changing face of advanced NSCLC
2000
An “easy- to -treat ” disease
2016
A “hard- to -treat ” disease
•
•
•
•
Tumor biology irrelevant
Tumor histology irrelevant
Amount of tissue not an issue
Cytology enough for any decision
•
•
•
•
Tumor histology relevant
Tumor biology highly relevant
Tissue is one issue
Cytology not enough for any decision
•
•
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Limited role for pathologist
Limited role for chest physician
No role for molecular biology
•
•
Relevant role for pathologist
Relevant role for chest physician,
medical/radiation oncologist,
surgeon
Critical role for molecular biology
•
Any NSCLC
Platinum-based chemotherapy
Each NSCLC
Personalized therapy
Istituto Toscano Tumori – Livorno, Italy
Oncogenic drivers in NonSquamous NSCLC
- Certain tumours arise as a result of aberrant activation of a single oncogene
and become dependent on this activation
- Identification of druggable oncogenic drivers creates the potential for highly
active therapeutic interventions
Sholl LM et al, JTO 2015
Barlesi F, et al, Lancet 2016
Istituto Toscano Tumori – Livorno, Italy
First-line therapy for metastatic NSCLC in 2016
Stratification for EGFR, ALK and histology
EGFR Mut+
EGFR TKI
Erlotinib (+/Bevacizumab*)
Gefitinib
Afatinib
ALK+
Crizotinib*
EGFR WT/ALKnon-squamous
EGFR WT/ALKsquamous
Platinum doublet
+ bevacizumab
OR
platinum
+ pemetrexed
Platinum-based
doublet
* Not in IT
Istituto Toscano Tumori – Livorno, Italy
The impact of targeted therapy on survival in oncogene
addicted NSCLC
Any druggable event
Barlesi F. et al, Lancet 2016
EGFRmut+
Zhou C, et al. Ann Oncol 2015
Istituto Toscano Tumori – Livorno, Italy
Epidemiology of BMs in EGFRmut+/ALK+ NSCLC
• Brain is a frequent site of metastatic spread in EGFRmut+/ALK+
NSCLC
• Incidence of BMs varies during the course of the disease
20-30% in patients not previously treated
30-40% in patients pretreated with two or more lines of
chemotherapy
45-70% in patients treated with one of more of targeted
agents
≈50% of patients will only develop intracranial progression
Istituto Toscano Tumori – Livorno, Italy
Expected survival in NSCLC patients with BMs
Sperduto PW, et al. JCO 2012
Istituto Toscano Tumori – Livorno, Italy
Prognostic impact of ALK fusions on BMs
Molecularly unselected NSCLC
Median OS 7.0 mos
ALK+ NSCLC
Median OS 49.5 mos
Sperduto PW, et al. JCO 2012; Johung KL, et al. JCO 2015
Istituto Toscano Tumori – Livorno, Italy
Two different clinical scenarios
Brain metastases at baseline
Advanced
ALK+ NSCLC
Brain metastases at progression
after crizotinib
Istituto Toscano Tumori – Livorno, Italy
PROFILE 1014 Study Design
Multicenter, randomized open-label phase III study
Key entry criteria
● ALK-positive by central FISH
testinga
● Locally advanced, recurrent,
or metastatic nonsquamous NSCLC
● No prior systemic treatment
for advanced disease
● ECOG PS 0−2
● Measurable disease
● Treated brain metastases
allowed
1:1
R
A
N
D
O
M
I
Z
E
N=334
Crizotinib
250 mg BID PO,
continuous dosing
(N=167)
Crizotinib continued
after PD
if ongoing clinical
benefit
Pemetrexed
500 mg/m2
+
cisplatin 75 mg/m2
OR
carboplatin AUC 5–6 q3w
for ≤6 cycles
(N=167)
Crossover to
crizotinib permitted
after PDb
Randomization stratified by:
● ECOG PS (0/1, 2),
● Race (Asian, non-Asian),
● Brain metastases (present, absent)
a
ALK status determined using standard ALK break-apart FISH assay
independent radiologic review
bAssessed by
PROFILE 1014: NCT01154140
Istituto Toscano Tumori –Livorno, Italy
PROFILE 1014: Intracranial DCR by IRR in Patients
with Previously Treated Brain Metastases at Baseline
Salomon et al, JCO 2016
Istituto Toscano Tumori – Livorno, Italy
Crizotinib activity in BMs: Retrospective
analysis from Profile 1005 and 1007
Costa D et al. JCO 2015
Istituto Toscano Tumori –Livorno, Italy
Activity of crizotinib in untreated and treated BMs
Costa D, et al. JCO 2015
Istituto Toscano Tumori – Livorno, Italy
Overall and sistemic PFS in patients with or
without baseline (BL) brain mets (BM)
Cranial+extracranial PFS
Extracranial PFS
Costa D et al. JCO 2015
Istituto Toscano Tumori –Livorno, Italy
Systemic and intracranial time to progression in
patients with previously untreated or treated BM
Previously untreated BM
Previously treated BM
Median 12.5 months
Median 7 months
Median 13.2 months
Median 14 months
Costa D et al. JCO 2015
Istituto Toscano Tumori –Livorno, Italy
iPFS and OS according to initial type of radiotherapy
Johung KL, et al. JCO 2015
Istituto Toscano Tumori – Livorno, Italy
Risk of neurocognitive impairment after WBRT
Weickhardt AS, JTO 2013
Cheng EL, Lancet Oncol 2009
Istituto Toscano Tumori – Livorno, Italy
Prevalence of brain interventions
Johung KL, et al. JCO 2015
Istituto Toscano Tumori – Livorno, Italy
Continuing EGFR/ALK Inhibition beyond progression
+ local ablative therapy
Weickhardt AS. et al , JTO 2013
Istituto Toscano Tumori – Livorno, Italy
Future perspectives
Could we avoid local ablative therapies ?
In other words …..
Are novel drugs more effective against BMs ?
Istituto Toscano Tumori –Livorno, Italy
Osimertinib is effective in presence of brain mets
LF, 62 y/o, female
2011 Dx of EGFRmut+ NSCLC with brain mets (single lesion, resected
RT)
2011-2015 treatment with gefitinib and three lines of chemotherapy
December 2015 Intracranial progression Osimertinib (3° generation
EGFRTKI) 80 mg orally once daily
Baseline, December 2015
+ 2 cycles, February 2016
Alectinib in crizotinib resistant ALK+ NSCLCs:
CNS activity and pattern of failure
ORR 57%
Ou SHI, JCO 2015
Istituto Toscano Tumori –Livorno, Italy
Future perspectives
Could we avoid local ablative therapies ?
NO
Reasonably, we should optimize the timing of systemic
and local ablative therapies in order to maximize
patient benefit
Multidisciplinary approach remains the standard of care
Istituto Toscano Tumori –Livorno, Italy