Table 3:

Clinical findings of published combination therapy trials in breast cancer brain metastases, as of October 31, 2019 (n=13)

Authors	Year	Trial	NCTID	Phase	Number Enrolled	Inclusion Criteria	Primary Outcome	Result
Morikawa et al.10	2017	Intermittent High-Dose Lapatinib in Tandem With Capecitabine for HER2 Overexpressed/Amplified Metastatic Breast Cancer With Central Nervous System (CNS) Metastases	NCT02650752	1	11	HER2+ BCBM	Maximum tolerated dose	No improvement in survival
Hurvitz et al.11	2018	Phase 1b/2 Trial Using Lapatinib, Everolimus and Capecitabine for Treatment of HER-2 Positive Breast Cancer With CNS Metastasis	NCT01783756	1/2	9	HER2+ BCBM	Objective response rate	The combination of lapatinib, everolimus, and capecitabine is well tolerated and yielded a 27% response rate in the CNS at 12 weeks in heavily pretreated participants
Murthy et al.12	2018	A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB)	NCT02614794	2	612	HER2+ BCBM	Progression-free survival	Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumor activity
Murthy et al.23	2020							The triple combination lowered the risk of disease progression or death by 52%
Yardley et al.13	2018	Cabazitaxel Plus Lapatinib as Therapy for HER2-Positive Metastatic Breast Cancer Patients With Intracranial Metastases	NCT01934894	2	11	HER2+ BCBM	Objective response rate, tolerated dose and toxicity	The combination of cabazitaxel plus lapatinib was not feasible because of toxicity and because no objective CNS activity was seen in the 5 evaluable patients
Cortés et al.14	2015	Lux-Breast 3; Afatinib Alone or in Combination With Vinorelbine in Patients With Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer Suffering From Brain Metastases	NCT01441596	2	121	HER2+ BCBM	Patient benefit rate	Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments, and afatinib-containing treatments were less tolerated
Van Swearingen et al.15	2018	A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases	NCT01305941	2	32	HER2+ BCBM	Objective response rate	Intracranial response rate to the triple therapy was low and progression-free survival/overall survival was like historical control
Wu et al.16	2015	Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis	NCT01281696	2	40	Histological confirmed invasive breast cancer	Objective response rate	Bevacizumab combined with etoposide and cisplatin exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis
Bachelot et al.17	2013	Lapatinib Ditosylate and Capecitabine in Treating Patients With Stage IV Breast Cancer and Brain Metastases	NCT00967031	2	45	HER2+ BCBM	Objective response rate	Objective CNS response was observed in 65·9%of cases; all were partial responses. The combination of lapatinib and capecitabine is active as first-line treatment of HER2+ BCBM
Cao et al.18	2015	Radiation Therapy With or Without Temozolomide in Treating Women With Brain Metastases and Breast Cancer	NCT00875355	2	100	BCBM	Objective response rate	WBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer
Lin et al.19	2011	Brain Metastases In ErbB2-Positive Breast Cancer	NCT00437073	2	22	HER2+ BCBM	Objective response rate	The study was closed early due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. No responses were observed in the lapatinib plus topotecan arm. Promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity
Pivot et al.20	2015	Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in ErbB2 (HER2) Positive Metastatic Breast Cancer	NCT00820222	3	540	HER2+ BCBM	CNS relapse	No difference was detected between lapatinib-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases; serious adverse events were reported in 13% and 17% of patients, respectively
Brown et al.21	2017	Stereotactic Radiation Therapy With or Without Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases	NCT00377156	3	213	Brain Metastases	Neurocognitive progression	No significant differences in survival according to receipt of WBRT. The use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration
Prat et al.22	2016	Study Comparing GW572016 And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer	NCT00073528	3	1285	HER2+ BCBM	Progression-free survival	Patients with HR-positive/HER2-negative disease with a HER2-enriched profile may benefit from lapatinib in combination with endocrine therapy. Patients with luminal A/HER2-negative metastatic breast cancer might be good candidates for letrozole monotherapy in the first-line setting