1 鄭教授以國際領導者的地位，先後主持多項重要藥物的跨國大型臨床試驗，包括sorafenib，sunitinib，dovitinib，tigatuzumab，cabozantinib，lenvatinib，及atezolizuman。在上述研究中担任全球總主持人。 2 2009年，擔任肝癌標靶藥物sorafenib在亞太地區進行的臨床試驗總主持人，其研究証實sorafenib可以顯著延長晚期肝癌患者的總存活率。該藥隨即獲得FDA及全球認証，成為第一個肝癌治療藥物。 3 2017年，鄭教授主持之誇國大型臨床試驗lenvatinib在第一線治療有優於sorafenib的臨床表現，鄭教授於2017年6月美國臨床腫瘤醫學會(ASCO)，代表全球專家學者，宣佈其結果。隨即在Lancet以資深作者身份發表，成為標靶治療時代最重要的突破。 4 2017年，鄭教授以atezolizumab (anti-PDL1) + bevacizumab (anti-VEGF)之複合處方逕行全球三期大型臨床試驗，即著名的IMbravel150研究，並担任全球總主持人。該研究是十年來肝癌最大的突破。鄭教授代表全球學者於2019年12月在國際學會上宣讀結果，論文隨即被NEJM接受刊載。目前是全世界公認的標準治療。 5 2012：Member of Governing Board, International Liver Cancer Association (ILCA) 6 2017：President, APPLE (Asia Pacific Primary Liver Cancer Expert Meeting) Society 7 2020：Blue Faery Award for Excellence in Liver Cancer Research, U.S.A.

1. 『晚期肝細胞癌(Advanced HCC)』藥物治療的臨床及轉譯研究： (A). 提升肝細胞癌分子標靶治療 (molecularly targeted therapy)療效的臨床及轉譯研究： 自2007年起，肝細胞癌的藥物治療進入了『標靶治療』的年代。我們在2006至2008年間進行了系列研究，指出”anti-angiogenic therapy plus metronomic chemotherapy”的可行性 (Hsu CH et al: Brit J Cancer 2010;102:981-986; Hsu CH et al: J Hepatol 2010;53:126-131; Shao YY et al: Oncol 2012;82:59-66 [本人為通訊作者])及探討”antiangiogenic therapy plus anti-EGFR” 的療效 (Hsu CH et al: Oncology 2013; 85: 44-52)。這些臨床研究，當時在亞洲、甚至全球都是領先的創見，也引發學界許多討論。由於有了多年來系列的臨床試驗，我們得以前瞻性、系統性地針對晚期肝癌病患的預後因子，進行仔細的研究(如Shao YY et al: J Hepatol 2014; 60:313-8 [本人為通訊作者]等)，這些重要的觀察，是目前晚期肝癌藥物臨床試驗設計重要的參考資料。 (B). 肝細胞癌免疫檢查點抑制劑（immune checkpoint inhibitors, ICIs）的臨床相關研究： 自2018年起，ICIs已成為晚期肝癌病患的標準治療。我們透過仔細的臨床觀察，發現肝癌腫瘤所在的器官不同，該腫瘤對ICIs治療療效也有顯著的差異，這暗示腫瘤的免疫微環境是腫瘤對ICIs治療反應與否重要的決定因子(Lu LC et al: Liver Cancer 2019; 8:480-490 [本人為通訊作者])。我們也發現使用過sorafenib後惡化的肝癌組織，PD-L1的表現顯著增加，這暗示合併anti PD-1/PD-L1可能會加強sorafenib或其他抗血管新生藥物治療肝癌的療效 (Lu LC et al: Liver Cancer 2019; 8:110–120 [本人為通訊作者])。 本人參與以atezolizumab+bevacizumab治療晚期肝細胞癌的早期臨床試驗研究案GO30140，並擔任該案在本院的主持人。我們在此一早期臨床試驗證實該處方的有效性和安全性(Lee MS, Ryoo BY, Hsu CH et al: Lancet Oncol 2020; 21:808-820)，本人也曾代表試驗團隊於亞太國際會議中進行口頭報告 (2019 APASL及2019 ESMO-Asia)。正因為此一初期試驗的正面的結果，促成後續IMbrave150第三期研究的執行和成功，為晚期肝癌的藥物治療學帶入了一個嶄新的境界。我們也逐步針對接受此一治療的肝癌病患的腫瘤檢體進行抗藥性機轉的研究(Wang Y et al: Exp Hema Oncol 2021; 10:45[本人為通訊作者])。 (C). 建立肝細胞癌的臨床前期的研究模式以探索嶄新的治療策略： 透過晚期肝癌病患的血清檢體、及實驗室建立sorafenib-resistant肝癌細胞株的研究，我們指出TGF-β1可能是sorafenib效果不佳或抗藥性的機轉 (Lin TH et al: Clin Cancer Res 2015; 21:3678-84 [本人為通訊作者])。我們也與腫瘤所張純榮老師合作，建構免疫健全小鼠肝癌的研究模式，探討腫瘤的免疫微環境，並研發嶄新的免疫治療。我們發現：小鼠肝癌經sorafenib 治療後，myeloid- derived suppressor cells(MDSCs)增加並引起抗藥性；若以anti-Ly6G Ab去除MDSCs，則可以改善腫瘤的免疫微環境，並加強sorafenib的療效 (Chang CJ et al: Int J Cancer 2018;142:1878-1889 [本人為通訊作者])。 2. 『食道癌』治療學的臨床及轉譯研究 個人在過去幾年間更努力地建立食道癌藥物治療臨床試驗及轉譯研究的平台。我們已針對局部擴散型食道鱗狀上皮細胞癌（ESCC）病患接受同步化學及放射治療再加手術治療後的預後因子進行分析(Guo JC et al: J Thorac Oncol 2015; 10:1481-9 [本人為通訊作者])，這些研究成果提供了未來設計食道癌相關臨床試驗時重要的參考資料。 針對局部擴散型食道癌檢體的分析，我們發現腫瘤內免疫細胞表達PD-L1者有較好的預後；反之，腫瘤內癌細胞表達PD-L1者的預後較差(Huang TC et al: J Cancer Res Clin Oncol 2021: in press[本人為通訊作者])。本人也積極參與ICIs免疫治療針對食道癌的跨國大型臨床研究，證實ICIs在ESCC第二線治療優於傳統化學治療（Kojima T,…Hsu CH,…et al: J Clin Oncol.; 38:4138-48及Kato K,…Hsu CH,…et al: Lancet Oncol 2019; 20:1506-17）。針對接受ICIs治療的食道癌病患，我們發現週邊血中neutrophil-to-lymphocyte ratio或病患使用抗生素治療，是接受ICFs免疫治療時不好的預後因子(Guo JC et al: Anticancer Res 2019;39:5675-5682[本人為通訊作者])。目前，我們正進行食道癌免疫治療相關生物標記的轉譯研究，並設計執行數個研究者自行發起研究案，以擴展ICIs在食道癌治療學上更多的應用。

I have established one of the largest oncology phase I centers in Asia for more than 10 years. I played a very important role in developing novel chemotherapies, e.g. TLC388 (topoisomerase I inhibitor), trastuzumab deruxtecan (DS8201, anti-HER2 antibody drug conjugate); and targeted therapies, e.g. volasertib (BI6727, polo-like kinase inhibitor), xentuzumab (BI836845, anti-IGF antibody), BI853520 (FAK inhibitor), vismodegib (LDE225, SMO inhibitor), osimertinib (AZD9291, EGFR inhibitor), TSR011 (ALK inhibitor), plexidartinib (PLX3397, CSF1R inhibitor). In recent years, we were also heavily involved in developing novel immunotherapies, e.g. pembrolizumab (MK3475, anti-PD1 antibody) in head and neck cancer, gastric cancer; spartalizumab (PDR001, anti-PD1 antibody) in malignant melanoma, non-small cell lung cancer, anaplastic thyroid cancer; spartalizumab (PDR001, anti-PD1 antibody) + MBG453 (anti-TIM3 antibody) in malignant melanoma, non-small cell lung cancer; tislelizumab (BGB-A317, anti-PD1 antibody) in non-small cell lung cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma; LY3300054 (anti-PD-L1 antibody) + LY3321367 (anti-TIM3 antibody) in MSI high colorectal cancer; bintrafusp alpha (MSB0011359C, anti-PD-L1 antibody + TGFβ trap); durvalumab (MEDI4736, anti-PD-L1 antibody) + ramucirumab (IMC1121B, anti-VEGFR antibody) in non-small cell lung cancer, gastric cancer, hepatocellular carcinoma.

1 Global leading PI:  A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination with Osimertinib vs Savolitinib in Combination with Placebo in Patients with EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer who have Progressed Following Treatment with Osimertinib(NCT04606771) o Drug: Savolitinib  A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) in Participants With Treatment-naïve, Metastatic Nonsmall Cell Lung Cancer (NSCLC) Whose Tumors Have a Tumor Proportion Score (TPS) Greater Than or Equal to 1% (LEAP-007)(NCT03829332) o Drug: Lenvatinib  A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with EGFR or HER2 mutation (NCT03974022) o Drug: DZD9008  A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer(NCT03255083) o Drug: DS-1205c  A Phase 1, open-label,Multicentre Study to assess the, tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of AZD3759 or AZD9291 in Patients with EGFR Mutation Positive advanced stage NSCLC(NCT02228369) o Drug: AZD3759  A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination With MEDI4736 Versus AZD9291 Monotherapy in Patients With Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy (CAURAL)(NCT02454933) o Drug: AZD9291 and MEDI4736  LUX-Lung 2: a phase II trial evaluating afatinib in NSCLC patients with EGFR mutations, either treatment-naïve or after one line of treatment with chemotherapy.(NCT00525148) o Drug: BIBW 2992 (Afatinib)  LUX-Lung 1: a phase IIb/III trial investigating afatinib plus best supportive care (BSC) versus placebo plus BSC in NSCLC patients who were previously treated with first-line chemotherapy and the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. (note: gefitinib is not available in the US) (NCT00656136) o Drug: BIBW 2992 (Afatinib)  LUX-Lung 3: a phase III trial investigating afatinib as a first-line treatment in patients with advanced NSCLC with EGFR mutations. (NCT00949650) o Drug: BIBW 2992 (Afatinib) 2 Steering committee member:  A Phase 1/2 Study of NM21-1480 (Anti-PDL-1/Anti-4-1BB/Anti-HSA Tri-Specific Antibody) in Adult Patients With Advanced Solid Tumors (NCT04442126) o Biological: NM21-1480  An Open-label Phase 1/1b Study to Evaluate the Safety and Pharmacokinetics of JNJ-73841937 (Lazertinib), a Third Generation EGFR-TKI, as Monotherapy or in Combinations With JNJ-61186372, a Human Bispecific EGFR and cMet Antibody in Participants With Advanced Non-Small Cell Lung Cancer (NCT04077463), o Drug: Lazertinib and Amivantamab  A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination With Osimertinib vs Savolitinib in Combination With Placebo in Patients With EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib (NCT04606771), o Drug: Savolitinib  A Phase 1/2a, Open-Label, Multi-Center Trial to Assess Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of CLN-081 in Patients With Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations (NCT04036682), o Drug: CLN-081  A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 510 Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and AMG 510 Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100) (NCT03600883) o Drug: AMG 510  A Phase II, Two-arm Study to Investigate Tepotinib Combined With Osimertinib in MET Amplified, Advanced or Metastatic NSCLC Harboring Activating EGFR Mutations and Having Acquired Resistance to Prior Osimertinib Therapy (INSIGHT 2) (NCT03940703) o Drug: Tepotinib  A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer(NCT02716116) o Drug: TAK-788  A Randomized, Double-blind, Placebo-controlled, Phase III Study Evaluating the Efficacy and Safety of Canakinumab in Combination With Docetaxel Versus Placebo in Combination With Docetaxel in Adult Subjects With Non-small Cell Lung Cancer (NSCLC) Previously Treated With PD-(L)1 Inhibitors and Platinum-based Chemotherapy (CANOPY 2)(NCT03626545) o Drug: Canakinumab  A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIG®) Versus Alectinib (ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)(NCT03596866) o Drug: Brigatinib  Phase II, Open Label, Single Arm Study of the Efficacy and Safety of Crizotinib in East Asian Patients With Advanced ALK-Negative NSCLC Harboring a Translocation or Inversion Involving the c-ROS Oncogene (ROS1) Locus (NCT01945021) o Drug: Crizotinib  A Phase 2 Precision Oncology Study of Biomarker-Directed, Pembrolizumab-(MK-3475, SCH 900475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (KEYNOTE-495; KeyImPaCT)( (NCT03516981) o Drug: Lenvatinib and Pembrolizumab  A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10296 in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer(NCT02981108) o Drug: HS-10296  LUX-Lung 7 (Clinical Trial Identifier NCT01466660): a phase IIb trial evaluating afatinib head-to-head versus gefitinib as a first-line treatment in patients with advanced NSCLC with EGFR mutations. o Drug: Afatinib  A Study of Nivolumab + Chemotherapy or Nivolumab + Ipilimumab Versus Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) Participants With Epidermal Growth Factor Receptor (EGFR) Mutation Who Failed 1L or 2L EGFR Tyrosine Kinase Inhibitor (TKI) Therapy (CheckMate722) (NCT02864251) o Drug: Nivolumab + Ipilimumab 3 Advisory board:  A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of a Single Oral Dose of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI (NCT02157883) o Drug: AZD9291  An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in First-line Treatment of Patients With Stage IIIB/IV Non-small Cell Lung Cancer Tumors With EGFR Activating Mutations (NCT02588261) o Drug: ASP8273  A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in Adult Patients With EGFRmut Solid Malignancies (NCT02108964) o Drug: EGF816  A Phase III, Open-label, Multicenter Trial of Avelumab (MSB0010718C) Versus Platinum-based Doublet as a First-line Treatment of Recurrent or Stage IV PD-L1+NSCLC (NCT02576574) o Drug: Avelumab  GioTag: Real-world Data Study on Sequential Therapy With Gi(l)Otrif®/ Afatinib as First-line Treatment Followed by Osimertinib in Patients With EGFR Mutation Positive Advanced Non-small Cell Lung Cancer (NCT03370770) o Drug: Afatinib  A phase I/II study of Pembrolizumab (MK-3475) in Combination With Chemotherapy or Immunotherapy in Participants With Lung Cancer (MK-3475-021/KEYNOTE-021)　(NCT02039674) o Drug: Pembrolizumab  A phase I/II, multicenter, open-label study of EGF816(EGFR-TKI) in adult patients with EGFR-mutant solid malignancies(NCT02108964) o Drug: EGF816  Phase 2, open-label, single-arm study of the efficacy and safety of CRIZOTINIB in east asian patients with advanced ALK-negative non-small cell lung cancer (NSCLC) harboring a translocation or inversion involving the c-ros oncogene (ROS1) locus (NCT01945021) o drug: Crizotinib  Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent (NCT01802632) o Drug: AZD9291  A Phase IB/II, Open Label, Multicenter Study of INC280 Administered Orally in Combination With Gefitinib in Adult Patients With EGFR Mutated, c-MET-amplified Non-small Cell Lung Cancer Who Have Progressed After EGFR Inhibitor Treatment (NCT01610336) o Drug: INC280 4 Involved in or cooperated with international organizations, conferences 5 Invited Reviewer of Manuscripts: New England Journal of Medicine, Lancet Oncology, Lancet Respiratory Medicine, Journal of Clinical Oncology, Nature Communication, Journal of Thoracic oncology, Cancer Research, Clinical Cancer Research, Lung Cancer, Urologic Oncology, Cancer Letter 6 Highly cited researcher of 2019 and 2020 in Clinical Medicine category awarded by Clarivate Analytics (Web of Science Group). World’s Top 2% Scientists 2020 and the 4th scientist among the Taiwanese Top 2% Scientists 2020.

1 (1) Establishment of clinical practice guidelines for the prevention of hepatitis B virus (HBV) reactivation in cancer patients who received immuno-suppressive therapy. Dr. Hsu is a world-renown leader in this field who helped establish clinical practice guidelines in the world for the prevention and treatment of this life-threatening complication. Dr. Hsu led a series of prospective, multi-center clinical trials in Taiwan to characterize the risk and severity of HBV reactivation in cancer patients who had chronic or resolved HBV infection and to define the optimal preventive strategy. Results of these trials also constituted the basis of current insurance reimbursement policy of prophylactic HBV antiviral therapy in Taiwan. (2) Development of immune checkpoint inhibitor (ICI) therapy for patients with Asian endemic cancers. Dr. Hsu is the first investigator in the world who reported the promising antitumor activity of the anti-PD-1 ICI pembrolizumab for patients with advanced nasopharyngeal carcinoma. Dr. Hsu also served as the senior author of the global, randomized trial of nivolumab (anti-PD1 ICI) plus ipilimumab (anti-CTLA4 ICI) for advanced hepatocellular carcinoma (HCC), which led to approval of this regimen by U.S. FDA in March 2020 for the treatment of patients with advanced HCC following sorafenib therapy. (3) Key opinion leader in translational research for the optimal biologically effective dosage of cancer immunotherapy. By using multi-kinase inhibitors (MKI) for the treatment of HCC as a model, Dr. Hsu has established pre-clinical platforms to define the optimal biologically effective dosage of MKI as immune modulatory agents. The results provide mechanistic basis for rational design of combination immunotherapy and led to a proof-of-concept clinical trial for advanced HCC (clinicaltrials.gov identifier: NCT04183088) 2 A Phase 1/2, Dose-escalation, Open-label, Non-comparative Study of Nivolumab or Nivolumab in Combination with Ipilimumab in Advanced Hepatocellular Carcinoma Subjects with or without Chronic Viral Hepatitis; and a Randomized, Open-label Study of Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma Subjects who are Naive to Systemic Therapy(US FDA accelerated approval in 2020) 3 Nivolumab plus ipilimumab as neoadjuvant therapy for hepatocellular carcinoma (HCC) 4 Atezolizumab plus bevacizumab for patients with advanced hepatocellular carcinoma (HCC) and chronic hepatitis B virus (HBV) infection 5 A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) with Pembrolizumab (MK-3475) in Combination with Transarterial Chemoembolization (TACE) Versus TACE in Participants with Incurable/Non-metastatic Hepatocellular Carcinoma (LEAP-012) 6 A Phase 2, Randomized, Open-labeled Clinical Study Investigating the Efficacy and Safety of Ociperlimab in Combination With Tislelizumab Plus BAT1706 and of Tislelizumab Plus BAT1706 as First-line Treatment in Patients With Advanced Hepatocellular Carcinoma 7 A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin as First-Line Therapy in Participants with Advanced and/or Unresectable Biliary Tract Carcinoma 8 A Randomized, Open-Label, International, MultiCenter, Phase 3 Clinical Study of PD-1 Antibody SHR-1210 Plus Apatinib (Rivoceranib) Mesylate Versus Sorafenib as First-Line Therapy in Subjects with Advanced Hepatocellular Carcinoma (HCC) Who Have Not Previously Received Systemic Therapy 9 A Phase 3 Double-blinded, Two-arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) versus Placebo as Adjuvant Therapy in Participants with Hepatocellular Carcinoma and Complete Radiological Response after Surgical Resection or Local Ablation (KEYNOTE-937) 10 Combination of GT90001 and Nivolumab in Patients with Metastatic Hepatocellular Carcinoma 11 A randomized, double-blind, phase III study comparing NIS793 in combination with gemcitabine and nab-paclitaxel versus placebo combined with gemcitabine and nabpaclitaxel for first line treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) 12 Open-Label, Multicenter, Phase II/III Study of Combination Therapy of D07001-Softgel Capsules and Xeloda/TS-1 in Subjects with Advanced Biliary Tract Cancer after Gemcitabine and Cisplatin-Based Treatment Failure

1 Global leading PI, steering committee chair: A Phase III randomized, double-blind, placebo-controlled study of LEE011 or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of premenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer (MONALEESA-7) 2 Global leading PI, steering committee chair: A phase II randomized study of the combination of Ribociclib plus goserelin acetate with Hormonal Therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients with hormone receptor-positive/HER2-negative inoperable locally advanced or metastatic breast cancer (RIGHT Choice) 3 Global leading PI (regional multi-country) trial, steering committee chair: A phase Ib study of the combination of Tamoxifen plus Goserelin Acetate with BYL719 or Buparlisib (BKM120) in premenopausal patients with hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (BYOND) 4 Member of Scientific Committee, TRIO (Translational Research in Oncology) 2019-presnet 5 Design and conduct one of the most effective regimen BEEP for breast cancer with brain metastases and breast cancer with leptomeningeal metastases. 1. A phase II study of Bevacizumab with Etoposide and Cisplatin in breast cancer patients with brain and/or leptomeningeal metastasis (BEEP study), 2. Randomized phase II study of induction Bevacizumab, Etoposide and Cisplatin followed by whole brain radiotherapy versus radiotherapy alone in breast cancer with untreated brain metastases (A-Plus study)