Transcript brain metastases: epidemiology

Terapia targeted :
limiti e successi nelle metastasi cerebrali
Riccardo Soffietti
U. O. Neuro-Oncologia
Università e Città della Salute e della Scienza, Torino.
55 ° Congresso Nazionale SNO
Como, 22-24 Aprile , 2015
CONFLICT OF INTEREST
• I have received grants and honoraria for Lectures and Advisory Boards
from MSD, Roche, Merck Serono and Mundipharma.
OUTLINE
• General concepts on systemic therapies
• Targeted therapies for non-small cell lung cancer (NSCLC)
• Targeted therapies for breast cancer
• Targeted therapies for melanoma
• Potential role of bevacizumab
• New RANO criteria for clinical trials
• Molecular prevention
Systemic therapy of brain metastases:
factors influencing the efficacy
• Sensitivity of neoplastic cells
Drug properties
(liposolubility, molecular weight)
• Drug exposure
blood-brain barrier
(including P-glycoprotein)
Peerebom, 2005
Gerber et al, 2014
Gerber et al, 2014
Brain metastases from ALK-rearranged NSCLC
• Crizotinib is associated with more than 55% disease control within CNS
at 12 weeks of therapy in both RT-naïve and RT pretreated patients
(Costa et al, 2015).
• Crizotinib is also associated with a moderate (18% to 33%) RECISTconfirmed response rate on CT/MRI (Costa et al, 2015).
• Other multitarget ALK-TKIs, such as ceritinib and alectinib are active in
patients with ALK-rearranged NSCLC who are naïve on resistant to
crizotinib therapy (Shaw et al, 2014; Godgeel et al, 2014).
Targeted therapies, alone or with WBRT, for brain
metastases from NSCLC : ongoing studies
• Multitarget TK inhibitors: ZD6474 (VEGFR and EGFR inhibitor);
sorafenib (VEGFR, Raf Kinase and PDGFR inhibitor); sunitinib
malate (VEGFR, PDGFR and c-Kit inhibitor); enzastaurin (PKCinhibitor).
• Histone deacetylase inhibitor vorinostat
Preusser et al, 2012-2013; Soffietti et al, 2012;
Kaneda et al, 2013; Maillet et al, 2013
Braccini et al, 2013
Targeted therapies for brain metastases from breast
cancer: ongoing studies
• Lapatinib and WBRT or SRS
• Neratinib (pan EGFR inhibitor)
• Pan-erb B receptor inhibitors (CI-1033)
• Vorinostat
Eichler et al, 2011; Larsen et al, 2013
Lin et al, 2014
Ongoing trials on bevacizumab in brain metastases
from solid tumors
• Bevacizumab alone
• Bevacizumab in combination with pemetrexed or erlotinib
(NSCLC).
• Bevacizumab in combination with lapatinib (breast)
Preusser et al, 2012-2013; Soffietti et al, 2012;
Kaneda et al, 2013; Maillet et al, 2013
Lin et al, 2014
Brain metastases from melanoma
• Standard drugs : fotemustine, temozolomide
• Immunomodulatory drugs : ipilimumab
• Targeted drugs : BRAF-inhibitors (vemurafenib; dabrafenib)
for BRAF-mutant patients
Long et al, 2010 ; Dummer et al, 2011; Rochet et al, 2011;
Weber et al, 2011; Margolin et al, 2012; Kolar et al, 2013
Knisely et al, 2012
CRITICAL ISSUES FOR TRIALS ON TARGETED AGENTS
IN ESTABLISHED BRAIN METASTASIS
• Presence of the molecular target in individual tumors.
• Measurement of drug activity in tumor tissue after treatment.
Soffietti et al, Curr Opin Oncol, 2012, 24:679-86
Lin et al,Curr Treat Opt Neurol, 2014, 16:276-293
RECOMMENDATIONS FOR FUTURE TRIALS
• Clinical trials must be focused on specific tumor types or molecular
subtypes and clarify in homogeneous populations the importance
of prognostic and predictive factors.
• Randomized phase II and III trials must be stratified appropriately
for prognostic classes (RPA, GPA) and include end-points such as
quality of life and neurocognitive function in addition to survival.
• The choice of key endpoints could vary according to the
investigational treatment (local vs systemic).
• A serial monitoring of cognitive functions must be performed by
specific batteries of neuropsycological tests, and include a
baseline measure before any treatment is performed
RANO Group, Lancet Oncology, 2013
ANTIEPILEPTIC DRUGS AND CHEMOTHERAPY
• Several
antiepileptic
drugs
(phenobarbital,
phenytoin,
carbamazepine) are metabolized by the cytocrome P450
• These drugs may accelerate the metabolism of chemotherapeutic
agents that are metabolized by cytochrome P450, such as
paclitaxel, CPT-11, vinorelbine, cyclophosfamide, ifosfamide,
doxorubicin, etoposide, teniposide, vinca alkaloids, thus reducing
their efficacy
• Molecular agents such as TK inhibitors (gefitinib, erlotinib, imatinib)
are metabolized through the P450 → interactions
• Non-inducing
antiepileptic
drugs
(levetiracetam,valproate,
gabapentin, topiramate, lamotrigine, lacosamide) must be choosen
for patients with epileptic seizures
Clinical Research Challenge : Molecular prevention
– Rationale:
• microscopic disease setting
– Prerequisites:
• brain as isolated site of relapse
• well defined risk factors
• Blood-brain barrier penetration on targeted agents
– Candidates:
• high risk patients with breast cancer ?
• high risk patients with NSCLC ?
• patients with advanced renal cancer ?
Soffietti et al, Curr Opin Oncol, 2012, 24:679-86
Lin et al,Curr Treat Opt Neurol, 2014, 16:276-293
PREVENTION OF BRAIN METASTASIS FROM BREAST
CANCER
• Experimental models have shown that some compounds, (lapatinib,
vorinostat, pazopanib, etc) are able to prevent the formation of brain
metastases by brain-tropic breast cancer cells (Gil et al, 2008-2011;
Palmieri et al, 2009).
• Clinically, a long-term follow-up of the phase III trial on lapatinib plus
capecitabine versus capecitabine alone in women with advanced
HER-2 positive breast cancer reported a significant reduction in the
incidence of metastases in the brain as first site of relapse after
combined treatment (Cameron et al, 2008).
PREVENTION OF BRAIN METASTASIS FROM NSCLC
BY EGFR-TKI THERAPY
• In a non-randomized retrospective study lower rates of CNS
progression in EGFR-mutant advanced NSCLC patients initially
treated with an EGFR-TKI compared with upfront chemotherapy :
the 6-, 12-, and 24- month cumulative risk of CNS progression of
1%, 6% and 21% in the EGFR-TKI group compared with 7%, 19%
and 32% in the chemotherapy group (P=0.02) (Heon et al, 2012).
• Pulsative dosing of EGFR TKI to improve the CNS penetration of
the drug? (Grommes et al, 2011).
FUTURE DIRECTIONS
• Association to targeted agents with WBRT or stereotactic
radiosurgery for symptomatic brain metastases.
• Targeted agents in lieu of WBRT or stereotactic radiosurgery for
asymptomatic small brain metastases.
• Better knowledge of mechanisms of acquired resistance.