Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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.