Phase II study of irinotecan and temozolomide in breast cancer patients with progressing central nervous system disease
Breast cancer patients with progressing central nervous system (CNS) disease have limited treatment options. Few chemotherapy drugs with activity in breast cancer have well-documented CNS penetration. This phase 2 trial evaluated efficacy and safety of irinotecan 125 mg/m2 on days 1 and 15 with temozolomide 100 mg/m2 days 1–7 and days 15–21 of a 28 day cycle.
Breast cancer patients of any biological subtype and progressing brain metastases and/or leptomeningeal disease (LMD) were eligible. The primary endpoint was CNS response rate. Secondary endpoints were clinical benefit rate (CBR), time to progression (TTP), and overall survival (OS). Imaging studies evaluating intracranial and extracranial response were performed every 8 weeks.
Thirty patients were evaluable for safety and efficacy. The most common hematologic and non-hematologic adverse events were neutropenia, and nausea and fatigue, respectively. There were two confirmed CNS partial responses (PR) and five patients with stable disease in the CNS ≥ 16 weeks, resulting in a 7% PR and 23% CBR. Median TTP was 2.3 months (range 13–444 days), and median OS from treatment initiation until death was 4.9 months (range 20–1023 days). Excluding patients with LMD, median TTP and OS were 3.1 and 5.6 months, respectively. Only one patient progressed systemically before CNS progression.
The combination of irinotecan and temozolomide was well tolerated, demonstrated some clinical activity across multiple breast cancer subtypes with progressing CNS disease, and offers a reasonable option for patients who are not candidates for further radiation or clinical trials.
KeywordsBreast cancer Brain metastases Chemotherapy Clinical trial Irinotecan Temozolomide
This research was funded by Pfizer (Grant Number 2005-0811) and Merck & Co. (Grant Number A105089).
Compliance with ethical standards
Conflict of interest
Michelle Melisko has received funding for clinical trials (paid to the UC Regents) from: Genentech, Merck, Astra Zeneca, Novartis, Lilly, Puma, Celldex, Galena, Nektar, and Daewha Pharmaceuticals, and honorarium from Agendia. Hope Rugo has received funding (paid to the UC Regents) from Genentech, Pfizer, Merck, Astra Zeneca, Novartis, Lilly, Nektar, Macrogenics, Immunomedics, Odonate, OBI, Seattle Genetics, Eisai, and Daiichi, and travel funding from Daiichi, Mylan, Pfizer, Amgen, Merck and Puma. John Park has stock ownership in Merrimack Pharmaceuticals and is a member of the speaker’s bureau for Genentech and Pfizer. The remaining authors have no conflicts to disclose.
This manuscript complies with all current laws of the country in which it was performed. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained by all individual participants included in the study and all procedures were performed after obtaining informed consent.
- 3.Doolittle ND, Peereboom DM, Christoforidis GA, Hall WA, Palmieri D, Brock PR, Campbell KC, Dickey DT, Muldoon LL, O’Neill BP et al (2007) Delivery of chemotherapy and antibodies across the blood-brain barrier and the role of chemoprotection, in primary and metastatic brain tumors: report of the Eleventh Annual Blood-Brain Barrier Consortium meeting. J Neurooncol 81(1):81–91CrossRefGoogle Scholar
- 4.Bachelot T, Romieu G, Campone M, Dieras V, Cropet C, Dalenc F, Jimenez M, Le Rhun E, Pierga JY, Goncalves A et al (2013) Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 14(1):64–71CrossRefGoogle Scholar
- 5.Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, Harris GJ, Bullitt E, Van den Abbeele AD, Henson JW et al (2008) Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26(12):1993–1999CrossRefGoogle Scholar
- 6.Anders C, Deal AM, Abramson V, Liu MC, Storniolo AM, Carpenter JT, Puhalla S, Nanda R, Melhem-Bertrandt A, Lin NU, Kelly Marcom P, Van Poznak C, Stearns V, Melisko M, Smith JK, Karginova O, Parker J, Berg J, Winer EP, Peterman A, Prat A, Perou CM, Wolff AC, Carey LA (2014) TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases. Breast Cancer Res Treat 146(3):557–566CrossRefGoogle Scholar
- 7.Freedman RA, Gelman RS, Anders CK, Melisko ME, Parsons HA, Cropp AM, Silvestri K, Cotter CM, Componeschi KP, Marte JM et al (2019) TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol 37(13):1081–1089CrossRefGoogle Scholar
- 8.Freedman RA, Gelman RS, Wefel JS, Melisko ME, Hess KR, Connolly RM, Van Poznak CH, Niravath PA, Puhalla SL, Ibrahim N et al (2016) Translational Breast Cancer Research Consortium (TBCRC) 022: a phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol 34(9):945–952CrossRefGoogle Scholar
- 10.Hurvitz S, Singh R, Adams B, Taguchi JA, Chan D, Dichmann RA, Castrellon A, Hu E, Berkowitz J, Mani A et al (2018) Phase Ib/II single-arm trial evaluating the combination of everolimus, lapatinib and capecitabine for the treatment of HER2-positive breast cancer with brain metastases (TRIO-US B-09). Ther Adv Med Oncol 10:1758835918807339CrossRefGoogle Scholar
- 11.Van Swearingen AED, Siegel MB, Deal AM, Sambade MJ, Hoyle A, Hayes DN, Jo H, Little P, Dees EC, Muss H et al (2018) LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases. Breast Cancer Res Treat 171(3):637–648CrossRefGoogle Scholar
- 13.Perez EA, Hillman DW, Mailliard JA, Ingle JN, Ryan JM, Fitch TR, Rowland KM, Kardinal CG, Krook JE, Kugler JW et al (2004) Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22(14):2849–2855CrossRefGoogle Scholar
- 14.Cortes J, Rugo HS, Awada A, Twelves C, Perez EA, Im SA, Gomez-Pardo P, Schwartzberg LS, Dieras V, Yardley DA et al (2017) Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat 165(2):329–341CrossRefGoogle Scholar
- 15.Cancer therapy evaluation program, common terminology criteria for adverse events, version 3.0. http://ctep.cancer.gov. Accessed 1 Mar 2019
- 16.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefGoogle Scholar
- 21.Lin NU, Gelman RS, Younger WJ, Sohl J, Freedman RA, Sorensen AG, Bullitt E, Harris GJ, Morganstern D, Schneider BP et al (2013) Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). J Clin Oncol. https://doi.org/10.1200/jco.2013.31.15_suppl.513 Google Scholar
- 22.Lu YS, Chen TW, Lin CH, Yeh DC, Tseng LM, Wu PF, Rau KM, Chen BB, Chao TC, Huang SM et al (2015) Bevacizumab preconditioning followed by etoposide and cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy. Clin Cancer Res 21(8):1851–1858CrossRefGoogle Scholar
- 24.Cortes J, Dieras V, Ro J, Barriere J, Bachelot T, Hurvitz S, Le Rhun E, Espie M, Kim SB, Schneeweiss A et al (2015) Afatinib alone or afatinib plus vinorelbine versus investigator’s choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol 16(16):1700–1710CrossRefGoogle Scholar
- 25.Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Dieras V, Muller V, Tagliaferri M et al (2019) ATTAIN Phase III study of etirinotecan pegol versus treatment of physician’s choice in patients with metastatic breast cancer and brain metastases. Future Oncol. https://doi.org/10.2217/fon-2019-0180 Google Scholar