Screening for brain metastases in patients with advanced non-small cell lung cancer and an actionable genomic alteration: A structured literature review

Abstract

Background

Brain metastases (BM) frequently occur in patients with non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGA). Targeted therapies (TTs) improve outcomes, but differences in BM screening and eligibility criteria across trials make comparisons challenging. While stage IV NSCLC guidelines recommend BM screening, it is not mandatory, and imaging techniques vary.

Methods

Registrational and phase II/III trials of FDA/EMA-approved TTs for advanced NSCLC with AGA, published since 2012, were included. Main focus of the review was evaluation of baseline brain screening practices across trials. Information on BM follow-up, BM incidence, and BM-related outcomes was retrieved.

Results

Of 51 trials, 71% mandated baseline BM screening, and 27% mandated follow-up imaging for all patients. MRI was specified for BM assessment in 31% of the trials. BM incidence at baseline was high, up to 40% in the first-line setting. While most trials included patients with BM, eligibility criteria varied, and 43% of trials prespecified BM-related outcomes; 56% of phase III trials used BM as a stratification factor.

Conclusion

This review highlights the increasing attention to BM screening in NSCLC TT trials. However, substantial heterogeneity remains in BM eligibility, screening, outcomes, and follow-up. Standardizing these aspects in future trials is essential.

Key Points.

• • BM screening procedures, follow-up, and inclusion criteria vary in NSCLC TT trials.

• • Standardization is crucial to improve understanding of new drugs and patient care.

Brain metastases (BM) are detected in around 20% of patients with stage IV non-small cell lung cancer (NSCLC) at the time of initial diagnosis, increasing to up to 40% during the course of the disease.¹ In patients with NSCLC and actionable genomic alterations (AGA), the percentage of baseline BM is even higher, up to 35%.² BM is associated with a reduced quality of life (QoL) and poor prognosis.³

Targeted therapies (TT) have notably improved outcomes of patients with stage IV NSCLC and AGA, including those with BM. These drugs have intracranial activity, with a durable intracranial response, a reduction in the risk of BM development, and a subsequent improvement in patient’s QoL.⁴

In the different registrational trials of the currently approved TT comparison of the above-mentioned outcomes is difficult due to heterogeneity regarding baseline and follow-up BM screening. In a systematic review and meta-analysis, only 30% of the 86 tyrosine kinase inhibitor (TKI) trials published between 2000 and 2020 required brain imaging at baseline and in 10% only if there was a clinical suspicion of BM.⁵ In addition, different brain imaging modalities were used (computed tomography [CT] and magnetic resonance imaging [MRI]), despite MRI being recommended.^5,6 Follow-up (time-interval, subgroups) of BM during treatment varied across and within trials.⁵

Moreover, especially in the first TT trials, patients with BM were not eligible. In 2017, to make clinical trials more inclusive and representative, the American Society of Clinical Oncology (ASCO), Friends of Cancer Research (FoCR), and the US Food and Drug Administration (FDA) taskforce proposed modification to default commonly used eligibility criteria.⁷ The ASCO/FoCR/FDA recommendations resulted in an increasing number of trials including patients with BM.⁸ More recently, the FDA and the Response Assessment in Neuro-Oncology (RANO) BM working group released detailed guidelines for enrollment of BM patients in clinical trials, provided BM screening recommendations, and addressed CNS-related outcomes.^9,10

With an increasing number of approved TT and the associated improved survival outcomes, treatment selection for optimal CNS control becomes highly relevant. An improved understanding of BM incidence, inclusion criteria for patients with BM, presence and modality of BM screening at baseline and during follow-up, and CNS-related outcomes in the registrational clinical trials could help to identify the best management both for patients with (symptomatic or asymptomatic) and without BM. This information could guide BM screening, selection of the right systemic therapy, optimal combination of systemic and local therapies, follow-up strategies for CNS efficacy, and avoidance of unnecessary radiological tests and toxicities of both systemic and local therapies.

The goal of this review is to obtain a complete overview of BM screening methods (at baseline and during treatment) required in the registrational and phase III clinical trials of the currently approved (by FDA and/or European Medicines Agency [EMA]) TT for treatment of stage IV NSCLC with AGA. Furthermore, we aim to evaluate the percentage, characteristics, and outcomes of patients with BM enrolled to those trials.

Methods

Registrational trials of the currently FDA and/or EMA-approved TT for advanced NSCLC (epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], ROS1, V-Raf murine sarcoma viral oncogene homolog B (BRAF), MET exon 14 skipping, human epidermal growth factor receptor 2 (HER2), EGFR exon 20 insertion, neurotrophic tyrosine receptor kinase [NTRK], Kirsten rat sarcoma [KRAS], and rearranged during transfection [RET]) from 2012 until November 2024 were included. In addition, phase III trials were included, or phase II trials if the TT’s approval was based on phase I/II studies. Further details are reported in the Supplementary Data.

Results

EGFR

Six TKIs (erlotinib, gefitinib, afatinib, dacomitinib, osimertinib, and lazertinib) and 1 bispecific antibody (amivantamab) are currently approved as first-line and/or subsequent treatment for patients with EGFR-mutated advanced NSCLC, alone or in combination with other drugs (chemotherapy, anti-VEGF). The included clinical trials are depicted in Table 1.

Table 1.

Overview of BM Baseline Screening, Follow-Up Methods, Eligibility Criteria, and Outcomes in the EGFR-TT Trials

Trial	Treatment	Enrollment period/protocol available	Prespecified BM-related outcome/stratification factor	BM-screening at baseline (image modality)	Follow-up BM-screening	BM inclusion criteria	% included BM/% of patients with BM with intracranial radiotherapy	Outcomes in patients with BM/BM-related outcomes
IFUM111 Phase IV 2014	First line gefitinib	2010–2012/No	No/NA	NR	NR	NR	NR/NR	NR
NEJ00912,13 Phase III 2019	First line gefitinib + carboplatin + pemetrexed vs gefitinib	2011–2015/Yes	No/No	All patients (MRI)	Brain imaging every 2 months if BM at baseline	Asymptomatic (enrollment accepted if symptoms disappear after radiotherapy)	26% (88/342)/9% (10% gefitinib + chemo, 9% gefitinib)	OS HR: 0.73 (BM present) vs. 0.79 (BM absent) in favor of gefitinib + chemo
EURTAC14 Phase III 2012	First line erlotinib vs platinum-based chemo	2007–2011/No	No/No	NR	NR	Asymptomatic and stable with medical treatment	12% (20/173)/NR	NR
JO2556715 Phase II 2014	First line erlotinib + bevacizumab vs erlotinib	2011–2012/No	NA/NA	NR	NR	Excluded	NA/NA	NA
RELAY16 Phase III 2019	First line erlotinib + ramucirumab vs placebo	2016–2018/Yes	NA/NA	All patients (MRI)	Only if clinically indicated	Excluded	NA/NA	NA
LUX-Lung 217 Phase II 2012	Second line afatinib	2007–2009/No	No/NA	Subjects with known or suspected BM (CT or MRI)	Only if clinically indicated	Asymptomatic and stable for at least 4 weeks not requiring treatment with anticonvulsants or steroids	24% (31/129)/NR	ORR BM group 65%
LUX-Lung 3 18,19 Phase III 2013	First line afatinib vs cisplatin + pemetrexed	2009–2011/Yes	No/No	Subjects with known or suspected BM (MRI or CT)	Brain imaging every 6 weeks if BM at baseline for the first 48 weeks, every 12 weeks thereafter	Asymptomatic and stable for at least 4 weeks not requiring treatment with anticonvulsants or steroids	14% (49/345)/34% WBRT (35% afatinib, 33% chemo)	PFS HR 0.54 (BM present) vs 0.48 (BM absent) in favor of afatinib. ORR in patients with BM: 70% (afatinib) vs 20% (chemotherapy). DCR in patients with BM: 95% (afatinib) vs 80% (chemo). Rate of CNS progression in patients with BM: 45% (afatinib) vs 33% (chemotherapy) Rate of CNS progression in patients without BM: 7.2% (afatinib) vs 3.7% chemotherapy. Median time to CNS progression in months: 15.2 (afatinib) vs 5.7 (chemo)
LUX-Lung 6 19,20 Phase III 2014	First line afatinib vs cisplatin + gemcitabine	2010–2011/Yes	No/No	Subjects with known or suspected BM (MRI or CT)	Brain imaging every 6 weeks if BM at baseline for the first 48 weeks, every 12 weeks thereafter	Asymptomatic and stable for at least 4 weeks not requiring treatment with anticonvulsants or steroids	14% (52/364)/26% WBRT (21% afatinib, 33% chemo)	PFS HR: 0.47 (BM present) and 0.22 (BM absent) in favor of afatinib. ORR in patients with BM: 75% (afatinib) vs 28% (chemotherapy). DCR in patients with BM: 89% (afatinib) vs 72% (chemo). Rate of CNS progression in patients with BM: 21.4% (afatinib) vs 27.8% (chemo) Rate of CNS progression in patients without BM: 5.4% (afatinib) vs 4.7% (chemo). Median time to CNS progression in months: 15.2 (afatinib) vs 7.3 (chemo)
LUX-Lung 721 Phase IIb 2016	First line Afatinib vs gefitinib	2011–2013/No	No/Yes	All patients (MRI or CT)	NR	Asymptomatic untreated or treated, not requiring corticosteroid and/or anticonvulsant treatment (at least 1 week off before study randomization)	16% (50/319)/NR	Median PFS in months in the BM group 7.2 (afatinib) vs 7.4 (gefitinib). PFS HR 0.76 (BM present) and 0.74 (BM absent) in favor of afatinib
ARCHER 105022 Phase III 2017	First-line dacomitinib vs gefitinib	2013–2015/Yes	NA/NA	All patients (MRI or CT)	Only if clinical symptoms or neurologic examination suspect for BM	Excluded	NA/NA	NA
AURA 323,24 Phase III 2017	Second line osimertinib vs platinum-based+pemetrexed chemo	2014–2015/Yes	No/No	Subjects with known or suspected BM (MRI or CT)	Brain imaging every 6 weeks if BM at baseline	Asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment	28% (116/419)/41% (37% osimertinib, 49 % chemo)	BM group osimertinib: CNS ORR 40% (70% for measurable BM), CNS ORR 64% in patients who received brain RT < 6 months of randomization and 34% in patients with no prior brain RT or brain RT > 6 months before randomization. CNS DCR 93% (measurable BM). CNS DoR 8.9 months. CNS PFS 11.7 months. BM group chemotherapy: CNS ORR 17% (31% for measurable BM), CNS ORR 22% in patients who received brain RT< 6 months of randomization and 5% in patients with no prior brain RT or brain RT > 6 months before randomization. CNS DCR 63% (measurable BM). CNS DoR 5.7 months. CNS PFS 5.6 months.
FLAURA25–27 Phase III 2018	First-line osimertinib vs standard EGFR-TKIs (gefitinib/ erlotinib)	2014–2016/Yes	Yes/No	Subjects with known or suspected BM (MRI or CT)	Brain imaging every 6 weeks if BM at baseline for the first 18 months, every 12 weeks thereafter	Asymptomatic or symptomatic but stable for at least 4 weeks and off steroids. Any previous definitive treatment had to be completed at least 2 weeks before initiation	21% (116/556)/ 24% (25% osimertinib and 24% standard EGFR-TKI)	BM group osimertinib: CNS ORR 66% (91% for measurable BM); CNS ORR (measurable BM) 100% if prior RT and 88% if no prior RT. CNS DCR 95% (measurable BM). CNS PFS not reached, CNS progression 20%. BM group standard EGFR TKIs: CNS ORR 43% (68% for measurable BM); CNS ORR (measurable BM) 70% if prior RT and 67% if no prior RT. CNS DCR 89% (measurable BM). CNS PFS 13.9 months, CNS progression 39%.
FLAURA 228,29 Phase III 2023	First-line osimertinib + platinum-based + pemetrexed chemo vs osimertinib	2020–2021/Yes	Yes/No	All patients (MRI /CT)	Brain imaging if BM at baseline at week 6, 12 and every 12 weeks thereafter All patients at time of systemic PD	Stable. Any previous radiation treatment or glucocorticoid therapy had to be completed at least 2 weeks before initiation of the trial treatment	41% (226/557)/15% (14% osimertinib + chemotherapy, 17% osimertinib)	CNS PFS HR 0.58 (0.40 for measurable BM) in favor of osimertinib + chemotherapy. BM group osimertinib + chemo: CNS ORR 73% (88% for measurable BM). CNS ORR in patients with prior RT 78%. CNS DoR not reached. BM group Osimertinib: CNS ORR 69% (87% for measurable BM). CNS ORR in patients with prior RT 71%. CNS DoR 26.2 months. 25% (40/161) of patients without baseline BM developed new BM in the osimertinib + chemo group compared to 27% (47/174) in the osimertinib group.
MARIPOSA 230 Phase III 2024	Second or subsequent line Arm A: lazertinib + amivantamab+ carboplatin + pemetrexed Arm B: amivantamab + carboplatin + pemetrexed Arm C: carboplatin +pemetrexed	2021–2023/Yes	Yes/Yes	All patients (MRI)	All patients at week 6, 12, and every 12 weeks thereafter	Asymptomatic or previously treated and stable (off corticosteroid or receiving ≤10 mg/day prednisone or equivalent) for at least 2 weeks before randomization Any definitive local therapy must have been completed at least 14 days prior to randomization	45% (298/657)/47% (51% Arm A, 41% arm B, 47% arm C)	BM group: IC PFS in months 8.3 (arm A), 12.5 (arm B), 12.8 (arm C). IC PFS HR 0.55 (arm B vs C) and 0.58 (arm A vs C). BM group without prior RT: IC PFS in months 11.1 (arm A), not estimable (arm B), 6.3 (arm C). IC PFS HR 0.36 (arm B vs C) and 0.44 (arm A vs C).
MARIPOSA31 Phase III 2024	First line Arm A: amivantamab + lazertinib Arm B: osimertinib Arm C: lazertinib	2020–2022/Yes	Yes/Yes	All patients (MRI)	Every 8 weeks for the first 30 months thereafter every 12 weeks if BM at baseline otherwise every 24 weeks	Asymptomatic or previously treated and stable (off corticosteroid or receiving ≤10 mg/day prednisone or equivalent) for at least 2 weeks before randomization.	41% (436/1074)/NR	BM group PFS in months: 18.3 (arm A) vs 13.0 (arm B)

Abbreviations: BM, brain metastases; NR, not reported; CT, computed tomography; MRI, magnetic resonance imaging; TKIs, tyrosine kinase inhibitor; NA, Not applicable; PFS, progression-free survival; ORR, objective response rate; DoR, duration of response; DCR, disease control rate; CNS, central nervous system; IC, intracranial; PD, progressive disease; WBRT, whole brain radiotherapy; HR, hazard ratio; RT, radiotherapy.

Only 7/15 (47%) analyzed trials^11–31 required baseline brain screening for all included patients (Table 1); baseline brain imaging was limited to subjects with known or suspected BM in 5 other (33%) trials while for the 3 (20%) remaining studies this information was not reported in the published manuscript and the original protocol was not available. Of note, the studies that mandated brain screening for the entire study population were the ones most recently published or those where all patients with BM were excluded. Different brain imaging modalities (MRI or CT) were used. Only 4 trials (27%) mandated brain MRI, in the FLAURA-2 study MRI was preferred but not mandatory.

Data regarding brain imaging follow-up were reported in 11 (73%) trials; 8 required brain follow-up only for patients with baseline BM or clinical suspicion of newly developing BM (Table 1). No data are available about brain follow-up in the JO25567 trial, in which patients with BM were excluded. Notably, the FLAURA-2 trial mandated brain imaging for all patients both at baseline and at systemic progression. Overall, brain follow-up was preferably performed with the same imaging modality used at baseline and was aligned with extracranial tumor assessment. The only exception was the MARIPOSA trial, in which follow-up brain MRI in patients without BM at baseline was scheduled every 24 weeks.

As mentioned earlier, 3/15 (20%) of the reviewed trials explicitly excluded patients with BM. Among the remaining studies, the baseline incidence of BM varied significantly, ranging from 12% to 45% (Figure 1). This variation is likely influenced by the different trial settings (line of treatment), with the highest incidence observed in the MARIPOSA II (second line) trial. Nonetheless, this also reflects a positive trend toward increased attention and a better representation of patients with BM in RCTs. However, in all the trials that allowed patients with BM, only those with asymptomatic, stable lesions and not requiring anticonvulsants or steroids (or receiving ≤10 mg/day prednisone) were enrolled. Inclusion criteria of the different trials are reported in Table 1.

Figure 1.

Baseline incidence of brain metastasis in phase II/III EGFR trials.

Prespecified exploratory outcomes related to BM and intracranial activity of the experimental EGFR inhibitors (eg, intracranial [IC] objective response rate [ORR], duration of response [DoR], and progression-free survival [PFS]) were included in 4 (27%) trials (Table 1).

Although older studies did not include specific BM-related outcomes, BM subgroup analyses were performed in 6 (40%) of these trials, yielding varied results depending on the drug/combination used and the treatment setting (Table 1). Additionally, only 4 trials incorporated BM as a stratification factor.

The number of patients previously treated with intracranial radiotherapy was reported in 7 (47%) trials. In the AURA 3 and FLAURA study, CNS-ORR according to previous RT was reported: benefit with osimertinib was seen irrespective of prior brain radiotherapy. However, detailed treatment-specific information (eg, dose, technique, fractionation, and timing) and outcomes are often lacking.

ALK

Several new therapies have been developed for ALK-positive NSCLC over the past decade. Currently, five TKIs are approved by the EMA and FDA as the first or subsequent treatment of ALK-positive NSCLC (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib).

Of these five approved TKIs, we analyzed 11 phase III RCTs.^32–46 With the exception of the PROFILE-1029 trial, 10 (91%) trials explicitly required baseline brain imaging for all patients (Table 3). Only three trials (27%) mandated MRI, while the majority (55%) allowed the use of either CT or MRI (Table 2). The three trials requiring MRI screening were also the most recent, reflecting a positive trend toward MRI usage in recent years.

Table 3.

Overview of BM Screening, Follow-Up Methods, Eligibility Criteria, and Outcomes in ROS1 Trials

Trial	Treatment	Enrollment period/protocol available	Prespecified BM-related outcome	BM-screening at baseline (image modality)	Follow-up BM-screening	BM inclusion criteria	% included BM/% of patients with BM with intracranial radiotherapy	Outcomes in patients with BM/BM-related outcomes
PROFILE 100147 Phase I 2014	First or subsequent line crizotinib	2010-2013/Yes	NR	Subjects with known or suspected BM (CT or MRI)	Brain imaging every 8 weeks if BM at baseline	Only treated, stable BM for at least 4 weeks	NR/NRa	NR
PROFILE II-00-120148 Phase II 2018	three or fewer lines of prior systemic therapy crizotinib	2013-2015/No	NR	All patients (NR)	Brain imaging every 8 weeks if BM at baseline	Asymptomatic or more than 2 weeks neurologically stable if treated	18% (23/127)/NR	Median PFS in BM group 10.2 months vs 18.8 months in the no BM group
AcSé49 Phase II 2019	First or subsequent line crizotinib	2013-2018/Yes	NR	All patients (CT or MRI)	Brain imaging every 8 weeks if BM at baseline	Only treated asymptomatic BM	22% (8/37)/NRa	NR
EUCROSS50 Phase II 2019	First or subsequent line crizotinib	2014-2015/No	NR	All patients (MRI)	If BM at baseline: Every 6 weeks first 6 months, every 8 weeks the following 6 months, and every 12 weeks thereafter	Asymptomatic without increasing steroid dose	21% (7/34)/43%	Median PFS and OS in BM group 9.4 months and 13.0 months vs 23.7 and not reached in the no BM group. BM group 4/17 had CNS progression only.
METROS51 Phase II 2019	Second or subsequent line crizotinib	2014-2017/No	NR	NR	NR	Asymptomatic BM only	23% (6/26)/33%	In BM group: 50% (3/6) had IC-progression only and 33% (2/6) had IC and extracranial progression. 33% (2/6) had a best IC response of CR
Integrated analysis of three phase I/II trials b52,53 2020	First or subsequent line entrectinib	2012-2018/Yes	Yes	All patients (CT or MRI)	If BM at baseline every 8 weeks until 12 months, thereafter every 12 weeks	Asymptomatic or treated and controlled after finishing local treatment (1 week for SRT and 2 weeks for WBRT). Steroids and seizure prophylaxis allowed	43% (23/53) in early report, 35% (60/172) in updated results/45% (27/60)	IC ORR 52% (80% in patients with measurable BM) and a median DoR of 12.9 months. Median IC-PFS for all patients with BM was 8.4 months. 79% (n = 38) experienced an IC-PFS event (28 patients had CNS progression and 10 died). Time to CNS progression was 13.6 months in patients with baseline BM. 5% (5/110) of no BM group reported new CNS metastases.
TRIDENT 154 Phase I-II 2024	First or subsequent line repotrectinib	2017-2022/Yes	Yes	All patients (MRI)	All patients every 8 weeks until 12 months, then every 12 weeks until 24 months thereafter every 16 weeks	Asymptomatic untreated or treated after finishing local treatment (1 week for SRT and 2 weeks for WBRT). Stable or decreasing dose of steroids and levetiracetam was allowed	Group without previous TKI: 24% (17/71)/NR Group with previous TKI 46% (16/56)/NR	Of patients with measurable BM 89% (8/9) had an IC-ORR in no previous TKI group compared to 38% (5/13) in previous TKI group; 83% and 60%, respectively had an intracranial response lasting at least 12 months. Estimated IC-PFS at 12 months for patients without baseline BM was 91% in the no previous TKI cohort vs 82% in previous TKI cohort

^aSince BM had to be locally treated before enrollment likely a very high percentage received previous cranial radiotherapy.

^bIntegrated analysis of 3 phase I/II trials: ALKA-372-001 (Phase I), STARTRK-1 (phase I) and STARTRK-2 (phase II).

Abbreviations: BM, brain metastases; NR, not reported; CT, computed tomography; MRI, magnetic resonance imaging; TKIs, tyrosine kinase inhibitor; NA, Not applicable; PFS, progression-free survival; ORR, objective response rate; DoR, duration of response; DCR, disease control rate; CNS, central nervous system; IC, intracranial; PD, progressive disease.

Table 2.

Overview of BM Screening, Follow-Up Methods, Eligibility Criteria, and Outcomes in Phase 3 Randomized Controlled ALK-TKI Trials

Trial	Treatment	Enrollment period/protocol available	Prespecified BM-related outcome/stratification factor	BM-screening at baseline (image modality)	Follow-up BM-screening	BM inclusion criteria	% included BM/% of patients with BM with intracranial radiotherapy	Outcomes in patients with BM/BM-related outcomes
PROFILE-100732 2013	Second-line crizotinib vs chemotherapy	2010–2012/Yes	No /Yes	All patients (CT or MRI)	Brain imaging every 6 weeks if BM at baseline	Asymptomatic (untreated) or treated and stable BM for 2 weeks	35% (120/347)/NR	PFS HR: BM 0.67 (BM present) vs. 0.43 (BM absent) in favor of crizotinib
PROFILE-101433,43 2014	First-line crizotinib vs chemotherapy	2011–2013/Yes	Yes/Yes	All patients (CT or MRI)	Brain imaging every 6 weeks if BM at baseline otherwise every 12 weeks	Only treated, stable BM without steroids for 2 weeks	27% (92/343)/NRa	PFS HR: BM 0.57 (BM present) vs 0.46 (BM absent) in favor of crizotinib. IC-TTP (HR, 0.60; 95% CI 0.34–1.05) in favor of crizotinib. IC-DCR at 24 weeks: 56% in crizotinib vs 25% in chemotherapy group (P = .006). BM group: 38% IC-PD only in crizotinib group vs 23% in chemotherapy. No BM group: 19% IC-PD only in crizotinib compared to 6% in chemotherapy.
PROFILE-102934 2018	First-line crizotinib vs chemotherapy	2012–2014/No	Yes/No	NR	Brain imaging every 6 weeks if BM at baseline	Only treated, stable BM	26% (53/207)/NRa	PFS HR: BM 0.50 (BM present) vs 0.37 (BM absent), Median ICC-TTP HR 0.67 (95% CI 0.34–1.34) favoring crizotinib. 17% (14/83) of patients without baseline BM developed new BM in the crizotinib group compared to 7% (5/71) in the chemotherapy group.
ASCEND-435 2017	First-line ceritinib vs chemotherapy	2013–2015/Yes	Yes/Yes	All patients (CT or MRI)	Brain imaging every 6 weeks if BM at baseline	Asymptomatic or treated and stable BM for 2 weeks, stable dose of corticosteroids allowed	32% (121/376)/42% (40% ceritinib, 42% chemo)	Median PFS in months in the BM group 10.7 (ceritinib) vs 6.7 (chemotherapy). IC-ORR: ceritinib 46% (73% in patients with measurable BM). Ceritinib BM group 48% (15/31) IC-PD only, ceritinib no BM group: 30% IC-PD only
ASCEND-536 2017	Ceritinib vs chemotherapy after previous chemotherapy and crizotinib	2013–2015/No	Yes/Yes	All patients (CT or MRI)	Brain imaging every 6 weeks if BM at baseline	Asymptomatic (untreated) or treated and stable BM without steroids	58% (134/231)/56% (56% ceritinib, 57% chemo)	Median PFS in months in BM group 4.4 ceritinib and 1.5 chemotherapy. In the BM group 51% had IC-PD only (21/41). In the no BM group 15% had IC-PD only. IC-ORR in patients with measurable BM 35%
ALUR37 2018	Alectinib vs chemotherapy after chemotherapy and crizotinib	2015–2017/No	Yes/Yes	All patients (CT or MRI)	All patients every 6 weeks	Symptomatic BM ineligible for radiotherapy allowed, treated and stable BM or asymptomatic (untreated)	71% (76/107)/54% (53% alectinib, 54% chemo)	PFS BM group in months: 9.7 (alectinib) vs 1.4 (chemotherapy). IC-ORR: alectinib 36% (54.2% in patients with measurable BM). IC-DCR alectinib 80%.
ALEX38,44 2017	First-line alectinib vs crizotinib	2014–2016/Yes	Yes/Yes	All patients (CT or MRI)	All patients every 8 weeks	Asymptomatic (untreated) BM or treated with radiotherapy and stable for 2 weeks	40% (122/303)/38% (39% alectinib, 36% crizotinib)	IC-PFS, alectinib vs crizotinib, HR 0.40 (in BM group) and HR 0.51 (no BM group). Patients BM group: CNS progression without prior non-CNS PD alectinib 18.8% and crizotinib 56.9%. Patients no BM group: CNS progression without prior non-CNS PD alectinib 6.8% and crizotinib 37.6%. IC-ORR in patients without prior RT: alectinib 74% (78.6% in patients with measurable BM) vs 24.3% (40% in patients with measurable BM) in crizotinib.
J-ALEX39,45 2017	First-line alectinib vs crizotinib	2013–2015/No	Yes/No	All patients (NR)	All patients every 8 weeks	Only asymptomatic BM, untreated or treated without steroids for 2 weeks and after finishing radiotherapy (2 weeks for SRT and 4 weeks for WBRT)	21% (43/207)/46% (38% alectinib, 52% crizotinib)	BM group: Time to CNS progression HR 0.51 (95% CI 0.16–1.64) in favor of alectinib. No BM group: Time to CNS progression 0.19 (95% CI 0.07–0.53) in favor of alectinib.
ALESIA40 2019	First-line alectinib vs crizotinib	2016–2017/No	Yes/Yes	All patients (MRI)	All patients every 8 weeks	Asymptomatic (untreated) or treated and stable for 2 weeks	36% (67/187)/17% (18% alectinib, 22% crizotinib)	Time to CNS progression, alectinib vs crizotinib, csHR 0.14. IC-ORR: alectinib 73% (94% in patients with measurable BM) vs 22% (29% in patients with measurable BM) in crizotinib
ALTA-1L41 2018	First-line brigatinib vs crizotinib	2016–2017/Yes	Yes/Yes	All patients (MRI)	All patients every 8 weeks	Treated or asymptomatic untreated and treated BM without increasing dose of steroids or need for anticonvulsants	29% (81/275)/46% (45% brigatinib, 46% crizotinib)	IC-ORR: brigatinib 83% (78% in patients with measurable BM) vs 33% (29% in patients with measurable BM) in crizotinib. 12-month survival without icPD in BM group: brigatinib 67%, crizotinib 21%
CROWN42,46 2020	First-line lorlatinib vs crizotinib	2017–2019/Yes	Yes/Yes	All patients (MRI)	All patients every 8 weeks	Asymptomatic treated (4 weeks before enrollment) or untreated BM, stable corticosteroid dose allowed	26% (78/296)/23% (21% lorlatinib, 25% crizotinib)	IC-ORR: lorlatinib 60% (92% in patients with measurable BM) vs 11% (33% in patients with measurable BM) in crizotinib. Percentage of patients who were alive without CNS progression at 12 months was 96% with lorlatinib and 60% with crizotinib. Median time to IC- progression at 5 years for lorlatinib was NR (95% CI NR–NR) and 16.4 months (95% CI 12.7–21.9) with crizotinib; HR 0.06 (95% CI 0.03–0.12)

^aSince BM had to be locally treated before enrollment likely a very high percentage received previous cranial radiotherapy.

Abbreviations: BM, brain metastases; NR, not reported; CT, computed tomography; MRI, magnetic resonance imaging; TKIs, tyrosine kinase inhibitor; NA, Not applicable; PFS, progression-free survival; ORR, objective response rate; DoR, duration of response; DCR, disease control rate; CNS, central nervous system; IC, intracranial; PD, progressive disease; cs, cause specific; HR, Hazard ratio; CI, confidence interval; NR (in outcomes), not reached; RT, radiotherapy.

Notable variations in follow-up brain imaging protocols across the trials were identified. Four trials (36%) required follow-up brain imaging only if baseline BM were detected; in the PROFILE-1014 different time intervals for brain follow-up were used, depending on baseline BM presence (Table 2). In the remaining trials, mandated brain follow-up was aligned with extracranial imaging and performed with the same modality used at baseline.

The reported baseline incidence of BM varied widely across the trials, ranging from 22% to 71% (Figure 2), probably due to differences in trial settings.

Figure 2.

Baseline incidence of brain metastasis in phase III ALK trials.

Eligibility criteria regarding BM were mostly similar across the trials, permitting enrollment only for patients with stable BM. However, a clear definition of “stable BM” was often lacking. Two trials (PROFILE 1014 and PROFILE 1029) required that all patients with BM undergo prior local treatment (not specified which treatment).

Of note, 10 (91%) trials had prespecified BM-related outcomes and in 9 (82%) the presence of BM was a stratification factor. The investigated BM-related outcomes differed significantly between the trials (Table 2). Although IC-PFS was often reported, no distinction was made between symptomatic and asymptomatic BM.

With the newer generation ALK-TKIs, intracranial activity markedly improved compared with the first-generation TKI crizotinib, but also with second-generation TKI (Table 2).

ROS1

No phase III trials have been published for the three ROS1-TKIs currently approved (crizotinib, entrectinib, and repotrectinib [only FDA-approved]), therefore we evaluated the registrational trials and for crizotinib the subsequent phase II trials since its approval was based on a phase I trial.

Of the five trials analyzing crizotinib,^47–51 three (60%) mandated baseline brain imaging for all patients enrolled and in all trials follow-up brain imaging was limited to patients with BM at baseline (Table 3). In the registrational trials of entrectinib and repotrectinib baseline brain screening was mandated, either with CT or MRI.^52–54 TRIDENT-1 was the only trial that mandated follow-up brain imaging for all patients and not only for those with baseline BM.

Different eligibility criteria for patients with BM were used across the trials (Table 3). In PROFILE-1001 patients with BM were only enrolled if the BM were appropriately treated and neurologically stable for 4 weeks. However, a clear definition of “stable” and “appropriate treatment” was lacking. In contrast, in the entrectinib trials patients with asymptomatic or previously treated and stable BM were enrolled. Additionally, seizure prophylaxis and corticosteroids were permitted.

The baseline incidence of BM in the different trials varied between 20% and 35%, up to 46% in the subgroup of patients previously treated with a different ROS1-TKI in the TRIDENT-1 study (Supplementary Figure 1) Of those, 82% received crizotinib, suggesting a higher incidence of BM in those treated with earlier-generation TKIs.

None of the five crizotinib trials included prespecified BM-related outcomes, however some reported those outcomes. The trials evaluating newer agents specifically included prespecified BM-related outcomes (Table 3).

Other AGAs

BRAF V600

Two combinations of BRAF and MEK inhibitors are currently approved for treating advanced NSCLC harboring a BRAFV600 mutation. The phase II BRF113928 trial investigated dabrafenib (BRAF-inhibitor) as a single agent (cohort A) and in combination with trametinib (MEK-inhibitor), showing promising results in both pretreated (cohort B) and untreated patients (cohort C) with the combination approach.⁵⁵ More recently, the single-arm phase II PHAROS trial evaluated encorafenib (BRAF-inhibitor) plus binimetinib (MEK inhibitor) in treatment-naïve and previously treated patients with BRAF V600-mutant metastatic NSCLC, confirming the validity of BRAF and MEK inhibition.⁵⁶

Unlike the BRF113928 trial, which performed baseline BM imaging only for patients with known or suspected BM, the PHAROS trial mandated brain MRI for all patients (Supplementary Table 1). For both trials, brain follow-up was only required for those with baseline BM, aligned with the extracranial tumor assessment.

In the BRF113928 study, only patients with asymptomatic, untreated BM ≤1 cm, or those with treated, stable BM (for at least 3 weeks postlocal therapy) were included. Similarly, patients with untreated symptomatic BM were excluded from the PHAROS trial. Overall, only a few patients with BM were enrolled in both trials. BM at baseline was observed in 1/59 (1.7%) patients in cohort B and 2/36 (5.5%) in cohort C of the BRF113928 trial. Similarly, in the PHAROS trial, 8/98 patients (8.2%) had BM at baseline, specifically 4/39 in the previously treated group and 4/59 in the treatment-naive cohort.

Neither trial had prespecified endpoints to evaluate the intracranial activity of the investigational treatment or specific outcomes for patients with BM. However, the best response of noncomplete response or nonprogressive disease in the nontarget brain lesions was reported for all three patients in the BRF113928 trial. No patients of Cohort B had documented new BM as part of their progression, suggesting potential intracranial activity of the combination of dabrafenib and trametinib; no data are available regarding the incidence of new BM in Cohort C. In the PHAROS trial, in patients with BM at baseline, all four treatment-naïve patients had a systemic CR or PR, but none of the four previously treated patients had a systemic objective response. One patient from each group experienced intracranial progression.

MET exon 14 skipping

Capmatinib and tepotinib are two MET TKI currently approved as second-line treatment for patients with MET exon 14 skipping mutations. This is based on the results reported in the GEOMETRY mono-1 trial (phase II evaluating capmatinib in patients with cMET amplification and/or mutations, both pretreated and untreated) and in the VISION trial (phase II investigating tepotinib in treatment-naive and pretreated subjects with MET mutation).^57–59

Baseline brain screening was mandated for all patients in both trials; brain MRI was required in the VISION trial while both CT and MRI were allowed in the GEOMETRY mono-1.

In the GEOMETRY mono-1 trial follow-up brain imaging was indicated on day 1 of cycle 3 and every 6 weeks (following the same schedule as extracranial tumor assessment) in patients with BM at baseline with the same imaging modality used at baseline, or if clinically indicated. Conversely, in the VISION study brain imaging follow-up was scheduled for all patients using the same imaging modality used at baseline every 6 weeks until 9 months and every 12 weeks thereafter, but was not mandatory.

Patients with BM were eligible in both trials if neurologically stable and without increasing glucocorticoid dosage 2 weeks before enrollment. Previous SRT within 2 weeks or other locoregional treatment for BM within 4 weeks before the start of the study were considered exclusion criteria in the VISION trial. Notably, treatment of BM with anticonvulsant was allowed.

Of 373 patients enrolled in the GEOMETRY mono-1, 160 had a MET exon 14 skipping mutation, including 26 (16%) with baseline BM. No baseline BM incidence data were available for the 213 patients with MET amplification. Of the 152 patients treated with tepotinib, 23 (15%) had baseline BM.⁶⁰

No specific endpoints regarding BM were included in the study protocol of the GEOMETRY mono-1. However, an ad hoc blinded review (by an independent neuroradiologic review committee) was conducted in patients with BM at baseline. Twenty-eight patients (13 previously locally treated) were evaluated: 16 had an intracranial response, including 9 who had a CR (1 first line, 8 subsequent line), observed at the first assessment. Of note, in patients without previous cranial radiotherapy, IC-ORR was 67% (10/15, 5 CR all in subsequent line).

On the contrary, assessment of CNS tumor response was an exploratory endpoint of the VISION trial, including IC-ORR according to modified RANO-BM criteria, IC-DCR, IC-DoR, and IC-PFS. Among 15 patients with BM target lesions evaluable by RANO-BM (12 patients had received prior brain radiotherapy with a median time between radiotherapy and tepotinib of 6.4 weeks), IC-ORR in patients with measurable BM was 71% (5/7, 3 CR).⁶⁰ Furthermore, of 8 patients with nonmeasurable BM, 7 achieved intracranial disease control, including 3 with CR. Median PFS and OS in patients with BM at baseline were 8.5 and 17.5 months, respectively. New BM was detected in 6 of 152 patients, 4 of whom had baseline brain lesions.

HER2

Based on the phase II DESTINY-Lung02 trial, the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is currently approved for treating patients with HER2-mutated metastatic NSCLC progressing during/after at least one regimen of prior anticancer therapy containing platinum-based chemotherapy.⁶¹ In the trial baseline screening for BM was mandatory with CT or MRI for all subjects enrolled. Brain follow-up with CT or MRI every 6 weeks was required for patients with BM at baseline; conversely, those without BM did not need additional brain scans for tumor assessment unless clinically indicated.

Patients with clinically active BM, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants, were excluded from the study. Of the 152 patients included in the trial, 35/102 (34.3%) in the 5.4 mg/kg arm and 22/50 (44%) in the 6.4 mg/kg arm had baseline BM. Although the protocol did not specify BM-related outcomes, a subgroup analysis showed an ORR of 60.0% in patients with BM treated with T-DXd 5.4 mg/kg, highlighting the high activity of T-DXd.

Recently, FDA granted accelerated approval of T-DXd for patients with metastatic HER2-positive (IHC3+) NSCLC due to the primary results of Cohort 1 (n = 49, T-DXd 6.4 mg/kg) and Cohort 1a (n = 41, T-DXd 5.4 mg/kg) of the phase II DESTINY-Lung01 trial.⁶² Similar to the DESTINY-Lung02 trial, CT or MRI of the brain was mandatory for all patients at baseline and every 6 weeks as follow-up for all subjects with baseline BM. No follow-up brain imaging was required for subjects without BM, unless clinically indicated.

Patients with clinically inactive BM were included in the study. Subjects with treated BM who were no longer symptomatic and did not require treatment with corticosteroids or anticonvulsants could be enrolled if the completion of whole brain radiotherapy was >2 weeks ago.

At baseline, 17 (35%) patients in Cohort 1 and 12 (29%) in Cohort 1a presented with BM. At both doses of T-DXd, consistent confirmed ORRs were observed across the subgroups assessed, including patients with BM (ORR 29% and 50%, respectively). No specific endpoints regarding BM were included in the study protocol.

EGFR exon 20 insertion

Amivantamab, an EGFR-MET bispecific antibody, was the first biologic therapy to demonstrate efficacy in EGFR-mutated NSCLC harboring exon 20 insertion (Exon20ins) and is currently approved as monotherapy in patients who have progressed after platinum-based chemotherapy or as first-line treatment in combination with carboplatin and pemetrexed.

We analyzed cohort D of the dose-escalation phase I CHRYSALIS trial, which investigated preliminary efficacy of amivantamab in pretreated EGFR ex20ins NSCLC,⁶³ and the phase III, randomized PAPILLON trial, in which first-line chemotherapy was compared to the combination of chemotherapy and amivantamab.⁶⁴

Baseline brain screening (with MRI or CT) was required for all patients enrolled in the PAPILLON trial while baseline brain MRI was only mandated for patients in the dose-expansion cohorts of the CHRYSALIS study. In both trials, follow-up brain imaging was not mandatory and performed in accordance with local practice.

Participants with untreated BM were excluded from the CHRYSALIS trial. However, patients with locally treated metastases, clinically stable and asymptomatic for at least 2 weeks and not receiving corticosteroid for at least 2 weeks prior to study treatment were eligible. Similarly, in the PAPILLON study, subjects with treated BM were enrolled if asymptomatic, clinically stable, and not treated with glucocorticoids for at least 2 weeks before randomization.

Neither of the two study protocols included BM-specific endpoints; nevertheless, in the PAPILLON trial randomization was stratified according to the history of BM.

About 22% of the patients enrolled in the efficacy population (n = 81) of the CHRYSALIS study had baseline BM. ORR in this subgroup was 39%, comparable to the one achieved in the overall population (ORR 40%).

In the PAPILLON study, 35 (23%) and 36 (23%) patients presented BM at baseline in the experimental arm (n = 153) and in the chemotherapy alone (n = 155) group, respectively. The combination of amivantamab and chemotherapy improved PFS compared to chemotherapy regardless of baseline BM (HR 0.63; 95% CI 0.38–1.06).

NTRK

Currently, larotrectinib and entrectinib are FDA and EMA-approved for treating NTRK-positive NSCLC. Recently, repotrectib also received FDA approval in this setting based on the results of the NTRK-positive group (n = 88, the majority with NSCLC) included in the TRIDENT-1 study. Given the rarity of these AGA, the registration of all 3 drugs was based on data from phase I/II basket trials.

Different brain screening approaches were used across the trials. Regarding the trials included in the integrated analysis that led to larotrectinib approval in adults, baseline brain imaging was only required if brain involvement was suspected in phase I LOXO-TRK-14001, while it was mandatory for all the patients enrolled in phase II LOXO-TRK-15002.⁶⁵ Either brain CT or MRI were allowed in both trials. Follow-up brain imaging was only required for patients with BM at baseline. Baseline brain imaging and follow-up imaging used in the TRIDENT-1 and in the entrectinib trials were previously discussed.

Inclusion criteria differed across the trials and long enrollment periods were observed. In the LOXO-TRK-14001 patients with BM were initially not allowed to enroll; however, after an amendment patients with stable BM were included. Stable BM was defined as neurologically stable for 14 days before enrollment without requiring an increase in steroid dose. In the LOXO-TRK-15002 only patients with asymptomatic BM were eligible. The eligibility criteria related to BM for the entrectinib and repotrectinib trials were analyzed in the ROS1 paragraph.

The approval of larotrectinib was based on the results achieved in 55 patients (7% with lung tumors). Of those, only 1 patient had BM (primary tumor histology not specified) at baseline. In an updated analysis 20 additional patients with NSCLC were included, of which 50% had baseline BM.⁶⁶ Although intracranial response was not a study endpoint, CNS metastases were included as target lesions for two patients, with PR and CR. Neither of these patients previously received brain radiotherapy. In the updated results of entrectinib, 51 patients with NSCLC were included, of which 39% had BM at baseline (10 patients previously treated with brain radiotherapy, 50% ≥ 6 months before enrollment).⁶⁷ Prespecified BM-related outcomes showed promising efficacy in patients with baseline BM: IC-ORR for patients with measurable or nonmeasurable BM was 64.3% and IC-DoR was 55.7 months. Most recently, FDA early access data of repotrectinib showed that 5/5 patients (3 of which were TKI-pretreated) with measurable baseline CNS metastasis in the overall study population had an IC objective response; however, specific data on NSCLC is still lacking and longer follow-up with more patients is needed.⁶⁸

KRAS G12C

Sotorasib and adagrasib are currently approved for treating patients with advanced KRAS^G12C NSCLC with disease progression after first-line (chemo)immunotherapy.

Approval of sotorasib is based on the phase II CodeBreaK 100 trial in which only patients with stable and treated BM were enrolled.⁶⁹ Similar eligibility criteria were applied in the phase III CodeBreaK 200 trial and in the phase II (KRYSTAL-1) and phase III (KRYSTAL-12) trials evaluating adagrasib.^70–72 All four trials mandated baseline brain imaging for every patient; however, follow-up brain imaging was restricted to patients with baseline BM in three of them. The KRYSTAL-12 was the only trial that mandated follow-up brain imaging for the entire study population: every 6 weeks (aligned with extracranial follow-up) for patients with baseline BM and every 12 weeks for those without. Brain MRI was mandatory in the sotorasib trials. In contrast, the KRYSTAL-1 trial permitted both brain MRI and CT, while the imaging modality in the KRYSTAL-12 trial was not specified.

Baseline incidence of BM varied across the different studies (21% in CodeBreaK 100, 34% in CodeBreaK 200, 36% in KRYSTAL 1, 25% in KRYSTAL 12). Unlike the CodeBreaK 200 trial, the KRYSTAL-12 trial did not incorporate BM as a stratification factor. Furthermore, none of the trials included prespecified BM-related endpoints but exploratory and subgroup analyses were performed in most of them. In a post hoc analysis of CodeBreak-100 an IC-DCR of 87.5% (100% in nontarget BM, 33% in target BM) was reported.⁷³ Similar results were achieved with adagrasib in the KRYSTAL-12 trial (IC-DCR 82% adagrasib, IC-ORR 24% [40% for measurable BM]). In CodeBreaK 200, time to CNS recurrence in the full analysis set was 9.6 months with sotorasib versus 5.4 months with docetaxel (HR 0.84 [95% CI: 0.32, 2.19], P = .37).⁷⁴

Another exploratory analysis of the KRYSTAL-1 trial assessing 33 patients with measurable baseline CNS involvement according to RANO BM showed IC-ORR of 33.3%, IC-DoR 11.2 months, IC-PFS 5.4 months. Of these, 27 patients (81.8%) received radiation therapy before adagrasib treatment (59% within 3 months before study entry).⁷¹ However, the observed IC-ORR in all four trials may have been influenced by prior local treatments, as all patients were required to undergo such treatments before enrollment. Notably, there is one phase IB trial that evaluated adagrasib in 19 patients with measurable untreated CNS metastases and showed an IC-ORR of 42% (including 3 CR and 5 PR).⁷⁵

RET

Two TT are now available for treating RET-positive NSCLC: selpercatinib and pralsetinib. Their approvals were initially based on phase I/II trials (LIBRETTO-001 for selpercatinib and ARROW for pralsetinib).^76,77 More recently the phase III trial LIBRETTO-431 evaluating selpercatinib has also been published.⁷⁸

Baseline screening for BM was mandatory in all trials, except for the phase I cohort of LIBRETTO-001, which required BM screening only for patients with suspected BM. Brain MRI or CT were both allowed in ARROW and LIBRETTO 431, the LIBRETTO-001 trial required MRI. In both phase I/II trials, follow-up brain imaging was mandated only for those with baseline BM while in the LIBRETTO 431 it was later extended to all patients.

Eligibility criteria for patients with BM were similar across the trials: patients with BM were eligible if they were asymptomatic or had been neurologically stable for >2 weeks before enrollment, without requiring an increasing corticosteroid dose. However, in the LIBRETTO-431 trial, corticosteroid therapy for BM had to be stopped at least two weeks before recruitment.

The highest incidence of BM was observed in the ARROW trial (37%), compared to 31% and 20% in the LIBRETTO-001 and LIBRETTO-431, respectively.

All trials reported BM-related outcomes and presence of BM was a stratification factor in the LIBRETTO-431. In LIBRETTO-001 the IC-ORR of patients with measurable BM was 91% (10/11), including 3 CR. Interestingly, in an updated report from the LIBRETTO-431, selpercatinib showed impressive intracranial protection, with a cumulative 12-month incidence rate of new BM of only 1% in patients without baseline BM and a 12-month cumulative incidence of BM progression of 22% in those with preexisting BM (compared to 15% and 34% in the control group, respectively).⁷⁹ In the ARROW trial, the IC-ORR rate for measurable BM was 70% (7/10, all pretreated).⁸⁰ Of note, 4 patients received previous brain radiotherapy. Furthermore, median intracranial DoR was 10.5 months (95% CI 5.5-12.6 months).

Summary of the Results

Baseline and Follow-Up Brain Imaging

Our analysis, including 51 trials evaluating the different approved TT for AGA, showed that a mandatory baseline screening for BM in all enrolled patients was required in 71% (36/51) of the studies. In ten (20%) trials, a baseline assessment of BM was mandated only for those with symptoms suggestive of CNS metastases, a previous history of BM, or only mandatory for a separate cohort (Figure 3). For five (10%) trials, published primarily between 2012 and 2017, screening was not mentioned in the trial methods or the original protocol (when available). Sixteen trials (31%) mandated the use of MRI for BM evaluation, while most others permitted the use of either MRI or CT scans.

Figure 3.

Percentage of trials with baseline screening for BM sorted per actionable genomic alteration. n = number of trials, *In the CHRYSALIS trial in the EGFR exon 20 insertion group baseline screening for all patients was only mandatory for the dose expansion cohort; in the LOXO-TRK-14001 + 15002 phase I/II basket trial in the NTRK group, baseline screening for all patients was only mandatory for the LOXO-TRK 15002; in the LIBRETTO-001 in the RET group baseline screening was only mandatory for the phase II cohort.

In terms of BM follow-up, 27 (53%) trials restricted follow-up to patients with BM at baseline. Conversely, 14 trials (27%) conducted brain follow-up for the entire study population. Of these, 11 trials aligned brain follow-up with extracranial follow-up. In the other 3 trials, where extracranial follow-up was not aligned with brain follow-up, brain imaging intervals varied depending on the presence of BM at baseline. The imaging modality used to assess BM during follow-up varied across the trials, but the same modality used at baseline was suggested.

BM Eligibility Criteria and Study Protocol Availability

Only 3 trials (6%), specifically older EGFR trials, explicitly excluded all patients with BM. In one trial, BM eligibility was not reported. Most other trials permitted enrollment of patients with BM, though specific inclusion criteria differed widely, mainly including asymptomatic patients, with stable lesions, not requiring treatment with anticonvulsants or steroids (or receiving ≤10 mg/day prednisone). In 10 trials patients with BM were only allowed if they were previously locally treated, influencing BM-related outcomes. Study protocols were available for 71% of the trials, while 29% (15 trials) lacked accessible full protocols hampering retrieval of full eligibility.

Prespecified BM-Related Outcomes, Stratification Factors, and Previous Radiotherapy Reported

BM-related outcomes were predefined in nearly half of the trials (43%), mainly as secondary or exploratory endpoints. However, subgroup analyses of patients with BM were performed in another 22 trials (43%). Furthermore, in 16 (31%) of all the trials the incidence of intracranial progression in patients without baseline BM was also evaluated.

In 56% of the phase III trials (15/27), BM presence was used as a stratification factor allowing for accurate comparison of BM-related outcomes between the treatment arms. Additionally, 23 trials (45%) reported data on prior brain radiotherapy among participants.

Discussion

Almost three-quarters of the studies evaluating the different approved TTs for AGA, with publication dates between 2012 and 2024, mandated baseline BM screening for all patients enrolled regardless of symptoms. If compared to the results reported in a systematic review, including trials between 2000 and November 2020,⁵ in which approximately 50% of the TKI trials included did not screen for BM, our work highlights increasing attention to a more comprehensive baseline staging that includes assessment of the CNS.

Baseline screening for BM in stage IV NSCLC is advised by current guidelines but is only strongly recommended if a patient has neurological symptoms suggestive of CNS involvement.^81,82 However, as noted in our review, the incidence of BM at baseline in patients with NSCLC and AGA is high. Although the specific percentage of asymptomatic patients with BM detected at baseline screening is not reported in most trials included in our review, real-world data and a prospective study (n = 496) suggest that up to 50% of patients with BM are asymptomatic.^1,83 Given the improving intracranial efficacy of newly approved drugs and the possibility to sequence different TT for several AGA, knowing the presence of BM at baseline, even if asymptomatic, is crucial for selecting the most appropriate systemic therapy. For example, in ALK-positive NSCLC, the proved absence of BM may support use of alectinib as first-line treatment, especially in older or more frail patients, due to the more favorable safety profile; on the contrary, patients with BM should be preferably treated with first-line lorlatinib. Furthermore, this information is needed for the discussion whether a patient needs upfront local therapy, as this would probably be the first choice to treat BM if systemic treatment with good CNS activity is not available.⁸⁴ While brain radiotherapy remains the treatment of choice in symptomatic BM, it may be postponed in asymptomatic patients by the upfront selection of systemic treatment with increased penetration of the blood–brain barrier (e.g lorlatinib, T-DXd, combination of osimertinib+chemotherapy), avoiding both short and long term radiotherapy-related complications including fatigue, neurocognitive decline, and radionecrosis. Conversely, a diagnosis of screening-detected BM in patients can cause anxiety and distress in patients themselves and relatives. However, as seen in a small qualitative study,⁸⁵ the experienced levels of distress diminished over time, especially after nonprogressive disease owing to effective systemic therapy.

Despite increased adoption of baseline screening for BM in RCTs, our results underline that heterogeneity remains regarding the imaging modality used. In the oldest studies, both CT and MRI were allowed, but the percentage of patients screened with each technique was not reported; this could have influenced the baseline incidence of BM due to lower sensitivity and specificity of CT for BM. For this reason, in the most recent trials MRI was required. Notably, rather than the modality chosen at baseline, as reported in all the analyzed trials, it is crucial that the same modality is consistently used during follow-up to accurately assess treatment response in patients with BM at baseline.

Our encouraging findings about the implementation of baseline brain screening in clinical trials reflect the shift in trial design that occurred after the release of the FDA and RANO guidelines.^9,10 These guidelines not only provided recommendations for BM screening but also suggested broader eligibility criteria for patients with BM. As noticed in our review, BM inclusion criteria widely differ across the studies, limiting the generalizability of the study findings. Additionally, a clear definition of asymptomatic patients is often lacking in the study protocols, and different criteria have been applied to define symptoms across trials, as standardized and validated tools are still unavailable. Finally, further details to clarify if patients with BM differ from the other trial population in any type are often not reported. Therefore, translating the results from these trials to the overall population with BM is often challenging, as the findings are confined to a specific subgroup that closely matches the characteristics of the enrolled participants. Broader eligibility criteria for patients with BM, excluding only those with clear safety concerns, and a clear definition of symptomatic BM through the adoption of standardized tools to assess neurological deficits could help to fill this gap.⁸⁶

Of note, most recently published trials seem to place greater emphasis on this aspect, expanding the included population and providing clearer specifications regarding the modalities and timing of prior locoregional and systemic treatments allowed in patients with BM. Additionally, these trials often incorporate specific secondary or exploratory outcomes tailored to the subgroup with BM at baseline, exploring the intracranial efficacy of the investigated drug (IC-PFS, IC-ORR, IC-DoR, IC-DCR). Including prespecified BM-related outcomes is crucial to generate high-level evidence about the efficacy and safety of new treatments in this patient population. Furthermore, the presence of BM should be a stratification factor to enable accurate comparisons across treatment arms.

The low rate of intracranial progression demonstrated in recent trials highlights the strong intracranial activity provided by some of the new TT. These findings also raise an important question about the frequency of brain surveillance follow-up, particularly given the lack of consensus in current practice guidelines. While brain monitoring is still essential for patients with BM at baseline to assess the response to the therapy, the need for brain follow-up in those without BM at diagnosis or neurological symptoms remains a matter of debate.

Previous work suggested a follow-up brain MRI after 12 months in patients with stage III-IV EGFR-mutated NSCLC without BM at baseline as new BM was detected in 16/101 patients during follow-up.⁸⁷ However, more solid data from RCTs and precisely tailored time intervals for surveillance brain MRI based on further risk stratification are needed. Especially in clinical trials, brain surveillance would be beneficial for the robustness of the data, as with regular follow-up in those without baseline BM, it can be evaluated whether a TT has a CNS protective effect.⁸⁸ Furthermore, regular brain imaging follow-up in a trial in which the investigational drug has a good CNS efficacy compared to a drug that does not influence PFS HR in favor of the investigational drug since the PFS will especially be shorter in the comparator arm.

Notably, regular imaging could help in the early detection and treatment of new brain lesions but it also might subject patients to unnecessary frequent tests, causing emotional stress and increasing healthcare costs. Given the high intracranial activity and protection offered by some of the TT, a tailored approach with less frequent imaging tests could be considered, especially for patients without BM. However, more data is needed before making firm recommendations in this regard. Furthermore, improved knowledge of the percentage of patients that developed symptomatic BM, often not reported in the trials, could help to further personalize the follow-up strategies.

In addition, our review shows that the incidence of BM as first and only site of progression is rarely described in the trials and no recommendations regarding the treatment of CNS oligoprogression are given. Most trials only included a broad statement allowing patients to continue treatment beyond progression if the investigator deemed the drug still beneficial. Only three trials (6%) explicitly specified that patients with isolated CNS progression could receive local treatment and continue study therapy until systemic progression. Given the potential for extended survival in patients with oligoprogressive disease, more attention to this subgroup should be provided and a personalized treatment approach should be considered as incorporating localized treatments can help prolong PFS and improve patient outcomes.

Furthermore, while the percentage of patients with BM previously treated with radiotherapy was reported in almost half of the trials, crucial details such as the timing of radiotherapy, dose, and fractionation were often missing. This lack of comprehensive reporting complicates the interpretation of the results, as these factors can have a significant impact on both treatment efficacy and patient outcomes. Therefore, new trials should include more detailed radiotherapy data.

To further improve the quality of future research, we recommend that trials not only provide more detailed radiotherapy information but also encourage the inclusion of patients with BM. Depending on the expected or previously reported intracranial efficacy of a drug, inclusion criteria should be broadened to include patients with limited symptomatic (if previously reported high intracranial efficacy) and previously untreated BM. Our review highlights the frequent lack of a clear definition for “symptomatic” versus “asymptomatic” BM. Future trials should address this by providing clear definitions, including the use of dexamethasone and antiepileptic medication. Next, to accurately analyze BM-related outcomes, it is essential that patients are stratified based on the presence of BM and that trials include predefined BM-related outcomes, such as IC-PFS, IC-ORR, IC-DoR, and IC-DCR. Lastly, we recommend that all TT trials for NSCLC mandate baseline and follow-up brain imaging with MRI for all participants. This approach not only ensures accurate monitoring of the investigational drug’s intracranial efficacy but can also provide valuable insights to select optimal brain follow-up schedules for patients outside the clinical trial setting (Figure 4).

Figure 4.

Future trial design recommendations for patients with NSCLC and BM.

Conclusion

Our review highlights the growing attention to baseline screening for BM in phase III and registrational trials of TT for NSCLC with AGA. However, heterogeneity remains across clinical trials regarding eligibility criteria for patients with BM, BM screening methods, BM-related outcomes, and follow-up protocols. Addressing these differences in future trials is essential to advance the understanding of TTs in NSCLC with BM involvement and optimize patient care. Moreover, future trials are needed to determine whether screening for BM in patients with NSCLC and an AGA is cost-effective and improves patient outcomes.

Supplementary material

Supplementary material is available online at Neuro-Oncology Practice (https://academic.oup.com/nop/).

Conflict of interest statement. ASB reports outside of this manuscript research support form Daiichi Sankyo, Roche; honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo, AstraZeneca, CeCaVa, Seagen, Alexion, Servier; travel support from Roche, Amgen, and AbbVie. PKB reports outside of this manuscript research support (institution) from Merck, Mirati, Eli Lilly, and Kinnate; consulted for ElevateBio, Genentech, Angiochem, Tesaro, Axiom Healthcare Strategies, InCephalo Therapeutics, Medscape, MPM Capital Advisors, Dantari Pharmaceuticals, SK Life Sciences, Pfizer, CraniUS, Eli Lilly, Kazia, Sintetica, Voyager Therapeutics, Advise Connect Inspire, Merck, and Atavistik; Speaker’s Honoraria from Genentech and Pfizer; on the Scientific Advisory Board for CraniUS and Kazia. DKMDR reports outside of this manuscript research Grant/support/Advisory Board: Institutional financial interests (no personal financial interests) from AstraZeneca, BMS, Beigene, Philips, Olink and Advisory Board: Institutional financial interests (no personal financial interests) for Eli-Lilly. LELH reports outside of this manuscript Research funding: Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda, Merck, Pfizer, Novartis, Gilead; Speaker educationals/webinars: AstraZeneca, Bayer, Lilly, MSD, high5oncology, Takeda, Janssen, GSK, Sanofi, Pfizer, Medtalks, Benecke, VJOncology, Medimix; Advisory boards: Abbvie, Amgen, Anhearth, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi, GSK, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Summit Therapeutics, Takeda; Member guideline committees: Dutch guidelines on NSCLC, brain metastases, and leptomeningeal metastases, ESMO guidelines on metastatic NSCLC, nonmetastatic NSCLC and SCLC (nonfinancial) Other (nonfinancial): secretary NVALT studies foundation, subchair EORTC metastatic NSCLC systemic therapy, vice-chair scientific committee Dutch Thoracic Group; local PI of clinical trials: AstraZeneca, GSK, Novartis, Merck, Roche, Takeda, lueprint, Mirati, Abbvie, Gilead, MSD, Amgen, Boehringer Ingelheim, Pfizer. The other authors have no conflicts of interest to declare.

Funding

None declared.

Authorship statement

Conceptualization: J.W.J.H., M.B., L.E.L.H., A.C. Literature review and data interpretation: J.W.J.H., M.B., L.E.L.H., A.C. Writing of the initial draft: J.W.J.H. and M.B. Manuscript revision and approval of the final version: J.W.J.H., M.B., A.S.B., P.K.B., J.H.R.J.D., D.K.M.D.R., A.C., L.E.L.H.