Table 4.

Targeted agents in brain metastases (BMs).

Main studies on targeted therapies in BMs				Results
Reference	Agent tested	Number of Pts	Clinical trial characteristics
NSCLC
Sperduto et al. (199)	Erlotinib	126	Phase III multicenter trial (RTOG 0320) Three arms: arm 1: WBRT + SRS; arm 2: WBRT + SRS + TMZ; arm 3: WBRT + SRS + erlotinib EGFR mutation not tested	MST: arm 1 (44 Pts): 13.4 months; arm 2 (40 patients): 6.3 months; arm 3 (41 Pts): 6.1 months CNS mPFS: arm 1: 8.1 months; arm 2: 4.6 months; arm 3: 4.8 months
Welsh et al. (197)	Erlotinib	40	Phase II study of erlotinib plus WBRT Erlotinib started 1 week before WBRT	ORR 86% (n = 36) MST 11.8 months 9 of 17 patients tested for EGFR mutation were positive MST in EGFR mutant: 19.1 months MST in EGFR wild-type 9.3 months
Rosell et al. (288)	Erlotinib + bevacizumab	109	Phase II trial, single-arm, multicentre	Overall median PFS: 13.2 months in T790M-positive group Median PFS: 16.0 months in the T790M-positive group while it was 10.5 months in T790M-negative
Ceresoli et al. (289)	Gefitinib	41	Phase II single-arm study No concurrent local therapy for BM Both squamous and adenocarcinoma included EGFR mutation not tested	ODC 27% mPFS 3 months Disease control better in patients who received prior WBRT and who had adenocarcinoma histology
Costa et al. (205)	Crizotinib		Retrospective analysis of trials	Poor activity against CNS metastasis in NSCLC as evidenced by low concentrations detected in CNS samples
Gadgeel et al. (290)	Alectinib	50	Pooled analysis of two phase II studies 136 patients had BM, 50 had measurable disease ALK-positive NSCLC, previously treated with crizotinib	CNS ORR 64% CNS DOR 10.8 months
Shaw et al. (291)	Ceritinib	122	Phase I study in advanced ALK-positive NSCLC	The ORR was 58% Among the 80 patients who failed crizotinib, the response rate was 56% NSCLC who received ceritinib with doses 400 mg or higher, the mPFS was 7.0 months
Crinò et al. (292)	Ceritinib	140 (100 with BM)	Phase I	Intracranial overall response rate: 45.0% (95% CI, 23.1–68.5%) Ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases
Gettinger et al. (293)	Brigatinib (dual inhibitor of ALK and EGFR)	137	Phase I/II single-arm, open-label, multicenter study in patient Pts with advanced NSCLC	50 Pts with BM Eight (53%) of 15 assessable patients with measurable BM had an intracranial response 11 (35%) of 31 assessable patients with only non-measurable BM had complete disappearance of lesions on imaging Median intracranial PFS for these Pts is 97 weeks
Yang et al. (294)	Osimertinib		Phase II AURA trial	Activity in patients with CNS metastases: 16 (64%) of 25 evaluable Pts had an objective response, including 4 complete responses Median PFS in Pts with CNS metastases was encouraging, although it was shorter than in those without (7.1 vs 13.7 months, respectively) Benefit was observed across all predefined subgroups, including patients with asymptomatic CNS metastases at baseline (PFS: 8.5 vs 4.2 months)
Planchard et al. (295)	Dabrafenib and trametinib	57 total (only one patient with asymptomatic BM)	Phase II, multicentre, non-randomized, open-label study	Dabrafenib plus trametinib is a promising new therapy for patients with BRAFV600E-mutant NSCLC, with high overall response, a prolonged duration of response, and manageable toxicity. Few data on efficacy on BM
Breast cancer (HER2-positive)
Bachelot et al. (231)	Lapatinib + capecitabine	45	Single-arm phase II study No prior WBRT, or lapatinib or capecitabine	CNS ORR 65.9% CNS mPFS 5.5 months mOS 17 months
Lin et al. (230)	Lapatinib + capecitabine	50	Phase II trial	CNS response of 20%PFS not reported
Cortes et al. (296)	Afatinib	121	Phase II, multicenter, randomized trial, open-label, three-arm study Arm A: afatinib, arm B: afatinib +vinorelbine, arm C: investigator choice	Arm A: PB = 30% Arm B: PB = 34.2% Arm C: PB = 41.9%
Freedman et al. (232)	Neratinib	40	Multicenter, open-label phase II study Patients who had progressed after one or More lines of CNS directed therapy	CNS ORR: 8% mPFS 1.9 months mOS 8.7 months
Melanoma
Long et al. (243)	Dabrafenib	172	Multicenter, open-label phase II study V600E or V600K BRAF-mutant patients Two cohorts: cohort A: BM treatment naive, cohort B: previously treated BM	Cohort A, V600E (74 patients) – CNS ORR 39.2% – CNS PFS 16.1 weeks – OS 33.1 weeks Cohort A, V600K (15 patients) – CNS ORR 6.7% – CNS PFS 8.1 weeks – OS 31.4 weeks Cohort B, V600E (65 patients) – CNS ORR 30.8% – CNS PFS 16.6 weeks – OS 16.3 weeks Cohort B, V600K (18 patients) – CNS ORR 22.2% – CNS PFS 15.9 weeks – OS 21.9 weeks
McArthur et al. (245)	Vemurafenib	146	Open-label, phase II study Two cohorts: – Cohort-1: previously untreated (90 Pts) – Cohort-2: previously treated (56 Pts)	Cohort-1: – CNS ORR 18% – CNS PFS 3.7 months – OS 8.9 months Cohort-2: – CNS ORR 23% – CNS PFS 4.0 months – OS 9.6 months

WBRT, whole-brain radiation therapy; SRS, stereotactic radiation; TMZ, temozolomide; Pts, patients; mPFS, median progression-free survival; EGFR, epidermal growth factor receptor; MST, median survival times; CNS, central nervous system; ODC, overall disease control; ORR, overall response rate; DOR, duration of response; mOS, median overall survival; PB, patient benefit (defined as intracranial or extracranial progression-free survival, no new neurologic signs or symptoms related to tumor, increase corticosteroid use) at 12 weeks; BM brain metastases; CT, chemotherapy.