Table 2.
Major clinical trials in systemic therapy for BCBM according to subtype.
| Systemic therapy for HER2-positive BCBM | |||||
| Treatment | Patients’ Population | Author |
Trial Name
(NCT Number) |
Phase | Primary Endpoint |
| Lapatinib | Progressive HER2-positive BCBM after prior trastuzumab, and cranial radiotherapy | Lin et al. [65] | EGF 105084 (NCT00263588) |
II | ORR in CNS |
| Lapatinib plus capecitabine | HER2-positive BCBM not previously treated with WBRT, capecitabine, or lapatinib | Bachelot et al. [66] | LANDSCAPE (NCT00967031) |
II | ORR in CNS |
| Lapatinib plus capecitabine vs. capecitabine alone | HER2-positive, locally advanced or MBC that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab | Geyer et al. [67] | EGF100151 (NCT00078572) |
III | Time to progression |
| Lapatinib plus WBRT | HER2-positive BCBM | Lin et al. [68] | (not available) | I | Maximum tolerated dose of concurrent lapatinib with WBRT |
| Pertuzumab plus trastuzumab and docetaxel vs trastuzumab plus docetaxel | HER2-positive locally recurrent, unresectable, or MBC without prior chemotherapy or biologic therapy for their advanced disease | Swain et al. [69] | CLEOPATRA (NCT00567190) |
III | PFS |
| T-DM1 vs. lapatinb plus capecitabine | HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane | Krop et al. [70]. | EMILIA (NCT00829166) |
III | Percentage of participants with progressive disease or death, PFS, OS, et al. |
| T-DM1 | HER2-positive locally advanced or MBC with prior HER2-targeted therapy and chemotherapy | Montemurro et al. [71] | KAMILLA (NCT01702571) |
III | Best overall response rate, clinical benefit rate |
| Neratinib plus paclitaxel vs. trastuzumab plus paclitaxel | Previously untreated recurrent and/or metastatic HER2-positive BC | Awada et al. [72] | NEfERT-T (NCT00915018) |
III | PFS |
| Neratinib plus capecitabine | Measurable, progressive, HER2-positive BCBM | Freedman et al. [73] | TBCRC 022 (NCT01494662) |
II | ORR |
| Neratinib plus capecitabine vs. lapatinib plus capecitabine | HER2-positive MBC with 2 or more previous HER2-directed MBC regimens. | Saura et al. [74] | NALA trial (NCT01808573) |
III | PFS, OS |
| Afatinib alone vs. afatinib plus vinorelbine vs. investigator’s choice | HER2-positive BCBM with recurrence or progression during or after treatment with trastuzumab, lapatinib, or both | Cortés et al. [75] | LUX-Breast 3 (NCT01441596) |
II | Patient benefit at 12 weeks |
| Tucatinib | HER2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine | Murthy et al. [76] | HER2CLIMB (NCT02614794) |
II | PFS |
| Tucatinib plus T-DM1 vs. T-DM1 | HER2-positive MBC previously treated with a taxane and/or trastuzumab | (Ongoing) | HER2CLIMB-02 (NCT03975647) |
III | PFS |
| Trastuzumab Deruxtecan | HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine | Jerusalem et al. [77] | DESTINY-Breast01 (NCT03248492) |
II | ORR |
| Systemic therapy for luminal-type BCBM | |||||
| Treatment | Patients’ Population | Author |
Trial Name
(NCT Number) |
Phase | Primary Endpoint |
| Taselisib plus fulvestrant vs. fulvestrant alone | ER-positive and HER2-negative locally advanced BC or MBC with recurrence or progression after aromatase inhibitor therapy | Dent et al. [78] | SANDPIPER (NCT02340221) |
III | PFS |
| Alpelisib plus fulvestrant vs. fulvestrant alone | HR-positive, HER2-negative, advanced BC with progression after aromatase inhibitor therapy | André et al. [79] | SOLAR-1 (NCT02437318) |
III | PFS |
| Buparlisib plus fulvestrant vs. fulvestrant alone | HR-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors | Di Leo et al. [80] | BELLE-3 (NCT01633060) |
III | PFS |
| Palbociclib | Measurable progressive luminal-type BCBM | (Ongoing) | (NCT02896335) | II | Clinical benefit rate at 8 weeks |
| Abemaciclib | BM from luminal-type BC, NSCLC, or melanoma | (Ongoing) | (NCT02308020) | II | ORR in CNS |
| Palbociclib plus trastuzumab plus lapatinib plus fulvestrant | ER-positive/HER2-positive BCBM | (Ongoing) | (NCT04334330) | ORR | |
| Abemaciblib plus SRS vs. palbociclib plus SRS vs. ribociclib plus SRS | ER-positive/HER-2 negative BCBM | (Ongoing) | (NCT04585724) | I | Incidence of grade 3+ radiation therapy oncology central nervous system toxicity |
| Systemic therapy for TN-type BCBM | |||||
| Treatment | Patients’ Population | Author |
Trial Name
(NCT Number) |
Phase | Primary Endpoint |
| Pembrolizumab | Advance TNBC, advanced head and neck cancer, advanced urothelial cancer, or advanced gastric cancer | Nanda et al. [81] | KEYNOTE-012 (NCT01848834) |
I | Adverse events and overall response rate |
| Atezolizumab plus nab-paclitaxel vs. nab-paclitaxel | unresectable locally advanced or metastatic TNBC | Schmid et al. [82] | IMpassion130 (NCT02425891) |
III | PFS and OS |
| Carboplatin and bevacizumab | New or progressive BCBM | Leone et al. [83] | (NCT01004172) | II | ORR in CNS |
| Bevacizumab, etoposide, cisplatin | Breast cancer brain and/or leptomeningeal metastasis | Wu et al. [84] | (NCT01281696) | II | ORR in CNS |
| Talazoparib vs. single agent chemotherapy investigator’s choice | Advanced and/or MBC patients with BRCA mutation, which received no more than 3 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease | Litton et al. [85] | EMBRACA (NCT01945775) |
III | PFS |
| Olaparib vs. single agent chemotherapy investigator’s choice | MBC who had received no more than two previous chemotherapy regimens for metastatic disease | Robson et al. [86] | OlympiAD (NCT02000622) |
III | PFS |
| Veliparib plus carboplatin plus paclitaxel vs. carboplatin plus paclitaxel | Advanced HER2-negative breast cancer with BRCA1 or BRCA2 mutation | Diéras et al. [87] | BROCADE3 (NCT02163694) |
III | PFS |
Abbreviations: BC, breast cancer; MBC, metastatic breast cancer; BM, brain metastasis; BCBM, breast cancer brain metastasis; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer; OS, overall survival; PFS, Progression-Free Survival; ORR, objective response rate; PS, performance status; CNS, central nervous system; T-DM1, trastuzumab emtansine; NSCLC, non-small cell lung cancer; BRCA, breast cancer gene.