Table 3.
Select trials of systemic agents for brain metastases according to primary cancer
| Study | Systemic Agent | Mechanism of Action | Population | Prior Treatment for BM? | Trial Design | N | Primary endpoint | CNS Response Rate (CR + PR) | Overall Survival |
|---|---|---|---|---|---|---|---|---|---|
| Melanoma | |||||||||
| Margolin et al, Lancet Oncol 2012111 | Ipilimumab | CTCL-4 inhibitor | Melanoma metastatic to brain | 41%–48% had received prior brain irradiation (WBRT or SRS) | Phase II | 72 total: 51 in cohort A: neurologically asymptomatic (N = 51) Cohort B: symptomatic (N = 21) |
Disease control (CR, PR, SD) at 12 wk = 18% in A and 5% in B | 16% cohort A, 5% cohort B | 7.0 mo in cohort A and 3.7 mo in cohort B |
| Long et al, Lancet Oncol 2012138 | Dabrafenib | BRAF inhibitor | Val600Glu or Val600Lys BRAF mutant melanoma metastatic to brain | Cohort A previously untreated BM. Cohort B prior local therapy (surgery, WBRT, SRS) |
Phase II | 172 total: 89 in cohort A and 83 in cohort B | Intracranial response (CR + PR) Val600Glu 39.2% cohort A, 30.8% cohort B. Val600 Lys 6.7% cohort A, 22.2% cohort B |
Val600Glu 39.2% cohort A, 30.8% cohort B. Val600 Lys 6.7% cohort A, 22.2% cohort B | Val600Glu 33.1 mo cohort A, 31.4 mo Cohort B Val600Lys 16.3 mo cohort A, 21.9 mo cohort B |
| Breast Cancer | |||||||||
| Lin et al, CCR 2009131 | Lapatinib | HER2 inhibitor | HER2+ breast cancer metastatic to brain | All previously treated with brain irradiation (WBRT or SRS) | Phase II | 242: 95 in cohort A (ECOG 0–1 and 1–2 prior trastuzumab regimens) and 147 in cohort B (ECOG 2 and/or >2 prior trastuzumab regimens) | CNS objective response (50% or greater volumetric reduction) | 6% in cohort A and cohort B | 6.4 mo (cohort A 9.6 mo, cohort B 5.5 mo) |
| Lapatinib + capecitabine | HER2 inhibitor (lapatinib) and prodrug that converts to 5-fluorouracil (capecitabine) | HER2+ breast cancer metastatic to brain | Extension phase for patients on study who progressed on lapatinib | Phase II | Subset of 50 patients in above study | CNS objective response (50% or greater volumetric reduction) | 20% | Not reported | |
| Bachelot Lancet Oncol 2013 LANDSCAPE132 | Lapatinib + capecitabine | HER2 inhibitor (lapatinib) and prodrug that converts to 5-fluorouracil (capecitabine) | HER2+ breast cancer metastatic to brain | Untreated (no prior WBRT, SRS, capecitabine, or lapatinib) | Phase II | 45 | CNS objective response rate (CR + PR) | 49% | 17 mo |
| Pivot et al, J Clin Onc 2015 CEREBEL126 | Lapatinib + capecitabine (lap + cap) vs trastuzumab + capecitabine (tras + cap) | HER2 inhibitors (lap, tras), prodrug that converts to 5-fluorouracil (cap) | HER2+ metastatic breast cancer without CNS metastases at baseline | No brain metastases at baseline | Phase III, randomized study, preventative trial. Study terminated early |
540 (271 lap + cap and 269 tras + cap) | Incidence of CNS mets as first site of relapse: 3% in the lap + cap and 5% in tras + cap, difference not statistically significant | n/a | 22.7 mo for lap + cap and 27.3 mo for tras + cap |
| NSCLC | |||||||||
| Bearz et al, Lung Cancer 2010146 | Pemetrexed | Folate anti-metabolite | NSCLC metastatic to brain | 71.8% received prior brain irradiation | Retrospective review | 39 | Not specified | 38.4% | 10 mo |
| Ceresoli et al, Ann Oncol 2004147 | Gefitinib | EGFR inhibitor | Unselected patients with NSCLC metastatic to brain | 2 groups: prior WBRT (44%) and no prior WBRT (56%) | Phase II | 41 | Disease control rate (CR + PR + SD) | 10% | 5 mo |
| Wu et al, Ann Oncol 2013 (CTONG-0803)148 | Erlotinib | EGFR inhibitor | East Asian patients with adenocarcinoma or EGFR mutant NSCLC, asymptomatic brain metastases (total 16.7% mutation positive) | 35.4% received prior WBRT | Phase II | 48 | PFS | 58.3% systemic +intracranial RR (intracranial RR alone not reported) | 18.9 mo [patients with EGFR mutant disease 37.5 mo vs EGFR wild-type 18.4 mo vs unknown EGFR status 19.4 mo, P-value .14] |
| Besse et al, Clin Ca Res 2015117 | Bevacziumab + carboplatin and paclitaxel | VEGF inhibitor (bevacziumab), alkylating agent (carboplatin), taxane (paclitaxel) | Unselected NSCLC patients with asymptomatic, prevously untreated brain metastases | No prior treatment | Phase II (noncomparative study with 2 arms atlhough only the bevacizuamb + carboplatin and paclitaxel arm results reported) | 67 in the B + CP arm | Investigator-assessed 6-month PFS rate | 61.2% | 16 mo |
| Ou et al, J Clin Oncol 2016155 | Alectinib | ALK inhibitor | ALK-rearranged NSCLC resistant to crizotinib, patients with stable treated or asymptomatic untreated brain and leptomeningeal metastases allowed | 61 (73%) of 84 patients with CNS metastases at study entry had prior brain irradiation | Phase II | 84 (61%) of the 138 patients enrolled on study had CNS metastases at baseline | Objective response rate (CNS objective response rate was a secondary objective) | 57% in 35 patients with measurable CNS lesions | Not reported |
| Boggs et al, Lung Ca 2014123 | Temozolomide (TMZ) | Alkylating agent | NSCLC stage IIIA, IIIB, or IV (only pleural or pericardia effusion), no brain metastases at baseline | No brain metastases at baseline | Phase II randomized trial – preventative trial Study terminated early |
53 (26 TMZ, 27 observation) | Incidence of brain metastases at 12 mo: 18% in TMZ, 13% in observation | n/a | 27.1 mo in TMZ vs 22.5 mo in observation (P = .7) |
Abbreviations: CR, complete response; PR, partial response; PFS, progression-free survival; RR, response rate; mets, metastases.