Table 1

Characteristics of clinical trials examining treatments for brain metastases (RT+chemo, RT+TT, and RT+IT)

Study	Study design	Number of patients	Primary tumor	Treatment	RT type	Drugs	Median OS (m)	Other results
RT+chemo
Antonadou et al., 2002²⁵	Phase II trial	52	Solid tumor	RT+chemo vs. RT alone	WBRT	TMZ		WBRT+TMZ: ORR significantly improved (P = 0.017)
Verger et al., 2005²⁶	Phase II trial	82	Solid tumor	RT+chemo vs. RT alone	WBRT	TMZ		Percentage of patients with PFS at 90 days: WBRT (54%) vs. WBRT+TMZ-72%
Chua et al., 2010²⁷	Phase II trial	70	NSCLC	RT+chemo vs. RT alone	WBRT	TMZ	WBRT+TMZ vs. WBRT: 4.4, 5.7	Median time to CNS progression: WBRT+TMZ (3.1 m) vs. WBRT (3.8 m)
RT+TT
Chen et al., 2016⁴⁰	Retrospective study	132	EGFR-mutated lung adenocarcinoma	RT+TT vs. TT alone	WBRT	Gefitinib or erlotinib	WBRT+TT vs. TT: 48.0, 41.1	Intracranial ORR: significantly higher in the WBRT+TT group (67.9%) than the TT group (39.2%) (P = 0.001)
Jiang et al., 2016⁴¹	Retrospective study	230	EGFR-mutant NSCLC	RT+TT vs. TT alone	WBRT	EGFR-TKI	WBRT+TT vs. TT: 21.6, 26.4	iPFS and systemic PFS: WBRT+TT (6.9 m, 7.5 m) vs. TT (7.4 m, 7.9 m)
Magnuson et al., 2017⁴⁹	Retrospective study	351	EGFR-mutant NSCLC	SRS followed by TT, WBRT followed by TT, or TT followed by SRS/WBRT	WBRT/SRS	EGFR-TKI	SRS, WBRT, and EGFR-TKI cohorts: 46, 30, and 25
Lee et al., 2014⁵³	RCT	80	NSCLC	RT+TT vs. RT+placebo	WBRT	Erlotinib	TT vs. placebo: 3.4, 2.9	Median iPFS: 1.6 m in both arms
Pesce et al., 2012⁴⁴	Phase II trial	59	NSCLC	RT+TT vs. RT+chemo	WBRT	Gefitinib vs. TMZ	Gefitinib vs. TMZ: 6.3, 4.9
Welsh et al., 2013⁴⁵	Single-arm phase II trial	40	NSCLC	RT+TT	WBRT	Erlotinib	11.8	ORR: 86%
Fan et al., 2015⁴⁷	Single-arm phase II trial	20	NSCLC	RT+TT	WBRT	Icotinib	14.6	ORR: 80.0%
Sperduto et al., 2013⁴⁸	Phase III trial	126	NSCLC	RT+TT vs. RT+chemo vs. RT alone	WBRT+SRS	Erlotinib vs. TMZ	WBRT+SRS, WBRT+SRS+TMZ, and WBRT+SRS+ETN: (13.4, 6.3, and 6.1)	Rates of serious (grade 3–5) toxicity: 11%, 41%, and 49%
Johung et al., 2016⁵²	Retrospective study	90	ALK-rearranged NSCLC	RT+TT	WBRT or SRS	ALK-TKI	49.5	Median iPFS: 11.9 m
Chargari et al., 2011⁵⁸	Retrospective study	31	EGFR-2-positive breast cancer	RT+TT	WBRT	Trastuzumab	18	Median iPFS: 10.5 m; clinical response: 87.1%
Yomo et al., 2013⁵⁹	Retrospective study	40	HER2-overexpressing breast cancer	RT+TT vs. RT alone	SRS	Lapatinib		Rate of 1-year LC: RT+TT (86%) vs. RT (69)
Wolf et al., 2016⁶⁵	Prospective study	80	Melanoma	RT+TT vs. RT alone	SRS	BRAF inhibitor	SRS+TT vs. SRS: 11.2, 6.7	Median iPFS: SRS+TT(3.9 m) vs. SRS (1.7 m)
RT+IT
Hubbeling et al., 2018⁸⁵	Retrospective study	50	NSCLC	RT+IT	WBRT, SRS, PBI	NIVO, PEMBRO or ATEZO		Grade ≥3 AEs in 8% of ICI-naive patients vs. in 9% of ICI-treated patients for SRS (P = 1.00)
Chen et al., 2018⁸⁷	Retrospective study	37	NSCLC	RT+IT	SRS	IPI, NIVO or PEMBRO	19.6	1 year LC□84%
Pike et al., 2018⁸⁶	Retrospective study	39	NSCLC	RT+IT	WBRT, SRS, WBRT+SRS	PEMBRO, NIVO or IPI	25.7
Williams et al., 2017¹⁰⁰	Phase I trial	16	Melanoma	RT+IT	WBRT vs. SRS	IPI	WBRT vs. SRS: 8, not reached	Concurrent ipilimumab 10 mg/kg with SRS is safe
Stokes et al., 2017¹⁰¹	Retrospective study	185	Melanoma	RT+IT	WBRT, SRS	Not specified	10.8
Fang et al., 2017¹⁰²	Retrospective study	137	Melanoma	RT+IT	SRS	Anti-CTLA-4 and/or anti-PD-1	16.9
Petrelli et al., 2019¹⁰⁵	Systematic review	1,520 (33 studies)	Melanoma (87%); NSCLC (11%); RCC (2%)	RT+IT	WBRT, SRS, WBRT+SRS	IPI (14 studies) PEMBRO (2 studies) anti-CTLA-4 and/or anti-PD-1 (16 studies)	15.9	1–2 year LC: 48% (523 patients), 31.6% (281 patients)
RT+TT/IT
Choong et al., 2017⁶⁶	Retrospective study	79	Melanoma	RT+TT/IT	SRS	Anti-CTLA4, anti-PD1 or BRAFi±MEKi	Anti-CTLA4, anti-PD1, BRAFi±MEKi: 7.5, 20.4, 17.8	Median iPFS: anti-CTLA4 (7.5 m), anti-PD1 (12.7 m), BRAFi±MEKi (12.7 m)
Gaudy-Marqueste et al., 2017⁶⁷	Retrospective study	179	Melanoma	RT+TT/IT vs. RT alone	Gamma-Knife (GK)	Anti-CTLA/anti-PD2 and/or BRAFi±MEKi	1st GK vs. RT: 10.95, 2.29

NR, not reported; BM, brain metastases; WBRT, whole brain radiotherapy; SRS, stereotactic radiosurgery; RT, radiotherapy; IT, immunotherapy; TT, target therapy; CHEMO, chemotherapy; OS, overall survival; iPFS, intracranial progression-free survival; LC, local control; ORR, objective response rate; m, months; IPI, ipilimumab; PEMBRO, pembrolizumab; NIVO, nivolumab; BRAFi, BRAF inhibitor; MEKi, MEK inhibitor.