TFDA Tyrosine Kinase Inhibitor

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2 TFDA 1. 癌症診療指引 Tyrosine Kinase Inhibitor Generic Name Imatinib Glivec / Novartis Leevk / Gefitinib Iressa / AstraZeneca Multikinase (BCR-ABL, KIT, PDGFR) EGFR 1.1 st line CML 2.1 st line GIST 1 st line and 2 nd line in Lung Adenocarcinoma with EGFR mutation Erlotinib Tarceva / Roche EGFR 2 nd line, 3 rd line and maintenance in Lung Adenocarcinoma with EGFR mutation Afatinib Gioreif / Boehringer Ingelheim EGFR 1 st line in Lung Adenocarcinoma with EGFR mutation 400 mg QD PO 250 mg QD PO 150 mg QD PO 40 mg QD PO

3 Name Generic 癌症診療指引421 Sorafenib Nexavar / Bayer Multikinase 1.Infeasible to local treatment of HCC with 400 mg BID PO (c-raf, b-raf, KIT, RET, VEGFR-1/2/3, FLT-3, PDGFR- ) Child-Pugh A liver function 2.2 nd line in RCC (failing to biotherapy) Sunitinib Sutent / Pfizer Multikinase (KIT, RET, 1.2 nd line in GIST 2.1 st line in renal clear cell carcinoma 50 mg PO 4 weeks on, 2 weeks off VEGFR-1/2/3, FLT-3, 3.1 st line in pancreatic NET PDGFR- /, CSF- 1) Dasatinib Syrcel / BMS Multikinase (SRC family, c-kit, BCR-ABL, EPHA-2, PDGFR- ) Lapatinib Tykerb / GSK EGFR/HER-2 dual 1.1 st line in Ph+ CML 2.2 nd line in CML failing to imatinib Anthracycline/Taxane/Trastuzumab-failed breast cancer with Her2 overexpression 70 mg BID PO Pazopanib Votrient / Novartis Multikinase 1.1 st line in renal clear cell carcinoma 2.2 nd line in soft tissue sarcoma except liposarcoma, rhambdomyosarcoma, Ewing s sarcoma, chondrosarcoma, GIST, OGS 800 mg QD PO Axitinib Inlyta / Pfizer Multikinase (PDGFR, c-kit, VEGFR-1/2/3) 2 nd line in RCC failing to sunitinib or biotherapy mg QD PO plus capecitabine mg QD PO plus aromatase 5 mg Q12H PO

4 Name Generic 癌症診療指引422 Regorafenib Stivarga / Bayer Multikinase (KIT, RET, b-raf, RAF-1, VEGFR-1/2/3, SAPK-2, PDGFR- /, DDR-2, TRK-2A, ABL, PTK-5, EPH- 2A, TIE-2) 1.3 rd line in colorectal adenocarcinoma 2.3 rd line in GIST failing to sunitinib or imatinib 160 mg PO 3 weeks on and 1 week off Nilotinib Tasigna / Novartis Multikinase (BCR-ABL, PDGFR, c-kit, DDR, CSR-1R) 2 nd line in CML failing or intolerable to imatinib 400 mg Q12H PO Crizotinib Xalkori / Pfizer Multikinase (ALK, ROS-1, cmet) 1 st line in ALK+or ROS-1+ NSCLC 250 mg BID PO Ceritinib Zykadia / Novartis Multikinase (ALK, ROS-1, IGF- 1R) 2 nd line in ALK+ NSCLC 750 mg QD PO in failure or inteorable to crizotinib Alecensa Alectinib / Chugai Multikinase (ALK, RET) 2 nd line in ALK+ NSCLC 600 mg BID PO in failure to crizotinib Ruxolitinib Jakavi / Novartis JAK-1/2 Moderate/High risk myelofibrosis or 20 mg QD PO polycythemia/essential thrombocytosis-related myelofibrosis Tagrisso Osimertinib / AZ EGFR T790M EGFR-mutant NSCLC 80 mg QD PO

5 Name Generic 癌症診療指引423 Levantinib Lenvima / Eisai Multikinase (VEGFR, FGF, SCF) 1 st line in I 131 -failed differentiated thyroid cancer 24 mg (14 mg if hepatic or renal impairment) QD PO Ibrutinib Imbruvica / Jassen BTK inhibtor 1.2 nd line in Mantle Cell Lymphoma 2.17p deletion in CLL 3.2 nd line in CLL 4.2 nd line (or 1 st line when Immunochemotherapy-unsuitable) in Waldenström s Macroglobulinemia mg QD PO mg QD PO mg QD PO mg QD PO Serine-Threonine Kinase or Inositol Kinase Inhibitor Generic Name Everolimus Afinitor / Novartis mtor 1.2 nd line in renal cell carcinoma 2.1 st line in pancreatic NET 3.2 nd line in breast cancer Temsirolimus Torisel / Pfizer mtor 1.High risk renal cell carcinoma 2.3 rd line in mantel cell lymphoma 10mg QD PO (in combination with exemstaine for HR+/HER2- postmenopausal breast cancer failing to letrozole or anastrozole) 1.25 mg QW IV for RCC mg QW * 3 weeks, then 75 mg QW IV Vemurafenib Zoboraf / Roche Multikinase (A/B/C-CRAF, SRMS, ACK-1, MAP4K5, FGFR) 1 st line in B-RAF V600 mutant melanoma 960 mg Q12H PO

6 Name Generic 癌症診療指引424 Palbociclib Ibrance / Pfizer CDK4/6 1.1 st line in breast cancer 2.2 nd line in breast cancer mg QD PO 3 weeks on and 1 week off (in combination with letrozole for HR+/HER2- postmenopausal breast cancer) mg QD PO 3 weeks on and 1 week off (in combination with fulvestrant for HR+/HER2- endocrine therapy-failed breast cancer) Cobimetinib Cotellic / Roche MET Melanoma with BRF V600E or V600K mutation 80 mg PO 3 weeks on and 1 week off (in combination with vemurafenib)

7 antibody Monoclonal 癌症診療指引425 Generic Name Bevacizumab Avastin / Roche Anti-VEGF Ab 1.1 st and 2nd line in colorectal cancer 2.1 st line in breast cancer with Her2-3.3 rd line in GBM s/p R/T & temozolomide 4.1 st line in non-small non squamous cell lung cancer 5.2 nd line in ovarian cancer, fallopian cancer, primary peritoneal cancer 6.1 st line in cervical cancer 1.5 mg/kg IV Q2W 2.10 mg/kg IV Q2W plus paclitaxel 3.10 mg/kg IV Q2W 15 mg/kg IV Q3W 4.15 mg/kg IV Q3W plus paclitaxel & carboplatin * 6 cycles, then maintenance to PD 5.15 mg/kg IV Q3W plus gemcitabine & carboplatin 6.15 mg/kg IV Q3W plus paclitaxel & platinum or paclitaxel & topotecan Cetuximab Erbitux / Merck Anti-EGFR Ab 1.1 st line and 3rd in colorectal cancer with EGFR (+), K-RAS (-) 2.1 st line in locally advanced oropharynx, hypopharynx, larynx cancer; 1st line in recurrent/mets HNSCC Panitumumab Vectibix / GSK Anti-EGFR Ab 3rd line in EGFR+ K-RAS- colorectal cancer 6 mg/kg Q2W IV 500 mg/m 2 IV Q2W or 400 mg/m 2 loading in 1st week, then 250 mg/m 2 IV QW plus 1. For CRC: plus Irinotecan/FU/LV in 1 st line or irinotecan in 3 rd line 2. For HNSCC: plus R/T for locally advanced oropharynx, hypopharynx, larynx cancer; plus platinum for recurrent/mets HNSCC

8 Name Generic 癌症診療指引426 Trastuzumab Herceptin / Roche Anti-HER2 Ab 1 st line in HER2+ breast cancer 1. Loading 8 mg/kg in 1 st week, then 6 mg/kg Q3W IV (especially with pertuzumab) 2. Loading 4 mg/kg in 1 st week, then 2 mg/kg QW IV Pertuzumab Perjeta / Roche Anti-HER2 Ab 1 st line in HER2+ breast cancer Loading 840 mg in 1 st week, then 420 mg Q3W IV plus trastuzumab/ docetaxel 1.Single use: 375 mg/m 2 QW IV for 4 weeks 2.Plus C/T: 375 mg/m 2 Q3W IV for 6-8 cycles mg on day 1 and 900 mg on day 2 Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2 6. (2.1 IV (in combination with Chlorambucil) 2.(in combination with Bendamustine) Anti-VEGF Ab 2 nd line in colorectal cancer 4 mg/kg Q2W IV plus FOLFIRI Rituximab Mabthera / Roche Anti-CD20 Ab 1.1 st line in CD20+ Non-Hodgkin lymphoma 2.1 st line in CD20+ CLL Obinutuzumab Gazyva / Genetech Anti-CD20 Ab 1.1 st line in CLL 2.2 nd line in follicular lymphoma failed to rituximab Aflibercept Zaltrap / Sanofi- Aventis Denosumab Xgeva / GSK Anti-RANKL Ab Malignancy with bony mets 120 mg Q4W SC

9 Name Generic 癌症診療指引427 Ramucirumab Cyramza/ Eli Lilly Anti-VEGFR2 Ab 1.2 nd line in gastric or GE junction adenocarcinoma failed to platinum- or fluoropyrimide-containing regimen 2.2 nd line in NSCLC failed to platinumcontaining 1.8 mg/kg Q2W IV (alone or in combination with Palictaxel) 2.10 mg/kg Q3W IV (in combination with docetaxel) regimen or EGFR/ALK 3.8 mg/kg Q2W IV (in combination 3. 2 nd line in CRC failed to bevacizumab, with FOLFIRI) oxaliplatin and fluoropyrimidine Atezolizumab Tecentriq / Anti-PD-L1 Ab 2 nd line in urothelial carcinoma failed to IV 1200 mg Q3W Genentech platinum-containing regimen Elotuzumab Emplicit / BMS SLAM7-directed immunostimulator Multiple myeloma failed to 1-3 lines 10 mg/kg IV Q2W (in combination wite lenalidomie and dexamethasone) Nivolumab Opdivo / BMS Anti-PD-1 Ab 1.Unresectable or metastatic melanoma 2.2 nd line in Platinum-failed or TKI-failed NSCLC 3.2 nd line in RCC failing to anti-angiogeneic agent 4.Classical Hodgkin s Lymphoma failing to 1.a. 240 mg IV Q2W alone b. 1 mg/ kg IV Q3W (with ipilimumab) * 4 cycles followed by 240 mg IV Q2W mg IV Q2W mg IV Q2W HSCT and post-transplantation brentuximab mg IV Q2W vedotin 5.2 nd line in platinum-failed HNSCC 5.3 mg/kg IV Q2W mg IV Q2W 6.2 nd line in urothelial carcinoma failing within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy

10 Name Generic 癌症診療指引428 Blinatumomab Blincyto / Amgen Bispecific anti-cd19- directed CD3 T-cell engager 2 nd line in Ph (-) pre-b ALL CIVI QD for 4 weeks on and 2 weeks off For 45 kg, 9 ug/day on Days 1-7 and 28 ug/day on Days 8-28 in 1 st cycle; 28 ug/day on Days 1-28 in later cycles For < 45 kg, 5 ug/m 2 /day on Days 1-7 & 15 ug/m 2 /day on Days 8-28 in 1st cycle; 15 ug/m 2 /day on Days 1-28 in later cycles Pembrolizumab Keytruda / MSD Anti-PD-1 Ab 1. Unresectable or metastatic melanoma 2. 1 st line in EGFR(-), ALK (-), NSCLC with 50%+ PD-L nd line in Platinum-failed or TKI-failed NSCLC with 1%+ PD-L nd line in platinum-failed HNSCC 5. 4 lines in classical Hodgkin s Lymphoma failing 1. 2 mg/kg IV Q3W mg IV Q3W mg IV Q3W mg IV Q3W mg IV Q3W Ipilimumab Yervoy / BMS Anti-CTLA-4 Ab 1.1 st line in advanced melanoma 2.Adjuvant in cutaneous melanoma with OP and LND 1.3 mg/kg IV Q3W * 4 doses 2.10 mg/kg IV Q3W * 4 doses, followed by 10 mg/kg Q12W for up to 3 years

11 antibody conjugated with anti-cancer drug Monoclonal 癌症診療指引429 Generic Name Trastuzumab emtansine Brentuximab vedotin Kadcyla / Roche Adcetris / Takeda Hormone therapy Generic Name Tamoxifen Nolvadex/ AstraZeneca Anti-HER2 Ab conjugated with DM1 Anti-CD30 Ab conjugated with MMAE 2 nd line in HER2+ breast cancer 3.6 mg/kg Q3W IV 1. 2 nd line in Hodgkin lymphoma; 2. 3 rd line in systemic anaplastic large cell lymphoma Selective estrogen receptor modulator (SERM) Toremifene Fareston / GTx Selective estrogen receptor modulator (SERM) Exemestane Aromasin / Pfizer Steroidal aromatase Anastrozole Arimidex / AstraZeneca Letrozole Nonsteroidal aromatase Femara / Novartis Nonsteroidal aromatase HR+ breast cancer HR+ breast cancer ER+ post-menopause breast cancer HR+ post-menopause breast cancer HR+ post-menopause breast cancer 1.8 mg/kg Q3W IV for 8-16 cycles (maximum 180 mg per dose) mg bid or mg QD PO 60 mg QD PO 25 mg QD PO 1 mg QD PO 2.5 mg QD PO

12 Name Generic 癌症診療指引430 Flutamide Fuprostat / Non-steroidal antiandrogen Prostate cancer 250 mg Q8H PO with or without LHRH analogs Bicalutamide Casodex / Non-steroidal antiandrogen Prostate cancer 50 mg QD PO with LHRH analogs AstraZeneca Abiraterone Zytiga / Janssen CYP17 Prostate cancer failing to anti-androgen and 1000 mg QD PO (17-hydroxylase / C17,20-lyase) docetaxel Leuprorelin Leuplin / Takeda GnRH analog 1. HR+ premenopausal breast cancer 2. Prostate cancer 3.75 mg Q4W SC Goserelin Zoladex / AstraZeneca Buserelin Supremon / Sanofi-aventis GnRH analog GnRH analog Triptorelin Decapeptyl / Ferring GnRH analog Degarelix Firmagon / Ferring GnRH receptor Octreotide Sandostatin / Novartis Active motif of Somatostatin analog 1. HR+ premenopausal breast cancer 2. Prostate cancer 1. HR+ premenopausal breast cancer 2. Prostate cancer 1. HR+ premenopausal breast cancer 2. Prostate cancer 3.6 mg Q1M or 10.8 mg Q3M SC Induction with 0.5 mg Q8H SC for 7 days, then nasal spary; plus antiandrogen 0.5 mg SC QD for 7 days, then 0.1 mg QD Prostate cancer Loading 240 mg SC (separate 2 injection site), then 80 mg Q4W Functional gastroenteropancreatic mg SC QD-Q8H neuroendocrine tumor

13 Name Generic 癌症診療指引431 Octreotide Sandostatin LAR / Novartis Active motif of Somatostatin analog Lanreotide Somatulin / Ipsen Active motif of Somatostatin analog Calcitonin Miacalcic / Decrease bone Novartis turnover rate 1. Functional gastroenteropancreatic neuroendocrine tumor 2. NET of midgut or well differentiated Carcinoid tumor 1. Malignancy-induced hypercalcemia 2. Paget s disease of bone 20 mg Q4W SC Epigenetic modifier Generic Name Vorinostat Zolina / MSD HDAC-1/2/3/6 Cutaneous T-Cell Lymphoma 400 mg QD PO Azacytidine Vidaza / Celgene Methyltransferase 1. High risk MDS 2. CMMoL Loading 90 mg Q4W SC for 8 weeks, then 120 mg Q4W 5-10 IU/kg separate into 2-4 times per day, via IV, IM or SC 75 mg/m 2 QD * 7 days in 1st cycle, then 100 mg/m 2 QD * 7 days IV * 4-6 cycles

14 Proteasome 癌症診療指引432 Generic Name Bortezomib Velcade / Janssen 26S proteasome 1. 2 nd line in multiple myeloma 2. 2 nd line in mantle cell lymphoma 1. For Multiple myeloma: 1.3 mg/ m 2 Q6W IV on Days 1, 4, 8, 11, 22, 25, 29 of Cycles 1-4 and Days 1, 8, 22, 29 of Cycles 5-9, plus melphalan & prednisolone 2. For mantle cell lymphoma: 1.3 mg/ m 2 Q3W IV on Days 1, 4, 8, 11 of Cycles 1-8 and Q4W on Days 1, 8, 15, 22 after Cycle 8. Immunomodulatory drugs (IMiDs: Analogs of thalidomide) Generic Name Thalidomide Thaldo / TTY 1.Immunomodulation 2.Antiangiogenesis Multiple myeloma 200 mg QD PO plus prednisolone and melphalan Lenalidomide Revlimid / Celgene *: Not approved by TFDA 1.Immunomodulation 2.Antiangiogenesis 1. 2 nd line in multiple myeloma 2. MDS with 5q-* 3. 3 rd line in mantle cell lymphoma* 25 mg D1-21 every 28 days, plus dexamethasone

15 agents Differentiating 癌症診療指引433 Generic Name Tretinoin Vesanoid / Roche PML-RAR 1 st line in Acute promyelocytic leukemia with 45 mg/m 2 PO split to twice a day for degradation t(15:17) days until complete remission Arsenic trioxide Asadin / TTY PML-RAR 2 nd line in Acute promyelocytic leukemia with 1.Induction: 0.15 mg/kg/day IV QD degradation t(15:17) for upto 60 days 2.Consolidation: 0.15 mg/kg/day

16 TFDA 4. 癌症診療指引 Serine-Threonine Kinase or Inositol Kinase Inhibitor Generic Name Ribociclib Kisqali / Novartis CDK4/6 1 st line in breast cancer 600 mg QD PO 3 weeks on and 1 week off (in combination with aromatase for HR+/HER2- post-menopausal breast cancer) Idelalisib Zydelig / Gilead PI3K 1.1 st line for CLL 2. 3 rd line for FL 3. 3 rd line for SLL mg BID PO (in combination with rituximab) mg BID PO mg BID PO

17 antibody Monoclonal 癌症診療指引435 Generic Name Ofatumumab Arzerra / GSK Anti-CD20 Ab 2 nd line in CD20+ CLL IV 300 mg in 1st week, weekly 2000 mg in 2 nd -8 th week, then 4-5 week later 2000 mg Q4W for 4 doses Alemtuzumab Campath / Anti-CD52 Ab 1 st linein CLL 30 mg/day IV TIW for 12 weeks Genzyme Necitumumab Portrazza / Lilly Anti-EGFR Ab 1 st line in squamous NSCLC 800 mg IV Q3W on Days 1 and Day 8 (in combination with gemcitabine and cisplatin) Dinutuximab Unituxin / United Therap Anti-GD2 Ab 2 nd line in pediatric high-risk neuroblastoma who achieve at least a PR to prior 1 st multiagent, multimodality therapy IV 17.5 mg/m 2 QD 4 days for 5 cycles (in combination with GM- CSF, IL-2 and 13-cis-RA Epigenetic modifier Generic Name Panobinostat Farydak / Novartis Pan-HDAC 3 rd line in Multiple Myeloma 20 mg TIW PO on Weeks 1 & 2 of each 3-week * 8 cycles or 16 cycles (if beneficial after 8 cycles) Belinostat Beleodaq / Spectrum Pan-HADC 2 nd line in Peripheral T-cell lymphoma 1000 mg/m 2 QD on D1-5 Q3W IV

18 Proteasome 癌症診療指引436 Generic Name Ixazomib Ninlaro / Millennium Anti-apoptotic Generic Name Venclexta Venetoclax / Abbvie Translocation Generic Name Sonidegib Odomzo / Novartis 26S proteasome 2 nd line in multiple myeloma 4 mg on Q4W on Days 1, 8,15 (in combination with Lenalidomide and Dexamethasone) BCL-2 2 nd line in Chronic lymphocytic leukemia with 17p deletion Smoothened Basal cell carcinoma 200 mg PO QD 20 mg PO once daily for 7 days, then a weekly ramp-up dosing upto 400 mg

19 repair inhibtor DNA 癌症診療指引437 Generic Name Olaparib Lynparza / Roche PARP inhibition 4 lines in BRCA-mutant ovarian cancer 400 mg bid po Rucaparib Rubraca / Clovis PARP inhibition 3 lines in BRCA-mutant ovarian cancer 600 mg bid po