Table 3.

Summary of studies for subgroup of patients with NSCLC, brain metastases, and actionable genomic alterations

Author year	Country/region	Study design	Total patients, N	BrM population, n (%)	Mutation	Line of therapy	Treatment	Arm, n	Asymptomatic BrM, n (%)	CNS-PFS median, months	Intracranial response, n (%)
Addeo et al. 2021 [17]	Multinational	OBS	896	332 (37.1)	EGFR	1L	1G or 2G EGFR TKI	332	–	–	–
Bai et al. 2017 [18]	China	OBS	148	148 (100)	EGFR	2L	GEF	–	47 (31.8)	–	33 (34.7)
							ERL	–		–	21 (39.6)
Baldacci et al. 2022 [19]	France	OBS	208	160 (76.9)	ALK	2L +	LOR	160	–	–	–
Bilgin et al. 2021 [20]	Turkey	OBS	283	68(24.0)	EGFR	1L	AFA	21	–	–	–
							ERL or GEF	47	–	–	–
Bozorgmehr et al. 2021 [21]	Germany	OBS	401	102 (25.4)	EGFR	1L to > 3L	EGFR TKI, CT, palliative RT, de novo stage IV	89	–	–	–
							EGFR TKI, CT, palliative RT, secondary stage IV	13	–	–	–
Camidge et al. 2018 [22]	Intercontinental	RCT	275	81 (29.4)	ALK	1L	Brigatinib	40	–	24	31 (65.6)
							CRIZ	41	–	5.6	7 (14.0)
Chang et al. 2021 [23]	Taiwan	OBS	205	67 (32.7)	EGFR	1L	EGFR TKI (GEF, ERL, AFA)	67	–	–	–
Chen et al. 2020 [24]	China	OBS	148	148 (100)	EGFR	1L to 2L	EGFR TKI only	72	–	10.2	–
							EGFR TKI + WBRT	76	–	11.9	–
Chen et al. 2019a [25]	Taiwan	OBS	134	134 (100)	EGFR	1L	GEF	62	–	23.6	33 (53.2)
							ERL	49	–	27.8	34 (69.4)
							AFA	23	–	17.2	15 (65.2)
Chen et al. 2019b [26]	Taiwan	OBS	141	141 (100)	EGFR	1L +	EGFR TKI + WBRT	94	–	–	–
							EGFR TKI alone	47
Chen et al. 2018 [27]	China	OBS	105	39 (37.1)	EGFR	1L or 2L	EGFR TKIs alone	39	9 (23.1)	6.8	26 (66.7)
							EGFR TKIs + concurrent WBRT	34	8 (23.5)	12.4	29 (85.3)
							WBRT followed by EGFR TKIs	32	8 (25.0)	9.1	24 (75.0)
Chiu et al. 2022 [28]	Taiwan	OBS	310	137 (44.2)	EGFR	1L	EGFR TKI (GEF or ERL) ± BEV	137	–	–	–
de Marinis et al. 2021 [29]	Intercontinental	SA	479	83 (17.3)	EGFR	1L +	AFA	83	–	–	–
Doherty et al. 2017 [30]	Canada	OBS	184	184 (100)	EGFR/ALK	1L	WBRT + SRS + TKIs	120	58 (48.3)	50.5	–
							SRS + TKIs	37	31 (83.8)	12
							TKIs	27	24 (88.9)	15
Duruisseaux et al. 2017 [31]	France	OBS	318	111 (34.9)	ALK	1L +	CRIZ	111	–	–	–
El Shafie et al. 2021 [32]	Germany	OBS	141	141 (100)	EGFR: 76.6% ALK: 23.4%	1L +	Delayed local therapy	54	45 (88.2)	10.6	–
							Early local therapy	87	41 (48.8)	19.4	–
Gijtenbeek et al. 2020 [33]	Netherlands	OBS	873	112 (12.8)	EGFR	1L	ERL	65	–	–	–
							GEF	29
							AFA	18
He et al. 2019 [34]	China	OBS	104	104 (100)	EGFR	1L	EGFR TKI (GEF, ERL, ICO) + WBRT	56	27 (48.2)	17.7	–
							EGFR TKI (GEF, ERL, ICO)	48	29 (60.4)	11	–
Horn et al. 2021 [35]	Intercontinental	RCT	290	90 (31.0)	ALK	1L	Ensartinib	40	40 (100)	–	–
							CRIZ	50	50 (100)	–	–
Huang et al. 2021 [36]	Taiwan	OBS	612	211 (34.4)	EGFR	1L +	GEF/ERL	113	–	–	–
							AFA	98
Huang et al. 2022 [37]	Taiwan	OBS	516	151 (30.3)	EGFR	1L	AFA	151	–	–	–
Hyun et al. 2020 [38]	South Korea	OBS	173	173 (100)	EGFR	–	EGFR TKI (GEF, ERL, AFA)	107	98 (91.6)	10.4	67 (62.6)
							WBRT followed by EGFR TKI (GEF, ERL, AFA)	36	22 (61.1)	10.8	26 (72.2)
							SRS followed by EGFR TKI (GEF, ERL, AFA)	30	21 (70.0)	15.8	18 (60.0)
Ito et al. 2021 [39]	Japan	OBS	160	160 (100)	EGFR	1L	AFA	75	–	–	–
							OSI	85
Jahanzeb et al. 2020 [40]	USA	OBS	581	160 (27.5)	ALK	1L and 2L	ALK TKIs (CRIZ, CER, ALEC, BRIG)	160	–	–	–
Jia et al. 2019 [41]	China	OBS	114	114 (100)	EGFR	1L	SRS + EGFR TKI (GEF, ERL)	57	9 (15.8)	12.2	–
							WBRT + EGFR TKI (GEF, ERL)	57	5 (8.8)	11.5	–
Jiang et al. 2019 [42]	China	OBS	208	208 (100)	EGFR	1L	EGFR TKI (GEF, ERL, ICO) + BEV	59	38 (64.4)	14	39 (66.1)
							EGFR TKI (GEF, ERL, ICO)	149	95 (63.8)	8.2	62 (41.6)
Jung et al. 2020 [43]	South Korea	OBS	559	198 (35.4)	EGFR	1L	GEF	68	–	–	22 (64.7)
							ERL	58	–	–	15 (68.2)
							AFA	72	–	–	27 (72.9)
Jung et al. 2022 [44]	South Korea	OBS	737	287 (38.9)	EGFR	1L and 2L	1L AFA + 2L OSI	54	42 (77.8)	–	71 (24.7)
							1L AFA + 2L CT or other treatments	61	40 (65.6)
							1L AFA + 2L systemic treatment or SC	46	37 (80.4)
							1L AFA only	126	96 (76.2)
Ko et al. 2022 [45]	Taiwan	OBS	400	140 (35.0)	EGFR	1L	GEF or ERL or AFA ± denosumab	140	–	–	–
Kong et al. 2021 [46]	USA	OBS	502	222 (100)	EGFR	–	EGFR TKI (AFA, ERL, GEF)	222	–	–	–
Lee et al. 2021 [47]	South Korea	OBS	422	168 (39.8)	EGFR	1L to 2L	AFA	168	–	–	–
Lee et al. 2019a [48]	Taiwan	OBS	100	100 (100)	EGFR	1L +	EGFR TKI + brain surgery + WBRT	40	6 (15.0)	–	–
							EGFR TKI + WBRT	60	16 (26.7)	–	–
Lee et al. 2019b [49]	Taiwan	OBS	198	198 (100)	EGFR	–	WBRT	75	–	–	–
							SRS	21
							Delayed radiation	27
							Never cranial irradiation	75
Lee et al. 2020 [50]	South Korea	OBS	351	351 (100)	EGFR	–	With or without OSI	351	–	–	–
Li et al. 2017 [51]	China	OBS	104	104 (100)	EGFR	–	EGFR TKI (GEF or ERL) or EGFR TKI (GEF or ERL) + WBRT	104	–	–	–
Li et al. 2019 [52]	China	OBS	195	195 (100)	EGFR	1L	WBRT followed by EGFR TKI (GEF, ERL, ICO)	67	51 (76.1)	–	–
							EGFR TKI (GEF, ERL, ICO) + WBRT	64	40 (68.8)	–	–
							EGFR TKI (GEF, ERL, ICO) followed by WBRT	64	46 (71.8)	–	–
Lin et al. 2019 [53]	Taiwan	OBS	125	125 (100)	EGFR	1L	GEF	28	–	–	–
							ERL	54	–	–	–
							AFA	43	–	–	–
Liu et al. 2017 [54]	China	OBS	11	113 (100)	EGFR	1L to 2L	EGFR TKI (GEF, ERL, ICO) + early RT (WBRT, SRS)	49	10 (20.4)	21.4	–
							EGFR TKI (GEF, ERL, ICO)	37	32 (86.4)	24.4	–
							EGFR TKI (GEF, ERL, ICO) + salvage RT (WBRT, SRS)	27	18 (66.7)	23.6	–
Liu et al. 2020 [55]	USA	OBS	365	145 (39.7)	EGFR	1L to > 4L	OSI	124	–	–	–
							OSI + ASA	21	–	–	–
Lu et al. 2022a [56]	China	RCT	429	115 (26.8)	EGFR	1L	Aumolertinib	56	–	–	–
							GEF	59	–	–	–
Lu et al. 2022b [57]	China	RCT	444	160 (36.0)	EGFR	2L and 3L	Sintilimab + IBI305 + CT	53	53 (100)	–	–
							Sintilimab + CT	52	52 (100)	–	–
							CT alone	55	55 (100)	–	–
Magnuson et al. 2017 [58]	USA	OBS	351	351 (100)	EGFR	1L	ERL followed by WBRT or SRS	131	115 (87.7)	17	–
							WBRT followed by ERL	120	69 (57.5)	24	–
							SRS followed by ERL	100	51 (51.0)	23	–
Masuda et al. 2018 [59]	Japan	OBS	496	496 (100)	ALK	1L +	ALEC	496	–	–	–
Mehlman et al. 2019 [60]	France	OBS	226	121 (53.5)	EGFR	1L and > 2L	OSI (≥ 2L with T790M)	92	–	–	–
							OSI (≥ 2L without T790M)	26
							OSI (1L)	3
Miyawaki et al. 2019 [61]	Japan	OBS	176	176 (100)	EGFR	1L	EGFR TKI	107	97 (90.6)	12	–
							Local therapy	69	42 (60.9)	22	–
Mok et al. 2017 [62] Wu 2017 [63]	Intercontinental	RCT	419	144 (34.4) n with CNS metastases	EGFR T790M	2L	OSI	93	93 (100)	–	–
							PBC + PEM	51	51 (100)
				116 (27.7) n with CNS lesions on BL brain scan (BICNR)			OSI	75	–	11.7	30 (40.0)
							PBC + PEM	41		5.6	7 (17.1)
Nadler et al. 2020 [64]	USA	OBS	402	201 (50.0)	EGFR	1L +	ERL	201	–	–	–
Patel et al. 2017 [65]	USA	OBS	189	78 (41.3)	EGFR	1L +	ERL	78	–	–	–
Peters et al. 2017 [66]	Intercontinental	RCT	303	122 (40.3)	ALK	1L	ALEC	64	–	–	–
							CRIZ	58	–	–	–
Ramotar et al. 2020 [67]	Canada	OBS	198	198 (100)	EGFR	1L	SRS	43	–	–	–
							WBRT	121
							TKI	34
Saida et al. 2019 [68]	Japan	OBS	104	104 (100)	EGFR	1L	EGFR TKI without upfront brain RT	65	55 (84.6)	11.1	24 (36.9)
							EGFR TKI with upfront brain RT	39	19 (48.7)	15.6	14 (35.6)
Saito et al. 2019 [69]	Japan	RCT	228	72 (31.6)	EGFR	1L	ERL + BEV	36	36 (100)	–	–
							ERL	36	36 (100)	–	–
Shaw et al. 2017 [70]	Intercontinental	RCT	231	134 (58.0)	ALK	2L/2L +	CER	65	–	–	–
							CT	69	–	–	–
Shaw et al. 2020 [71]	Intercontinental	RCT	296	78 (26.4)	ALK	1L	LOR	38	–	–	23 (60.5)
							CRIZ	40	–		6 (15.0)
Shi et al. 2017 [72]	China	RCT	296	81 (27.3)	EGFR	1L	ICO	41	–	–	–
							CT	40	–	–	–
Shi et al. 2022 [73]	China	RCT	358	127 (35.4)	EGFR	1L	Furmonertinib	65	–	20.8	–
							GEF	62	–	9.8	–
Solomon et al. 2018 [74]	Intercontinental	RCT	343	92 (26.8)	ALK	1L	CRIZ	45	–	–	–
							CT	47	–	–	–
Soria et al. 2017 [75]	Intercontinental	RCT	376	121 (32.2)	ALK	1L	CER	59	–	–	25 (46.3)
							PBC	62	–	–	11 (21.2)
Soria et al. 2018 [76] and Reungwetwattana et al. 2018 [77]	Intercontinental	RCT	556	116 (21.0)	EGFR	1L	OSI	53	–	–	40 (65.6)
							GEF or ERL	63	–	–	29 (43.3)
Tang et al. 2021 [78]	China	OBS	351	132 (37.6)	EGFR T790M	–	OSI	132	–	–	–
Teocharoen et al. 2021 [79]	Thailand	OBS	304	149 (49.0)	EGFR	1L to > 2L	EGFR TKI	149	–	–	–
Tu et al. 2022 [80]	Asia	SA	541	103 (19.0)	EGFR	1L to 3L +	AFA	103	103 (100)	–	–
Wang et al. 2018 [81]	China	OBS	181	181 (100)	EGFR	1L to > 2L	Asymptomatic pts EGFR TKI ± RT (WBRT, SRS)	132	132 (72.9)	iPFS in 181 pts	B/C RT n = 91:51 (55.6)
										B/C RT n = 91: 11.7
							Symptomatic pts EGFR TKI ± RT (WBRT, SRS)	49		Upfront RT n = 90: 9.7	Upfront RT n = 90: 56 (62.6)
Wang et al. 2020 [82]	China	OBS	113	113 (100)	EGFR	–	None	18	67 (59.3)	–
							RT (WBRT, SRS)	27		12
							EGFR TKIs in TKI-naïve	14		7
							CT	15		10
							EGFR TKIs + RT (WBRT, SRS)	39		21
Wolf et al. 2022 [83]	Intercontinental	RCT	119	76 (63.9)	ALK	3L	ALEC	50	–	9.6	–
							PEM or DOC	26	–	1.4	–
Wu et al. 2018 [84]	Intercontinental	RCT	207	53 (25.6)	ALK	1L	CRIZ	21	–	NR	–
							CT	32	–	16	–
Yang et al. 2017a [85]	China	OBS	228	228 (100)	EGFR	–	BEV + GEF + WBRT	77	–	–	–
							WBRT	75
Yang et al. 2017b [86]	China	RCT	176	176 (100)	EGFR	1L to 2L	ICO	85	–	10	–
							WBRT ± CT	91	–	4.8	–
Yang et al. 2021a [87]	China	OBS	124	124 (100)	EGFR	2L	OSI	60	–	–	–
							AFA	64	–	–	–
Yang et al. 2021b [88]	China	OBS	198	198 (100)	EGFR	–	Delayed RT	94	73 (77.7)	11.1	38 (40.4)
							Upfront RT	104	45 (43.3)	19.9	79 (76.0)
Yomo et al. 2018 [89]	Japan	OBS	133	133 (100)	EGFR	1L +	SRS ± EGFR TKI (GEF, ERL, AFA, OSI)	133	–	–	–
Yu et al. 2019 [90]	China	OBS	261	261 (100)	EGFR	1L +	EGFR TKIs (ICO, GEF, ERL)	261	114 (43.7)	–	–
Yu et al. 2021a [91]	China	OBS	205	205 (100)	EGFR	1L to 2L	OSI with upfront cranial RT	48	–	24.1	–
							OSI without upfront cranial RT	157	–	17.7	–
Yu et al. 2021b [92]	China	OBS	571	571 (100)	EGFR	1L to > 2L	EGFR TKI (GEF, ICO, ERL, AFA, OSI), local brain therapies (surgery, WBRT, SRS)	571	–	–	–
Zeng et al. 2022 [93]	China	OBS	1081	293 (27.1)	EGFR	1L	EGFR TKI	293	–	–	–
Zhao et al. 2021 [94]	China	RCT	313	92 (29.4)	EGFR	1L	APA + GEF	51	–	–	–
							PBO + GEF	41
Zhao et al. 2019 [95]	China	OBS	344	344 (100)	EGFR	2L +	WBRT (TKI-naïve group)	207	0	7.7	–
							WBRT (TKI-resistant group)	137	0	5.4	–
Zhao et al. 2022 [96]	China	OBS	367	367 (100)	EGFR	1L	1G EGFR TKI (GEF or ERL)	265	117 (44.1)	–	133 (50.0)
							OSI	102	57 (55.8)	–	69 (68.3)
Zhou et al. 2019 [97]	Asia	RCT	187	67 (35.8)	ALK	1L	ALEC	44	–	–	32 (72.7)
							CRIZ	23	–		5 (21.7)
Zhu et al. 2017 [98]	China	OBS	133	133 (100)	EGFR	–	1G EGFR TKI + RT	67	–	16	–
							1G EGFR TKI	66	–	11.5	–

Dash ( -) not reported; 1L/2L/3L/4L first-/second-/third-/fourth-line, 1G/2G first-/second-generation, AFA afatinib, ALEC alectinib, ALK anaplastic lymphoma kinase, APA apatinib, ASA aspirin, B/C before or concurrent, BEV bevacizumab, BICNR blinded independent central neuroradiology review, BL baseline, BRIG brigatinib, BrM brain metastasis, CER ceritinib, CNS central nervous system, CRIZ crizotinib, CT chemotherapy, DOC docetaxel, EGFR epidermal growth factor receptor, ERL erlotinib, GEF gefitinib, ICO icotinib, iPFS intracranial progression-free survival, LOR lorlatinib, NE not evaluable, NR not reached, OBS observational study, OSI osimertinib, PBC platinum-based chemotherapy, PBO placebo, PEM pemetrexed, PFS progression-free survival, pts patients, RCT randomized controlled trial, RT radiotherapy, SA single-arm, SC supportive care, SRS stereotactic radiosurgery, TKI tyrosine kinase inhibitor, USA United States of America, WBRT whole-brain radiation therapy, Y yes