1. Terapia targeted : limiti e successi nelle metastasi cerebrali 55 ° Congresso Nazionale SNO Como, 22-24 Aprile, 2015 Riccardo Soffietti U. O. Neuro-Oncologia Università e Città della Salute e della Scienza, Torino.

2. CONFLICT OF INTEREST I have received grants and honoraria for Lectures and Advisory Boards from MSD, Roche, Merck Serono and Mundipharma.

3. 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

4. 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 )

5. Peerebom, 2005

13. Gerber et al, 2014

16. 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 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 ).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 ).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 ).

17. 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

22. Braccini et al, 2013

23. Targeted therapies for brain metastases from breast cancer: ongoing studies Lapatinib and WBRT or SRSLapatinib and WBRT or SRS Neratinib (pan EGFR inhibitor)Neratinib (pan EGFR inhibitor) Pan-erb B receptor inhibitors (CI-1033)Pan-erb B receptor inhibitors (CI-1033) VorinostatVorinostat Eichler et al, 2011; Larsen et al, 2013 Lin et al, 2014

25. 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

26. 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

28. Knisely et al, 2012

29. CRITICAL ISSUES FOR TRIALS ON TARGETED AGENTS IN ESTABLISHED BRAIN METASTASIS Presence of the molecular target in individual tumors.Presence of the molecular target in individual tumors. Measurement of drug activity in tumor tissue after treatment.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

32. 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.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.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).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 performedA 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

33. 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

34. Clinical Research Challenge : Molecular prevention –Rationale: microscopic disease settingmicroscopic disease setting –Prerequisites: brain as isolated site of relapsebrain as isolated site of relapse well defined risk factorswell defined risk factors Blood-brain barrier penetration on targeted agentsBlood-brain barrier penetration on targeted agents –Candidates: high risk patients with breast cancer ?high risk patients with breast cancer ? high risk patients with NSCLC ?high risk patients with NSCLC ? patients with advanced renal cancer ?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

35. PREVENTION OF BRAIN METASTASIS FROM BREAST CANCER Gil et al, 2008-2011; Palmieri et al, 2009Experimental 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 ). Cameron et al, 2008Clinically, 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 ).

36. 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 ).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 ).Pulsative dosing of EGFR TKI to improve the CNS penetration of the drug? ( Grommes et al, 2011 ).

37. FUTURE DIRECTIONS Association to targeted agents with WBRT or stereotactic radiosurgery for symptomatic brain metastases.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.Targeted agents in lieu of WBRT or stereotactic radiosurgery for asymptomatic small brain metastases. Better knowledge of mechanisms of acquired resistance.Better knowledge of mechanisms of acquired resistance.