Terapia targeted : limiti e successi nelle metastasi cerebrali

55 ° Congresso Nazionale SNO

Como, 22-24 Aprile , 2015

Riccardo Soffietti

U. O. Neuro-OncologiaUniversità e Città della Salute e della Scienza, Torino.

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%) RECIST-confirmed 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 (PKC-

inhibitor).

• 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, 2013Lin 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.