Pharmacoeconomic analysis of atezolizumab plus nab-paclitaxel in the treatment of the advanced or metastatic triple-negative breast cancer

Objective. To determine the pharmacoeconomical feasibility of using a combination of atezolizumab + nab-paclitaxel in the 1st line of therapy for locally advanced or metastatic triple negative breast cancer (TNBC) in adult PDL1 positive patients in the Russian healthcare system. Materials and methods. A decision analysis model was used followed by Markov modelling for the economic evaluation of the drugs in the treatment of metastatic TNBC. We used the «cost-effectiveness» analysis and the «impact on the budget» (BIA) analysis. Two therapeutic approaches were evaluated: the use of combined therapy with atezolizumab + nab-paclitaxel and monotherapy with nab-paclitaxel. The analysis included direct costs. Additionally, the obtained pharmacoeconomical indicators of the use of a combination of atezolizumab and nab-paclitaxel and other drugs for the treatment of locally advanced and metastatic breast cancer were compared. Results. The use of the estimated therapeutic approaches in the treatment of metastatic TNBC was characterized by the following costs: with a modelling horizon of 1 year, the cost of using atezolizumab in combination with nab-paclitaxel was 5,076,321 rubles per patient. The costs for the use of single agent nab-paclitaxel with was 60 % less than: — 2 020 038,78 RUB. At the same time, the effectiveness of therapy with a combination of atezolizumab and nab-paclitaxel clinically significantly exceeded that of nab-paclitaxel monotherapy: a 38 % reduction in the risk of death or progression, a 10-fold increase in the frequency of complete response to therapy (10 vs 1 %), and a 7-month increase in the median overall survival (25 vs 18 months). The economic evaluation of the combination of atezolizumab with nab-paclitaxel was carried out with the calculation of the incremental cost-effectiveness ratios (ICER) — the calculation of the additional cost for each additional year of life in comparison with standard therapy. Due to the fact that currently in Russia for patients with metastatic TNBC no similar performance modes of therapy ICER for the combination atezolizumab + nab-paclitaxel compared with the ICER for palbociclib in combination with fulvestrant (drugs, showed improved overall survival in clinical research and included in clinical guidelines for the treatment of diseases of the same class ICD-10 in locally advanced and metastatic breast cancer). The ICER for overall survival at the end of the first year of follow-up for atezolizumab + nab-paclitaxel and palbociclib + fulvestrant was 30.5 million rubles and 47.4 million rubles, respectively. For the combination of atezolizumab + nab-paclitaxel, ICER is lower than the similar ICER for the palbociclib + fulvestrant mode by 36 %. Analysis of trends in the weighted average cost of systemic pathogenetic treatment of breast cancer (breast cancer) shows the following: increased use of the combination of atezolizumab + nab-paclitaxel for the treatment of patients with metastatic TNBC doesn’t lead to a considerable growth in the cost of therapy in patients with breast cancer — providing therapy to 1400 patients that includes the entire target population of patients with TNBC and expression of PD-L1 in Russia changes in the costs of chemotherapy and immunotherapy of breast cancer will remain within 2.6 %. Conclusion. Pharmacoeconomic indicators of the use of atezolizumab in combination with nab-paclitaxel are more cost-effective in comparison with other expensive schemes for the treatment of breast cancer, and tumors of other localities that are actively used in current practice, which suggests the acceptability and feasibility of introducing and expanding the use of this therapeutic option in the target population.

1. Злокачественные новообразования в России в 2018 году / Под ред. Каприн А.Д., Старинский В.В., Петрова Г.В. — М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИРЦ» Минздрава России; 2019. [Zlokachestvennye novoobrazovaniya v Rossii v 2018 godu / Ed by Kaprin AD, Starinskii VV, Petrova GV. Moscow: MNIOI im. P.A. Gercena — filial FGBU «NMIRC» Minzdrava Rossii; 2019. (In Russ).]

2. Летягин В.П. Опухоли молочной железы. — М.: 2000; 113-25. [Letiagin VP. Opuholi molochnoj zhelezy. Moscow: 2000; 113-25. (In Russ).]

3. Dent R, Hanna WM, Trudeau M, et al. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res. Treat. 2009;115(2):423-428. DOI: 10.1007/s10549-008-0086-2

4. Nishimura R, Arima N. Is triple negative a prognostic factor in breast cancer? Breast Cancer. 2008;15(4):303-308. DOI: 10.1007/s12282-008-0042-3.

5. Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin. Cancer Res. 2008;14(5):1368-1376.

6. Hines SL, Vallow LA, Tan WW, et al. Clinical outcomes after a diagnosis of brain metastases in patients with estrogen- and/or human epidermal growth factor receptor 2-positive versus triple-negative breast cancer. Ann. Oncol. 2008;19(9):1561-1565. DOI: 10.1093/annonc/mdn283

7. Yuan ZY, et al. Clinical Characteristics and Prognosis of Triple-negative Breast Cancer: A Report of 305 Cases. Ai Zheng. 2008;27(6):561-565.

8. Phipps AI, Malone KE, Porter PL, et al. Reproductive and hormonal risk factors for postmenopausal luminal, HER-2-overexpressing, and triple-negative breast cancer. Cancer. 2008;113(7):1521-1526. DOI: 10.1002/cncr.23786.

9. Nam BH, Kim SY, Han HS, et al. Breast cancer subtypes and survival in patients with brain metastases. Breast Cancer Res. 2008;10(1):R20. DOI: 10.1186/bcr1870.

10. Брагина О.Д. Клинико-морфологические особенности трипл-негативного рака молочной железы // Сибирский онкологический журнал. 2010; Приложение 1: 26. [Bragina OD. Kliniko-morfologicheskie osobennosti tripl-negativnogo raka molochnoj zhelezy. Sibirskij onkologicheskij zhurnal. 2010; suppl. 1:26. (In Russ).]

11. Карселадзе Д.А. Тройной негативный рак молочной железы (клинико-биологические особенности): Автореф. дис....канд. мед. наук. — М.: 2010. [Karseladze DA. Trojnoj negativnyj rak molochnoj zhelezy (klinikobiologicheskie osobennosti): [dissertation] Moscow: 2010. (In Russ).] Доступно по: http://medical-diss.com/docreader/326710/d#?page=1 Ссылка активна на 25.03.2020.

12. Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin. Cancer. Res. 2005;11(16):5678-85. DOI: 10.1158/1078-0432.CCR-04-2421

13. Reis-Filho JS, Tutt AN. Triple negative tumors: a critical review. Histopathology. 2008;52(1):108-18. DOI: 10.1111/j.1365-2559.2007.02889.x

14. Муфазалов Ф.Ф., Шарипова Н.С. Тройной негативный рак молочной железы: современное состояние проблемы и не совсем обычный случай лечения // Злокачественные опухоли. — 2014. — Т.8. — №1. — C.19-31. [Mufazalov FF, SHaripova NS. Trojnoj negativnyj rak molochnoj zhelezy: sovremennoe sostoyanie problemy i ne sovsem obychnyj sluchaj lecheniya. Journal of Malignant tumours. 2014;8(1):19-31. (In Russ).]

15. Смирнова О.В., Борисов В.И., Генс Г.П. Эволюция представления о тройном негативном раке молочной железы: от биологии опухоли к современному лекарственному лечению // Злокачественные опухоли. — 2017. — №1. — С.5-17. [Smirnova OV, Borisov VI, Guens GP. The evolution of knowledge of triple-negative breast cancer: from biology to novel drug treatment. Malignant Tumours. 2017;(1):5-17. (In Russ).] DOI: 10.18027/2224—5057—2017—1—5—17

16. Смирнова О.В., Борисов В.И., Генс Г.П. Непосредственные и отдаленные результаты лекарственного лечения больных с метастазами тройного негативного рака молочной железы // Злокачественные опухоли. — 2018. — №3. — С.68-77. [Smirmova OV, Borisov VI, Guens GP. Immediate and long-term outcomes of drug treatment in patients with metastatic triple negative breast cancer. Malignant Tumours. 2018;(3):68-77. (In Russ).] DOI: 10.18027/2224—5057—2018—8—3—68—77

17. Кеnnecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010 Jul 10;28(20):3271-7. DOI: 10.1200/JCO.2009.25.9820.

18. Dent R, et al. Triple-negative breast cancer: clinical features and patterns of recurrens. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4429-34. DOI: 10.1158/1078-0432.CCR-06-3045

19. Жукова Л.Г. Клинические и фундаментальные аспекты прогноза и рационального лечения рака молочной железы с тройным негативным фенотипом: Автореф. дис.... докт. мед. наук. — М.: 2015. [ZHukova LG. Klinicheskie i fundamental’nye aspekty prognoza i racional’nogo lecheniya raka molochnoj zhelezy s trojnym negativnym fenotipom. [dissertation] Moscow: 2015. (In Russ).] Доступно по: http://medical-diss.com/docreader/326710/d#?page=1 Ссылка активна на 25.03.2020.

20. Takahashi M, Yonemori K, Yamamoto H, et al. A phase I/II trial of olaparib in combination with eribulin in patients with advanced or metastatic triple negative breast cancer (TNBC) previously treated with anthracyclines and taxanes: The analyses of efficacy and safety from phase II. J Clin Oncol. 2016; 34(15_suppl):1080-1080. DOI: 10.1200/JCO.2016.34.15_suppl.1080

21. Baselga J, Stemmer S, Pego A, et al. Cetuximab + cisplatin in estrogen receptor-negative, progesterone receptor-negative, HER2-negative (triple negative) metastatic breast cancer: results of the randomized phase II BALI-1 trial. Cancer Res. 2010;70:(Abstr PD01—01, presented data — SABCS 2010).

22. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res. 2013;19(19):5505-5512. DOI: 10.1158/1078-0432.CCR-12-3327

23. Tutt A, Ellis P, Kilburn L, et al. Abstract S3-01: The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). San Antonio, TX: 2014 San Antonio Breast Cancer Symposium. Cancer Research 2014;75(9 Supplement):S3-01-S3-01. DOI: 10.1158/1538-7445.SABCS14-S3-01

24. Fan Y, Xu BH, Yuan P, et al. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in first-line treatment of metastatic triple-negative breast cancer. Ann Oncol. 2013 May;24(5):1219-25. DOI: 10.1093/annonc/mds603

25. Hu XC, Zhang J, Xu BH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine at first-line therapy for metastatic triple-negative breast cancer (CBCG006): a randomized, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015;16(4): 436-446. DOI: 10.1016/S1470-2045(15)70064-1

26. Kaufman PF, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015;33(6):594-601. DOI: 10.1200/JCO.2013.52.4892

27. Pivot X, Im SA, Guo M, et al. Subgroup analysis of patients with HER2-negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine. Breast Cancer. 2018;25:370-374. DOI: 10.1007/s12282-017-0826-4

28. Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). [ASCO 2016 abstract 1009]. J Clin Oncol. 2016;34 (suppl.). DOI: 10.1200/JCO.2016.34.15_suppl.1009

29. Emens LA, Adams S, Loi S, et al. Impassion 130: a Phase III randomized trial of atezolizumab with nab-paclitaxel for first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC). [ASCO 2016 abstract TPS1104]. J Clin Oncol. 2016;34 (suppl.).

30. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018;379(22):2108-2121. DOI: 10.1056/NEJMoa1809615

31. Dirix LY, Takacs I, Nikolinakos P, et al A Phase I Trial to Investigate the Tolerability, Safety, Pharmacokinetics, Biological and Clinical Activity of Avelumab (MSB0010718C) in Japanese Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion Part in Asian Subjects With Gastric Cancer (Javelin Solid Tumor JPN). 2015. SABCS. Abstract S1-04.

32. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. 2014, San Antonio, TX: 2014 San Antonio Breast Cancer Symposium.

33. Winer EP, Dang T, Karantza V, et al. KEYNOTE-119: A randomized phase III study of single-agent pembrolizumab (MK-3475) vs single-agent chemotherapy per physician’s choice for metastatic triple-negative breast cancer (mTNBC). [ASCO 2016 abstract TPS1102]. J Clin Oncol. 2016; 34 (suppl).

34. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature. 2012 Oct 4;490(7418):61-70. DOI: 10.1038/nature11412

35. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-370. DOI: 10.1158/2326-6066.CIR-13-0127

36. Ghebeh H, Mohammed S, Al-Omair A, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006;8(3):190-198. DOI: 10.1593/neo.05733

37. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triplenegative breast cancer. 2014, San Antonio, TX: 2014 San Antonio Breast Cancer Sympsoium. Cancer Research. 75:PD1-PD6

38. Ali HR, Glont SE, Blows FM, et al. PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol. 2015;26(7):1488-1493. DOI: 10.1093/annonc/mdv192

39. Muenst S, Schaerli AR, Gao F, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146(1):15-24. DOI: 10.1007/s10549-014-2988-5

40. Сайт Государственного реестра лекарственных средств. [Sajt Gosudarstvennogo reestra lekarstvennyh sredstv. (In Russ).] Доступно по: http://grls.rosminzdrav.ru. Ссылка активна на 25.03.2020.

41. Инструкция по применению лекарственного препарата для медицинского применения Тецентрик®. [Instrukciya po primeneniyu lekarstvennogo preparata dlya medicinskogo primeneniya Tecentriq. (In Russ).] Доступно по: https://www.vidal.ru/drugs/tecentriq Ссылка активна на 25.03.2020.

42. Schmid P, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). 2019 ASCO Annual Meeting. Journal of Clinical Oncology. 2019;37(15 suppl):1003-1003. DOI: 10.1200/JCO.2019.37.15_suppl.1003

43. Постановление Правительства РФ от 10.12.2018 N 1506 «О Программе государственных гарантий бесплатного оказания гражданам медицинской помощи на 2019 год и на плановый период 2020 и 2021 годов». [Resolution of the Government of the Russian Federation of 10.12.2018 N 1506. «O Programme gosudarstvennyh garantij besplatnogo okazaniya grazhdanam medicinskoj pomoshchi na 2019 god i na planovyj period 2020 i 2021 godov». (In Russ).] Доступно по: https://www.garant.ru/products/ipo/prime/doc/72023058/ Ссылка активна на 25.03.2020.

44. Федеральный фонд обязательного медицинского страхования [Federal’nyj fond obyazatel’nogo medicinskogo strahovaniya. (In Russ).] Доступно по: http://www.ff oms.ru/ Ссылка активна на 25.03.2020.

45. Об утверждении отраслевого стандарта «клинико-экономические исследования. Общие положения»: приказ №163 Министерства Здравоохранения Российской Федерации от 27.05.2011. [Ob utverzhdenii otraslevogo standarta «kliniko-ekonomicheskie issledovaniya. Obshchie polozheniya»: order No. 163 of the Ministry of Health of the Russian Federation of 27.05.2011. (In Russ).]

46. Методические рекомендации по проведению сравнительной клинико-экономической оценки лекарственного препарата. ФГБУ «ЦЭККМП» Минздрава России. Утверждены приказом ФГБУ «ЦЭККМП» Минздрава России от «29» декабря 2018 г. No 242-од. Москва 2018. [Metodicheskie rekomendacii po provedeniyu sravnitel’noj klinikoekonomicheskoj ocenki lekarstvennogo preparata. FGBU «CEKKMP» Minzdrava Rossii. Approved by order No. 242-od of the Ministry of health of the Russian Federation dated December 29, 2018. Moscow 2018. (In Russ).] Доступно по: https://rosmedex.ru/wp-content/uploads/2019/06/MRKE%60I_novaya-redaktsiya_2018-g..pdf Ссылка активна на 25.03.2020.

47. Weinstein MC, O’Brien B, Hornberger J, et al. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices—Modeling Studies. Value Health. 2003;6(1):9-17. DOI: 10.1046/j.1524-4733.2003.00234.x

48. Основные понятия в оценке медицинских технологий: метод. пособие / Под общ. ред. Колбина А.С., Зырянова С.К., Белоусова Д.Ю. — Москва: Издательство ОКИ, 2013. [Osnovnye ponyatiya v ocenke medicinskih tekhnologij: metod. posobie. Ed by Kolbina AS, Zyrianova SK, Belousova DYu. Moscow: LLC «Publishing OKI»; 2013. (In Russ).]

49. Методические рекомендации по оценке влияния на бюджет в рамках реализации программы государственных гарантий бесплатного оказания гражданам медицинской помощи. ФГБУ «ЦЭККМП» Минздрава России. Утверждены приказом ФГБУ «ЦЭККМП» Минздрава России от «23» декабря 2016 г. No 145-од. Москва 2016. [Metodicheskie rekomendacii po ocenke vliyaniya na byudzhet v ramkah realizacii programmy gosudarstvennyh garantij besplatnogo okazaniya grazhdanam medicinskoj pomoshchi. FGBU «CEKKMP» Minzdrava Rossii. Approved by order No. 145-od of the Ministry of health of the Russian Federation dated December 23, 2016. Moscow 2016. (In Russ).] Доступно по: https://rosmedex.ru/wpcontent/uploads/2016/12/MR-KE%60I-23.12.2016.pdf Ссылка активна на 25.03.2020

50. Методические рекомендации по расчету затрат при проведении клинико-экономических исследований лекарственных препаратов. ФГБУ «ЦЭККМП» Минздрава России. Утверждены приказом ФГБУ «ЦЭККМП» Минздрава России от «29» декабря 2017 г. № 185-од. [Metodicheskie rekomendacii po raschetu zatrat pri provedenii klinikoekonomicheskih issledovanij lekarstvennyh preparatov. FGBU «CEKKMP» Minzdrava Rossii. Approved by order No. 185-od of the Ministry of health of the Russian Federation dated December 29, 2017. (In Russ).] Доступно по: https://rosmedex.ru/wp-content/uploads/2018/02/Metodicheskie-rekomendatsii-poraschetu-zatrat-pri-provedenii-kliniko-e%60konomicheskih-issledovaniylekarstvennyih-preparatov-2017.pdf Ссылка активна на 25.03.2020.

51. Информационный портал ОМС Санкт-Петербурга. [Informacionnyj portal OMS Saint-Petersburg’s (In Russ).] Доступно по: http://www.spboms.ru/ Ссылка активна на 25.03.2020.

52. http://zakupki.gov.ru/epz/main/public/home.html

53. https://www.pharmindex.ru/

54. По данным аналитической компании IMS, дата выгрузки 28.07.2019 г. [Po dannym analiticheskoj kompanii IMS, data vygruzki 28.07.2019 g. (In Russ).]

55. Клинические рекомендации. Диагностика и лечение рака молочной железы, 2018 г. [Клинические рекомендации. Диагностика и лечение рака молочной железы, 2018 г. (In Russ).] Доступно по: https://oncologyassociation.ru/files/clinical-guidelines_adults%C2%A0-%20projects2018/rak_molochnoy_zhelezy_pr2018.pdf Ссылка активна на 25.03.2020.

56. Инструкция по применению лекарственного препарата для медицинского применения Абраксан® [Instrukciya po primeneniyu lekarstvennogo preparata dlya medicinskogo primeneniya Abraxane (In Russ).] Доступно по: https://www.vidal.ru/drugs/abraxane__38394 Ссылка активна на 25.03.2020.

57. Turner NC, et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018;379(20):1926-1936. DOI: 10.1056/NEJMoa1810527

58. Cristofanilli M, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016; 17(14):425-439. DOI: 10.1016/S1470-2045(15)00613-0

59. Поддубная И.В., Франк Г.А., Ягудина Р.И. и др. Результаты эпидемиологической программы скрининга HER2-статуса у пациенток с раком молочной железы в федеральных округах Российской Федерации за 2015 г. // Современная Онкология. — 2016. — Т.18. — №3. — С.19-26. [Poddubnaya IV, Frank GA, Yagudina RI, Koroleva NI, Zavalishina LE. The results of epidemiological screening program of HER2 status in patients with breast cancer in the federal districts of the Russian Federation in 2015. Sovremennaya onkologiya. 2016;18(3):19-26. (in Russ).]

60. Указ Президента РФ от 07.05.2018 «О национальных целях и стратегических задачах развития Российской Федерации на период до 2024 года». [Decree of the President of the Russian Federation from 07.05.2018 «O nacional’nyh celyah i strategicheskih zadachah razvitiya Rossijskoj Federacii na period do 2024 goda». (in Russ).]

61. Хачатрян Г.Р., Федяев Д.В., Авксентьева М.В., Домбровский В.С. Клинико-экономическое исследование применения брентуксимаба ведотина у взрослых пациентов с рецидивирующей или рефрактерной лимфомой Ходжкина. Фармакоэкономика. Современная Фармакоэкономика и Фармакоэпидемиология. — 2016. — №1. — С.3-14. [Khachatryan GR, Fedyaev DV, Avxentyeva MV, Dombrovskiy VS. Cost-effectiveness analysis of brentuximab vedotin in adults with relapsed or refractory Hodgkin’s lymphoma. Farmakoekonomika. Sovremennaya farmakoekonomika i farmakoepidemiologiya. Pharmacoeconomics. Modern pharmacoeconomics and pharmacoepidemiology. 2016;(1):3-14 (In Russ).] DOI: 10.17749/2070-4909.2016.9.1.003-014

62. Arai S, Fanale M, DeVos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics aft er relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013 Nov;54(11):2531-3. DOI: 10.3109/10428194.2013.798868. Epub 2013 Jun 5.

63. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015 Feb 19;125(8):1236-43. DOI: 10.1182/blood-2014-08-595801. Epub 2014 Dec 22.

64. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010 May 1;28(13):2137-43. DOI: 10.1200/ JCO.2009.26.5561. Epub 2010 Apr 5.

65. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. DOI: 10.1200/JCO.2013.52.4892. Epub 2015 Jan 20.

66. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, noninferiority phase 3 study. Lancet Oncol. 2014 May; 15(6):569-79. DOI: 10.1016/S1470-2045(14)70118-4. Epub 2014 Apr 14.

67. De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376 (9747): 1147-54. DOI: 10.1016/S01406736(10)61389-X.