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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 林家齊(Chia-Chi Lin) | |
dc.contributor.advisor | 林家齊(Chia-Chi Lin | cclin1@ntu.edu.tw | ), | |
dc.contributor.author | Ying-Jan Chen | en |
dc.contributor.author | 陳盈然 | zh_TW |
dc.date.accessioned | 2023-03-19T22:25:50Z | - |
dc.date.copyright | 2022-10-05 | |
dc.date.issued | 2022 | |
dc.date.submitted | 2022-08-31 | |
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Eur J Cancer, 126, 33-44. https://doi.org/10.1016/j.ejca.2019.11.016 Ascierto, P. A., McArthur, G. A., Dréno, B., Atkinson, V., Liszkay, G., Di Giacomo, A. M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., de la Cruz-Merino, L., Dutriaux, C., Garbe, C., Yan, Y., Wongchenko, M., Chang, I., Hsu, J. J., Koralek, D. O., Rooney, I., . . . Larkin, J. (2016). Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol, 17(9), 1248-1260. https://doi.org/10.1016/s1470-2045(16)30122-x Atkins, M. B., Lee, S. J., Chmielowski, B., Ribas, A., Tarhini, A. A., Truong, T.-G., Davar, D., O'Rourke, M. A., Curti, B. D., Brell, J. M., Kendra, K. L., Ikeguchi, A., Wolchok, J. D., & Kirkwood, J. M. (2021). DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): A phase III trial—ECOG-ACRIN EA6134. 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Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol, 19(10), 1315-1327. https://doi.org/10.1016/s1470-2045(18)30497-2 Dummer, R., Ascierto, P. A., Gogas, H. J., Arance, A., Mandala, M., Liszkay, G., Garbe, C., Schadendorf, D., Krajsova, I., Gutzmer, R., Chiarion-Sileni, V., Dutriaux, C., de Groot, J. W. B., Yamazaki, N., Loquai, C., Moutouh-de Parseval, L. A., Pickard, M. D., Sandor, V., Robert, C., & Flaherty, K. T. (2018). Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol, 19(5), 603-615. https://doi.org/10.1016/s1470-2045(18)30142-6 Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., & Chapman, P. B. (2010). Inhibition of Mutated, Activated BRAF in Metastatic Melanoma. New England Journal of Medicine, 363(9), 809-819. https://doi.org/10.1056/NEJMoa1002011 Garzón-Orjuela, N., Prieto-Pinto, L., Lasalvia, P., Herrera, D., Castrillón, J., González-Bravo, D., Castañeda-Cardona, C., & Rosselli, D. (2020). Efficacy and safety of dabrafenib-trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF-V600 mutation: A systematic review and network meta-analysis. Dermatol Ther, 33(2), e13145. https://doi.org/10.1111/dth.13145 Hamid, O., Cowey, C. L., Offner, M., Faries, M., & Carvajal, R. D. (2019). Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma. Cancers (Basel), 11(11). https://doi.org/10.3390/cancers11111642 Heinzerling, L., Eigentler, T. K., Fluck, M., Hassel, J. C., Heller-Schenck, D., Leipe, J., Pauschinger, M., Vogel, A., Zimmer, L., & Gutzmer, R. (2019). Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open, 4(3), e000491. https://doi.org/10.1136/esmoopen-2019-000491 Hofschröer, V., Koch, A., Ludwig, F. T., Friedl, P., Oberleithner, H., Stock, C., & Schwab, A. (2017). Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells. Sci Rep, 7, 42369. https://doi.org/10.1038/srep42369 Larkin, J., Ascierto, P. A., Dréno, B., Atkinson, V., Liszkay, G., Maio, M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., de la Cruz-Merino, L., Dutriaux, C., Garbe, C., Sovak, M. A., Chang, I., Choong, N., Hack, S. P., McArthur, G. A., & Ribas, A. (2014). Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med, 371(20), 1867-1876. https://doi.org/10.1056/NEJMoa1408868 Long, G. V., Flaherty, K. T., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., Chiarion-Sileni, V., Lebbe, C., Mandalà, M., Millward, M., Arance, A., Bondarenko, I., Haanen, J., Hansson, J., Utikal, J., . . . Grob, J. J. (2017). Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol, 28(7), 1631-1639. https://doi.org/10.1093/annonc/mdx176 Long, G. V., Grob, J. J., Nathan, P., Ribas, A., Robert, C., Schadendorf, D., Lane, S. R., Mak, C., Legenne, P., Flaherty, K. T., & Davies, M. A. (2016). Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol, 17(12), 1743-1754. https://doi.org/10.1016/s1470-2045(16)30578-2 Long, G. V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., Grob, J. J., Chiarion Sileni, V., Lebbe, C., Mandalà, M., Millward, M., Arance, A., Bondarenko, I., Haanen, J. B., Hansson, J., Utikal, J., . . . Flaherty, K. (2014). Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med, 371(20), 1877-1888. https://doi.org/10.1056/NEJMoa1406037 Oberholzer, P. A., Kee, D., Dziunycz, P., Sucker, A., Kamsukom, N., Jones, R., Roden, C., Chalk, C. J., Ardlie, K., Palescandolo, E., Piris, A., MacConaill, L. E., Robert, C., Hofbauer, G. F. L., McArthur, G. A., Schadendorf, D., & Garraway, L. A. (2012). RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 30(3), 316-321. https://doi.org/10.1200/JCO.2011.36.7680 Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., & Rosen, N. (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 464(7287), 427-430. https://doi.org/10.1038/nature08902 Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., Lichinitser, M., Dummer, R., Grange, F., Mortier, L., Chiarion-Sileni, V., Drucis, K., Krajsova, I., Hauschild, A., Lorigan, P., Wolter, P., Long, G. V., Flaherty, K., Nathan, P., . . . Schadendorf, D. (2015). Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med, 372(1), 30-39. https://doi.org/10.1056/NEJMoa1412690 Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroyakovskiy, D., Dummer, R., Grange, F., Mortier, L., Chiarion-Sileni, V., Drucis, K., Krajsová, I., Hauschild, A., Mookerjee, B., Legos, J. J., Zhang, Y., Lane, S., & Schadendorf, D. (2016). Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K mutant cutaneous melanoma. Annals of Oncology, 27, vi575. https://doi.org/10.1093/annonc/mdw435.37 Sheen, Y. S., Liao, Y. H., Liau, J. Y., Lin, M. H., Hsieh, Y. C., Jee, S. H., & Chu, C. Y. (2016). Prevalence of BRAF and NRAS mutations in cutaneous melanoma patients in Taiwan. J Formos Med Assoc, 115(2), 121-127. https://doi.org/10.1016/j.jfma.2015.02.001 Sosman, J. A., Kim, K. B., Schuchter, L., Gonzalez, R., Pavlick, A. C., Weber, J. S., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., Hersey, P., Kefford, R., Lawrence, D., Puzanov, I., Lewis, K. D., Amaravadi, R. K., Chmielowski, B., Lawrence, H. J., Shyr, Y., . . . Ribas, A. (2012). Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib. New England Journal of Medicine, 366(8), 707-714. https://doi.org/10.1056/NEJMoa1112302 Su, F., Viros, A., Milagre, C., Trunzer, K., Bollag, G., Spleiss, O., Reis-Filho, J. S., Kong, X., Koya, R. C., Flaherty, K. T., Chapman, P. B., Kim, M. J., Hayward, R., Martin, M., Yang, H., Wang, Q., Hilton, H., Hang, J. S., Noe, J., . . . Marais, R. (2012). RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors. New England Journal of Medicine, 366(3), 207-215. https://doi.org/10.1056/NEJMoa1105358 Ward WH, L. F., Goel N, et al. Clinical Presentation and Staging of Melanoma. In: Ward WH, Farma JM, editors. Cutaneous Melanoma: Etiology and Therapy [Internet]. Brisbane (AU): Codon Publications; 2017 Dec 21. Chapter 6. Available from: https://www.ncbi.nlm.nih.gov/books/NBK481857/ doi: 10.15586/codon.cutaneousmelanoma.2017.ch6. Yamazaki, N., Tsutsumida, A., Takahashi, A., Namikawa, K., Yoshikawa, S., Fujiwara, Y., Kondo, S., Mukaiyama, A., Zhang, F., & Kiyohara, Y. (2018). Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma. J Dermatol, 45(4), 397-407. https://doi.org/10.1111/1346-8138.14210 Protocol 200104 (NCT number: NCT02083354) Protocol CDRB436J12301 (NCT number: NCT04940052) Protocol coBRIM (NCT number: NCT01689519) | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84791 | - |
dc.description.abstract | 晚期腫瘤無法切除或轉移的黑色素細胞癌帶有BRAF V600E基因突變的患者,給予BRAF抑制劑合併MEK抑制劑比上單獨使用BRAF抑制劑,能增加腫瘤緩解率(response rate)、疾病無惡化存活期(progression free survival)及整體存活期(overall survival)。目前對於帶有BRAF基因突變的黑色素細胞癌沒有直接比較不同組合的BRAF抑制劑合併MEK抑制劑之間療效與安全性差異的臨床試驗。 藉由網絡統合分析(network meta-analysis)比較三組不同的BRAF抑制劑合併MEK抑制劑 (dabrafenib-trametinib, vemurafenib-cobimetinib, and encorafenib- binimetinib),各組之間療效與安全性的差異。經由系統性回顧,針對四個皆是BRAF抑制劑合併MEK抑制劑比上單獨使用BRAF抑制劑用於帶有BRAF基因突變的晚期黑色素細胞癌之臨床試驗進行統合分析。 統合分析主要針對疾病無惡化存活期(PFS)及整體存活期(OS)的風險比值(hazard ratio)與安全性的危險比值(risk ratio),進行三組藥物的比較。疾病無惡化存活期及整體存活期的風險比值在三組藥物治療間,無統計上的顯著差異。在安全性的部分,dabrafenib-trametinib與單獨使用vemurafenib (RR 1.19, 95% CI 1.03–1.37)治療相比,以及與vemurafenib-cobimetinib (RR 1.47, 95% CI 1.22–1.77) 及encorafenib-binimetinib (RR 1.24, 95% CI 1.01–1.51) 相比,產生嚴重度3-5的不良事件(Grades 3-5 AE)風險最低,並且達到統計上的顯著差異。 因為目前沒有直接比較不同組合的BRAF抑制劑合併MEK抑制劑之間療效與安全性差異的臨床試驗,經由統合分析以間接比較的方式可以了解各組之間療效與安全性的差異,對於臨床上的運用可以作為一個參考依據。 | zh_TW |
dc.description.abstract | For patients with unresectable advanced or metastatic melanoma with BRAF V600E mutation, administration of BRAF inhibitor combined with MEK inhibitor can improve response rate, progression free survival and overall survival when the combination compares to the single agent of BRAF inhibitor. However, BRAF inhibitor and MEK inhibitor combined treatments for BRAF-mutant melanoma are not placed in head-to-head clinical trials to compare efficacy and safety. This network meta-analysis evaluates the efficacy and safety of three combination therapies (dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib). We conducted a systematic review and meta-analysis of four clinical trials of BRAF inhibitor plus MEK inhibitor vs. BRAF inhibitor in the treatment of BRAF-mutant advanced malignant melanoma. Hazard ratio (HR) for overall survival (OS), progression free survival (PFS), and risk ratio (RR) for safety, along with 95% credible intervals (95% CI), are used to compare the treatments in this network meta-analysis. No significant differences were observed in OS and PFS among these three combined regimens. Lower risk of Grades 3-5 AE in the treatment of dabrafenib-trametinib is statistically significant in comparing with vemurafenib (RR 1.19, 95% CI 1.03–1.37), vemurafenib-cobimetinib (RR 1.47, 95% CI 1.22–1.77) and encorafenib-binimetinib (RR 1.24, 95% CI 1.01–1.51). No head-to-head studies have compared the combination of BRAFi and MEKi in BRAF-mutant melanoma. This analysis to characterize differences in efficacy and safety may be valuable for therapeutic decision making. | en |
dc.description.provenance | Made available in DSpace on 2023-03-19T22:25:50Z (GMT). No. of bitstreams: 1 U0001-2308202214174400.pdf: 2298139 bytes, checksum: 4bdddf84fc01a03f3a187f85cbbbb1ef (MD5) Previous issue date: 2022 | en |
dc.description.tableofcontents | 口試委員會審定書..........I ACKNOWLEDGEMENTS........II 摘要....................III ABSTRACT................IV TABLE OF CONTENTS.......V INTRODUCTION............1 MATERIALS AND METHODS...3 RESULT..................4 ELIGIBLE STUDIES........4 OVERALL SURVIVAL........5 PROGRESSION FREE SURVIVAL.......6 ADVERSE EVENT IN ANY GRADE......6 ADVERSE EVENT IN GRADE 3-5......6 OS AND PFS FOR BRAF MUTATION MELANOMA WITH NORMAL AND RAISED LDH.......7 DISCUSSION.......8 CONCLUSION.......9 REFERENCE........11 TABLES AND FIGURES.......15 TABLE 1. BRAF-MUTANT MELANOMA 1ST LINE TREATMENT, RANDOMIZED PHASE 3 TRIALS.......15 TABLE 2. FREQUENCIES OF AE GRADE 3-5 OF COMBINATION THERAPY ARMS.......16 FIGURE 1. FLOW DIAGRAM OF STUDY SELECTION.......17 FIGURE 2. RISK OF BIAS GRAPH.......18 FIGURE 3. RISK OF BIAS SUMMARY.....18 FIGURE 4A. GEOMETRY OF THE NETWORK AND FOREST PLOT OF THE NMA FOR OS COMPARISON BETWEEN DABRAFENIB–TRAMETINIB AND OTHER INTERVENTIONS.......19 FIGURE 4B. FOREST PLOT OF THE NMA FOR PFS COMPARISON BETWEEN DABRAFENIB–TRAMETINIB AND OTHER INTERVENTIONS.......20 FIGURE 5A. THE NETWORK META-ANALYSIS RESULTS OF ADVERSE EVENT IN ANY GRADE.......21 FIGURE 5B. THE NETWORK META-ANALYSIS RESULTS OF ADVERSE EVENT IN GRADE 3-5.......22 FIGURE 6. OS FOR BRAF MUTATION MELANOMA WITH NORMAL AND RAISED LDH.......23 FIGURE 7. PFS FOR BRAF MUTATION MELANOMA WITH NORMAL AND RAISED LDH......23 APPENDIX A. PROTOCOL.......24 LIST OF ABBREVIATION.......25 PROTOCOL SUMMARY...........27 1 INTRODUCTION.............30 1.1 BACKGROUND............30 1.2 RATIONALE.............31 1.3 BENEFITS AND RISKS ASSESSMENT.......32 2 HYPOTHESIS.......33 3 OBJECTIVES AND ENDPOINTS.......33 TABLE 1 STUDY OBJECTIVES AND ENDPOINTS.......33 4 STUDY DESIGN.......34 FIGURE 1 STUDY SCHEMA.......34 5 SUBJECT SELECTION AND DISCONTINUATION/COMPLETION CRITERIA.......34 5.1 SUBJECT SELECTION CRITERIA........34 5.1.1 Number of Subjects.......34 5.1.2 Inclusion Criteria.......35 5.1.3 Exclusion Criteria.......36 5.2 PERMANENT DISCONTINUATION FROM STUDY TREATMENT AND STUDY COMPLETION......37 5.2.1 Permanent Discontinuation from Study Treatment.......37 5.2.2 Study Completion.......38 6 STUDY TREATMENTS.......38 6.1 INVESTIGATIONAL PRODUCT.......39 6.1.1 Dabrafenib and Trametinib...39 6.1.2 Vemurafenib and Cobimetinib.39 6.2 DOSAGE, ADMINISTRATION, AND COMPLIANCE......39 6.2.1 Dabrafenib and Trametinib Combination......40 6.2.2 Vemurafenib and Cobimetinib Combination....40 6.3 HANDLING AND STORAGE OF STUDY TREATMENTS....40 6.4 TREATMENT ASSIGNMENT.......41 6.5 BLINDING.......41 6.6 PRODUCT ACCOUNTABILITY.......41 6.7 TREATMENT COMPLIANCE.........41 6.8 DOSE MODIFICATION GUIDELINES.......41 6.8.1 Dose Levels of dabrafenib and trametinib......42 Table 2 Dose Level Reduction Guidelines of Dabrafenib and Trametinib.......42 6.8.2 Dose Levels of vemurafenib and cobimetinib.......42 Table 3 Dose Level Reduction Guidelines of Vemurafenib and Cobimetinib.......42 6.8.3 General Guidelines for Clinically Significant Toxicities.......42 Table 4 General Dose Adjustment Guidelines for Considering Events Related to Study Treatment.......42 7 CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES.......43 7.1 PERMITTED MEDICATIONS AND NON-DRUG THERAPIES........43 7.2 PROHIBITED MEDICATIONS AND NON-DRUG THERAPIES.......43 8 STUDY ASSESSMENTS AND PROCEDURES.......44 TABLE 5 TIME AND EVENTS TABLE.......45 9 CRITICAL BASELINE ASSESSMENTS....49 9.1 BASELINE CONFIRMATION OF BRAF V600E MUTATION-POSITIVE MELANOMA.......49 10 SAFETY.......49 10.1 SAFETY ENDPOINTS.......49 10.2 ADVERSE EVENTS.......49 10.2.1 Definition of an AE.......49 10.2.2 Definition of an SAE......50 10.3 OTHER SAFETY OUTCOMES.......51 10.3.1 Laboratory Assessments....51 Table 6 Clinical Chemistry and Hematology Parameters.......52 10.3.2 Vital Signs.......52 10.3.3 Physical Examinations......53 10.3.4 Performance status.........53 Table 7 ECOG performance status scale.......53 10.3.5 Electrocardiograms (ECG).......53 10.3.6 Echocardiograms (ECHO).........53 10.3.7 Ophthalmic exam.......54 11 EFFICACY.......54 11.1 EFFICACY ENDPOINTS.......54 11.2 FOLLOW-UP ASSESSMENTS FOR SUBJECTS PERMANENTLY DISCONTINUED FROM ALL STUDY TREATMENTS.......54 12 DATA COLLECTION.......54 13 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.......55 13.1 SAMPLE SIZE ASSUMPTION.......55 13.2 ANALYSIS POPULATIONS.........55 13.3 SAFETY ANALYSES.......56 13.4 EFFICACY ANALYSES.....56 14 REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING THE INFORMED CONSENT PROCESS..57 15 REFERENCES.......58 | |
dc.language.iso | en | |
dc.title | BRAF抑制劑併用MEK抑制劑用於BRAF基因突變陽性黑色素細胞癌的系統性回顧與統合分析及臨床試驗計畫書 | zh_TW |
dc.title | BRAF Inhibitor Combined with MEK Inhibitor in BRAF Mutation-Positive Advanced Melanoma: A Systematic Review and Meta-Analysis, A Clinical Study Protocol | en |
dc.type | Thesis | |
dc.date.schoolyear | 110-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 邵文逸(Wen-Yi Shau),廖怡華(Yi-Hua Liao) | |
dc.subject.keyword | BRAF抑制劑,BRAF基因突變,惡性黑色素細胞癌,MEK抑制劑,統合分析,系統性回顧, | zh_TW |
dc.subject.keyword | BRAF inhibitors,BRAF mutation,malignant melanoma,MEK inhibitors,meta-analysis,systematic review, | en |
dc.relation.page | 60 | |
dc.identifier.doi | 10.6342/NTU202202697 | |
dc.rights.note | 同意授權(限校園內公開) | |
dc.date.accepted | 2022-08-31 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
dc.date.embargo-lift | 2022-10-05 | - |
顯示於系所單位: | 臨床醫學研究所 |
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