Efficacy of Different Therapies for Brain Metastases of Non-Small Cell Lung Cancer

A Systematic Review and Meta-Analysis

Mo Chen; Lingyun Wei; Qin Wang; Jingyuan Xie; Ke Xu; Tangfeng Lv; Yong Song; Ping Zhan

Transl Lung Cancer Res. 2023;12(4):689-706.

Abstract and Introduction

Abstract

Background: As one of the most common causes of death in advanced non-small cell lung cancer (NSCLC), brain metastases (BM) have attracted attention and debate about treatment options, especially for patients with negative driver genes or resistance to targeted agents. Therefore, we conducted a meta-analysis to investigate the potential benefit of different therapeutic regimens for intracranial lesions in non-targeted therapy NSCLC patients.

Methods: A comprehensive search was conducted in databases including PubMed, Embase, and the Cochrane Library. The primary endpoints included the intracerebral objective response rate (icORR) and intracerebral progression-free survival (iPFS) in patients with BM.

Results: Thirty-six studies involving 1,774 NSCLC patients with baseline BM were included in this meta-analysis. Antitumor agents plus radiotherapy (RT) showed the most significant synergistic effects; the highest pooled icORR that appeared in the combination of immune checkpoint inhibitor (ICI) and RT was 81% [95% confidence interval (CI): 16–100%], and the median iPFS was 7.04 months (95% CI: 2.54–11.55 months). The pooled icORR and median iPFS of RT plus chemotherapy were 46% (95% CI: 34–57%) and 5.7 months (95% CI: 3.90–7.50 months), respectively. The highest median iPFS in nivolumab plus ipilimumab plus chemotherapy was 13.5 months (95% CI: 8.35–18.65 months). ICI plus chemotherapy also showed potent antitumor activity in BM, with a pooled icORR of 56% (95% CI: 29–82%) and a median iPFS of 6.9 months (95% CI: 3.20–10.60 months). Notably, the subgroup analysis indicated that the pooled icORR of patients in programmed cell death-ligand 1 (PD-L1) (≥50%) who received ICI was 54% (95% CI: 30–77%), and that of patients who received first-line ICI was 69.0% (95% CI: 51–85%).

Conclusions: ICI-based combination treatment provides a long-term survival benefit for non-targeted therapy patients, with the most significant benefits observed in improving icORR and prolonging overall survival (OS) and iPFS. In particular, patients who received first-line treatment or who were PD-L1-positive had a more significant survival benefit from aggressive ICI-based therapies. For patients with a PD-L1-negative status, chemotherapy plus RT led to better clinical outcomes than other treatment regimens. These innovative findings could help clinicians to better select therapeutic strategies for NSCLC patients with BM.

Introduction

Despite the recent progress in therapeutic strategies for metastatic non-small cell lung cancer (NSCLC), the prognosis of NSCLC patients with brain metastases (BM), which is one of the most common metastatic sites and fatal factors, has failed to show substantial improvements. Without effective treatment, the overall survival (OS) of such patients ranges from several weeks to several months. However, the selectivity of the blood-brain barrier (BBB) limits the delivery of drugs to the brain parenchyma during systemic therapy, and the prognosis also relies on several essential characteristics of intracranial lesions, such as the number, size, locations, and central nervous system (CNS) symptoms.^[1] Generally, patients choose radiotherapy (RT) or surgery to rapidly alleviate their neurological symptoms. Among the systemic therapies, which include chemotherapy, angiogenesis inhibitors, immune checkpoint inhibitors (ICIs), and targeted agents, the latter are the best choice for patients with molecular drivers.^[2] However, there is an ongoing concern and debate about the optimal therapies for BM patients with negative driver genes or resistance to tyrosine kinase inhibitors (TKI).^[3]

Unfortunately, few trials have evaluated the clinical benefits of systemic therapies for intracranial lesions in NSCLC patients who cannot benefit from targeted therapy. Traditionally, chemotherapy is reserved as a salvage therapy for BM because the BBB resists the passage of chemotherapeutic agents. Thus far, several chemotherapeutic agents, such as paclitaxel, vinorelbine or gemcitabine, cisplatin, and others, seem to be effective for CNS lesions.^[4] Currently, ICI-combined therapies are widely considered for patients with NSCLC. However, patients with BM are excluded from most clinical trials on programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors. KEYNOTE-189, which included the most extensive subgroup analysis of patients with BM, reported that the OS of patients treated with pembrolizumab combined with chemotherapy was significantly superior to those subjected to pure chemotherapy [hazard ratio (HR) =0.36; 95% confidence interval (CI): 0.20–0.62].^[5,6]

A better understanding of the activity of different antitumor agents in the CNS is very important for making the optimal clinical choice. Therefore, in this study, we performed a meta-analysis to make reasonable suggestions for clinical treatment by comparing different therapies and assessing the most effective strategies for intracranial lesions in non-targeted therapy NSCLC patients. This meta-analysis was reported in accordance with the PRISMA reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-515/rc).^[7]

1 2 3 4 5

Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References
Sidebar

Table 1. Baseline characteristics of NSCLC patients with BM in the included studies
Author	Year	Type	Therapy regimen	Treatment line	Sex (F/M), %	Median age	Smoke %	Response Assessment method	ECOG 0–1, %	Refs
Sun L	2021	Retro	Pembro	≥1	47.6/52.4	66	85.7	–	82.5	(8)
Goldberg SB	2020	Pro	Pembro	≥1	33/67	60	93	mRECIST	100	(9)
Gauvain C	2018	Retro	Nivo	≥1	24/76	59.5	91	RECIST 1.1	–	(10)
Dudnik E	2016	Retro	Nivo	–	60/40	78	80	mRECIST 1.1	–	(11)
Hendriks L	2019	Retro	ICI	–	62/28	61.5	93.4	NS	77.2	(12)
Wakuda K	2021	Retro	Pembro	1	74/26	70	91	RECIST 1.1	39	(13)
Zhang GW	2020	Retro	Nivo	≥2	78/22	57.7	–	RECIST 1.1	84	(14)
Song P	2019	Retro	ICI	–	–	–	–	RECIST 1.1	–	(15)
Skribek M	2020	Retro	ICI	≥1	54.9/45.1	69	86.3	mRECIST 1.1	75.8	(16)
Kitai H	2013	Retro	Chem	–	44.4/55.6	63	48	–	–	(17)
Barlesi F	2011	Pro	PP	1	67.4/32.6	60.4	–	RECIST	97.7	(18)
Chouahnia K	2010	Pro	PP	–	–	–	–	–	100	(19)
Hu Q	2011	Retro	Chem	–	–	–	–	–	–	(20)
			Chem + WBRT	–	–	–	–	–	–
Bailon O	2012	Pro	PP	1	70/30	58	–	RECIST	90	(21)
Bearz A	2010	Retro	Pemetrex	–	–	–	–	RECIST	–	(22)
Monnet I	2020	Pro	PP + Bev	1	78.3/22.7	60.5	89.2	RECIST 1.1	100	(23)
Tian Y	2019	Retro	PP	1	40/60	54	24.4	RECIST 1.1	–	(24)
			PP + Bev	1	61.5/38.5	58	26.9	NA	–
Li X	2019	Retro	PP	1	–	–	–	RECIST 1.1	–	(25)
			PP + Bev	1	–	–		–	–
Besse B	2015	Pro	TP + Bev	1	69/31	61	79	RECIST 1.0	100	(26)
Ashinuma H	2014	Retro	Chem + Bev	–	50/50	62.5	–	RECIST 1.1	–	(27)
Hirano S	2006	Retro	Chem	1	52.6/47.4	61	–	RECIST 1.1	–	(28)
Metro G	2021	Retro	Pembro	1	44.4/55.6	74	77.8	mRECIST1.1	88.9	(29)
			Pembro + WBRT	1	37.5/62.5	63	87.5	mRECIST 1.1	–
			Pembro + SRS	1	76.9/22.1	69	92.3	mRECIST 1.1	–
Shepard MJ	2019	Retro	ICI + SRS	–	64.7/35.3	64.4	–	RANO-BM	–	(30)
Afzal MZ	2018	Retro	PP + Pembro	≥1	–	63.7	100	RECIST 1.1	82.4	(31)
He Q	2017	Pro	PP + WBRT	1	34.4/65.6	58	31.3	RANO-BM	–	(32)
Dinglin XX	2013	Pro	PP + WBRT	≥1	64.3/35.7	55.4	54.8	RECIST 1.0	100	(33)
Quantin X	2010	Pro	Chem + WBRT	–	75.7/24.3	59.1	–	RECIST	–	(34)
				–	75.8/24.2	56	–	–	–
Chen L	2009	Pro	Chem + WBRT	≥1	60.8/39.2	53	–	RECIST	–	(35)
Lee DH	2008	Pro	Chem (earlier) + WBRT	1	76/24	60	–	WHO	100	(36)
			Chem + WBRT (earlier)	1	83/17	62	–	WHO	95.6
Carbone D	2021	Pro	Pembro + Ipili + Chem	1	31.4/68.6	61	78	mRECIST 1.1	98	(37)
			Chem	1	48/52	64	92	mRECIST 1.1	100
Lau SCM	2021	Retro	ICI + RT	–	47/53	64	77	RECIST 1.1	92	(38)
			Chem + RT	–	51/49	62	67	RANO—BM	88
Lim SH	2015	Pro	Chem + SRS (earlier)	–	71/29	58	58	RECIST 1.1	100	(39)
			Chem (earlier) + SRS	–	73/27	57	65		100
Azzam G	2018	Retro	ICI + SRS	–	–	–	–	–	–	(40)
Li J	2020	Pro	Pembro + ipili + SRS	–	–	–	–	–	–	(41)
Lee M	2021	Retro	ICI	–	62.5/27.5	61	–	–	92.3	(42)
			ICI + RT (concurrent)	–	80/20	62	–	–	100
			ICI + RT (non-concurrent)	–	70/30	59	–	–	100
Nadal E	2019	Pro	ICI + Chem	–	29/71	–	75	RANO—BM	65	(43)

NSCLC, non-small cell lung cancer; BM, brain metastases; F, female; M, male; ECOG, Eastern Cooperative Oncology Group; Refs, references; Retro, retrospective; Pro, prospective; ICI, immune checkpoint inhibitor, Chem, chemotherapy; Pembro, pembrolizumab; Nivo, nivolumab; Ipili, ipilimumab; PP, pemetrexed plus cisplatin; TP, paclitaxel plus cisplatin; Bev, bevacizumab; No-sq, no-squamous; RT, radiotherapy; WBRT, whole brain radiotherapy; SRS, stereotactic radiosurgery.

Table 2. Clinical characteristics of NSCLC patients with BM of studies
Author	Year	PD-L1 ≥1, %	Steroid, %	Number of BM, %	CNS symptom, %	Treated BM, %	Dose	Refs
Sun L	2021	–	–	–	–	60.30	–	(8)
Goldberg SB	2020	–	–	100% 1–5	–	67	–	(9)
Gauvain C	2018	–	–	76% 1–3	–	–	–	(10)
Dudnik E	2016	–	0	–	–	–	–	(11)
Hendriks L	2019	61.5	27.4	47% 1–3	14.7	82.2	–	(12)
Wakuda K	2021	–	–	–	–	57	–	(13)
Zhang GW	2020	–	–	–	–	50	–	(14)
Song P	2019	–	–	–	–	–	–	(15)
Skribek M	2020	80	54.1	63.6% 1–3	54.5	78.8	–	(16)
Kitai H	2013	–	–	–	–	–	–	(17)
Barlesi F	2011	–	–	–	0	–	–	(18)
Chouahnia K	2010	–	–	–	–	–	–	(19)
Hu Q	2011	–	–	–	–	–	–	(20)
Bailon O	2012	–	63	60% 1–3	72	0	–	(21)
Bearz A	2010	–	–	–	–	–	–	(22)
Monnet I	2020	–	–	93.5% 1–5	–	0	–	(23)
Tian Y	2019	–	–	–	42.2	–	–	(24)
		–	–	–	34.6	–	–
Li X	2019	–	–	–	–	–	–	(25)
Besse B	2015	–	–	100% 0–2	–	–	–	(26)
Ashinuma H	2014	–	–	–	–	80	–	(27)
Hirano S	2006	–	–	31.6% 1–2	–	–	–	(28)
Metro G	2021	–	11.1	66.7 % 1–3	–	–	–	(29)
		100	37.5	12.5% 1–3	–	0	–
		100	38.5	68.2% 1–3	–	0	–
Shepard MJ	2019	76.5	58.80	–	–	35.4	Median 19	(30)
Afzal MZ	2018	–	–	–	–	50	–	(31)
He Q	2017	–	–	34% 1–2	–	–	30	(32)
Dinglin XX	2013	–	100	28.6% 1–2	–	–	30	(33)
Quantin X	2010	–	–	59.5 % 1–2	–	–	54	(34)
		–	–	51.2 % 1–2	–	–	–
Chen L	2009	–	–	47.1% 1–3	–	–	30–60	(35)
Lee DH	2008	–	–	–	0	–	–	(36)
		–	–	–	0	–	30
Carbone D	2021	64	6	–	–	36	–	(37)
		67	16	–	–	45	–
Lau SCM	2021	–	–	–	44	–	–	(38)
		–	–	–	39	–	–
Lim SH	2015	–	–	Median 2	0	0	–	(39)
		–	–	Median 1.82	0	0	–
Azzam G	2018	–	–	–	–	–	–	(40)
Li J	2020	–	–	–	–	–	–	(41)
Lee M	2021	30.8	–	Median 2	–	15.4	–	(42)
		58.3	–	Median 2	–	12.5	Median 19
		29.6	–	Median 2	–	11.1	–
Nadal E	2019	–	–	–	–	–	–	(43)