Combined BBB-penetrant tyrosine kinase inhibitor and intracranial radiotherapy versus BBB-penetrant tyrosine kinase inhibitor alone for the treatment of EGFR-mutated non-small cell lung cancer patients with brain metastases

doi:10.21203/rs.3.rs-2960400/v1

Purpose

This study was to determine whether combining blood-brain-barrier-penetrant tyrosine kinase inhibitor (TKI), osimertinib, with intracranial radiotherapy (TKI + RT) would confer benefits exceeding those of osimertinib alone (TKI-alone) in terms of treatment outcomes among non-small cell lung cancer (NSCLC) patients with brain metastases and epidermal growth factor receptor (EGFR) mutation.

Methods

This single-center retrospective study focused on gamma-knife radiosurgery (GKRS) and whole brain radiotherapy (WBRT). Treatment outcomes included intracranial local tumor control, intracranial distant tumor control and overall survival (OS) rates.

Results

This study included 567 brain metastases in 69 patients: TKI-alone (n = 38) and TKI + RT (n = 31) including GKRS (n = 25) and WBRT (n = 6). Intracranial local tumor control at 36 months was significantly higher in the TKI + RT than in the TKI-alone (77% vs. 23%; p < 0.001). Intracranial distant tumor control was significantly higher in the TKI + RT than in the TKI-alone (median survival: 23.2 ± 1.5 vs. 8.7 ± 0.2 months; p < 0.001). We observed no difference between the two cohorts in terms of OS (p = 0.271). T790M point mutation (HR = 0.359, p = 0.008) and TKI + RT (HR = 0.396, p = 0.010) were positively correlated with intracranial local tumor control. The number of brain metastases was negatively correlated with intracranial distant tumor control (HR = 2.253, p = 0.034) and OS (HR = 2.049, p = 0.019).

Conclusions

The efficacy of osimertinib therapy for NSCLC patients with brain metastases and EGFR mutation was enhanced by combining this treatment with intracranial radiotherapy. Benefits were observed in terms of intracranial local control and distant control rates; however, no benefits were observed in terms of OS. Further prospective studies will be required to confirm these findings.

osimertinib

tyrosine-kinase inhibitor

gamma-knife radiosurgery

whole brain radiotherapy

non-small cell lung cancer

brain metastases

Lung cancer is a major contributor to cancer deaths worldwide [1]. Among patients with non-small cell lung cancer (NSCLC), 10% present brain metastases at the time of diagnosis and 40% experience brain metastases during their lives [2]. The prevalence of brain metastases in NSCLC patients with the epidermal growth factor receptor (EGFR) mutation can reach 46.7% at 3 years, and 64.7% of these patients harbor brain metastases during their lifetime [3, 4]. EGFR tyrosine kinase inhibitors (TKIs) have proven more effective than chemotherapy in controlling lung cancer, and can be detected in cerebrospinal fluid (CSF) with regression of brain metastases [5–8]. It has been reported that the most recent (third generation) of TKIs outperform first generation TKIs in terms of progression-free survival (PFS) and overall survival (OS) [9, 10].

Intracranial radiation therapy, such as whole brain radiotherapy (WBRT) and gamma-knife radiosurgery (GKRS), is the conventional approach to treating brain metastasis. Combining target therapies with GKRS or WBRT has been shown to promote intracranial tumor control beyond what can be achieved using the target therapy alone [11–13]. In one study on 280 patients with EGFR-mutated NSCLC and brain metastases, Chiou et al. reported that in terms of cumulative tumor control, a combination therapy involving TKI plus GKRS outperformed TKI alone.

The third generation of TKIs, such as osimertinib, are highly effective in the crossing blood-brain barrier (BBB), resulting in intracranial tumor control rates superior to those of first and second generation TKIs [14–17]. These advances have made it feasible to treat NSCLC patients with brain metastases using a single agent; however, the issue of whether combining intracranial radiotherapy with TKI therapy remains unclear. Thomas et al. reported no difference between osimertinib alone and a combination therapy of osimertinib with intracranial radiotherapy in terms of time to tumor progression or treatment failure among 95 EGFR-mutated NSCLC patients [18]. Yu et al. reported that when treating patients with this combination of therapies, the time to intracranial progression was longer than when using osimertinib alone [19]. Note that this combined therapy was also shown to significantly improve intracranial PFS and OS rates in the subcohort of patients with oligo-metastases. Our objective in the current study was to determine whether the addition of intracranial radiotherapy would confer benefits in NSCLC patients with brain metastases and EGFR mutation.

This retrospective study was conducted between August 2014 and July 2022 at a single medical center located at Taipei Veterans General Hospital. Patient data was abstracted from medical records. Patient inclusion criteria included the followings: (1) EGFR-mutated NSCLC; (2) treatment using osimertinib, and (3) at least one magnetic resonance imaging (MRI) session revealing brain metastasis prior to osimertinib initiation. Patient exclusion criteria included the followings: (1) Leptomeningeal seeding without any parenchymal metastasis, and (2) lack of follow-up neuroimaging or clinical follow-up. Patients were categorized within two cohorts: (1) Combined osimertinib and intracranial radiotherapy (TKI + RT), involving WBRT or single-session GKRS within three months of initiation of osimertinib; and (2) osimertinib alone (TKI-alone), without WBRT or GKRS within three months of initiation of osimertinib. We prescribed Osimertinib (Tagrisso) 80 mg once a day orally in all patients, and performed either GKRS using the Gamma-knife unit model 4C or Perfexion, Elekta AB) or WBRT using Varian LINAC model True-Beam (Varian Medical Systems, Palo Alto, CA). The dose protocol of GKRS was based on tumor size as suggested by Radiation Therapy Oncology Group and Japanese study group: 22–25 Gray for tumor size ≤ 20 mm, 18–20 Gray for tumor size > 20 mm [20, 21]. The protocol of WBRT was given with a total dose of 30 Gray in ten fractions. We collected the baseline factors, including the age, gender, race, ever smoke status, pathological reports, and lung cancer genotype. We also acquired data pertaining to Karnofsky Performance Scale (KPS), the size and number of brain metastases, neurological signs induced by brain metastases, and leptomeningeal seeding at osimertinib initiation. We extracted previous treatments prior to osimertinib initiation, including medications, surgery, and intracranial or extracranial radiation therapy. GKRS treatment parameters were noted, including tumor volume, margin dose, maximal dose, and isodose level. We recorded the dates for the following events: diagnosis of lung cancer and brain metastases, initiation of osimertinib, progression of brain tumor, last follow-up, and death. This study was approved by the Institutional Review Board of Taipei Veterans General Hospital.

We characterized three possible outcomes based on the duration between the initial use of osimertinib and the corresponding endpoints. The endpoint of intracranial local tumor control was defined as progression of the original tumor at osimertinib initiation, calculated on a per-tumor basis. The endpoint of intracranial distant tumor control was defined as the development of a new parenchyma tumor following osimertinib initiation, calculated and weighted on a per-intracranial-local-tumor basis. The endpoint of OS was death or the last follow-up. We opted not to follow the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Rather, we determined the location and timing of brain metastases progression based the analysis of neuroimaging results by radiologist.

Statistical Analysis

All statistical analysis was performed using SPSS version 26 and GraphPad prism version 9. Categorical variables between cohorts were compared using the chi-square test or Fisher exact test, and continuous variables were computed using independent two-sample t-test or the two-sample Wilcoxon test. Intracranial local tumor control, intracranial distant tumor control, and OS were analyzed using the Kaplan-Meier (KM) method and the curves were compared using the log-rank test. Univariable and multivariable Cox regression analysis was used to identify possible independent predictors from among the followings: age, gender, smoking, number of brain metastases, maximal dimensions of brain metastases, symptoms induced by brain metastases, leptomeningeal seeding, KPS, previous systematic therapy, craniectomy for brain metastases, GKRS or WBRT 3 months before using osimertinib, Exon 19 deletion, T790M point mutation, L858R point mutation and intracranial RT (WBRT or GKRS) within 3 months of using osimertinib. Variables with a p value of < 0.2 in univariate analysis were entered into the final multivariable model. Hazard ratios (HRs) and corresponding 95% confidence intervals were computed. A p value of < 0.05 indicated a difference of statistical significance, and all tests were two-tailed. Missing data was not imputed.

Between August 2014 and July 2022, we used osimertinib to treat 69 NSCLC patients with brain metastases and EGFR mutation. These patients were categorized as TKI+RT (n=31 patients) or TKI-alone (n=38 patients). In the TKI+RT cohort, 25 patients underwent GKRS and 6 patients underwent WBRT. Table 1 lists the characteristics of patients in the two cohorts. The percentage of patients who underwent prior TKI or chemotherapy treatment were similar: TKI-alone (94.7%) and TKI+RT (93.5%).

Table 1. Patient characteristics and clinical response

Characteristics	TKI-alone, n=38		TKI+RT, n=31		p Value
Duration of FU (mo)	9.7±9.3	0.7-50.1	12.9±11.9	0.7-60.0	0.183
Age at diagnosis	58.5±11.7	42.0-83.3	57.4±10.5	40.4-76.8	0.683
Gender					0.177
Male	9	23.7	12	38.7
Female Race: Asian	29 38	76.3 100	19 31	61.3 100
Smoking					0.185
Never	32	84.2	22	71.0
Previously Pathology: adenocarcinoma	6 38	15.8 100	9 31	29.0 100
Type of EGFR mutation
Exon 19 deletion	13	34.2	18	58.1
T790M point mutation	26	68.4	19	61.3
L858R point mutation	24	63.2	9	29.0
G719X point mutation	0	0	2	6.5
Exon 20 insertions	0	0	1	3.2
L861Q point mutation	1	2.6	1	3.2
Combined mutation
Exon 19 & T790M	9	23.7	8	25.8
T790M & L858R	16	42.1	7	22.6
KPS <80 80-100	9 29	23.7 76.3	3 28	9.7 90.3	0.127
Symptom from brain mets	16	42.1	17	54.8	0.292
Leptomeningeal seeding	6	15.8	4	12.9	1.000
Number of brain mets					0.566
1-3	14	36.8	14	45.2
4-6	7	18.4	6	19.4
7-9	5	13.2	1	3.2
≥10	12	31.6	10	32.3
Max length of brain mets					0.085
<1.0	20	52.6	103	41.9
1.0-1.9	9	23.7	7	22.6
2.0-2.9	6	15.8	8	25.8
≥3.0	3	7.9	3	9.7
Site of brain mets	336		231
Frontal lobe	111	33.0	92	39.8
Parietal lobe	64	19.1	32	13.9
Temporal lobe	70	20.8	33	14.3
Occipital lobe	38	11.3	35	15.2
Basal ganglia & thalamus Brainstem	7 5	2.1 1.5	7 4	3.0 1.7
Cerebellum	41	12.2	28	12.1
Pre-treatment before 3^rd TKI Pre-systematic treatment	36 35	94.7 92.1	29 28	93.5 90.3	1.000 1.000
1^st generation TKI	31	81.6	22	71.0	0.299
2^nd generation TKI	9	23.7	10	32.3	0.428
Platinum-based 　chemotherapy	18	47.4	21	67.6	0.089
Other systematic therapy	15	39.5	17	54.8	0.203
Anti-VEGF therapy	3	7.9	8	25.8	0.054
Immunotherapy	2	5.3	3	9.7	0.651
Craniectomy for mets	4	10.5	6	19.4	0.327
Previous GKRS	7	18.4	6	19.4	0.921
Previous WBRT	9	23.7	9	29.0	0.615
CNS radiation at time of 3^rd TKI
GKRS	0	0	25	80.6
WBRT	0	0	6	19.4
GKRS protocol
Tumor volume (cc)			0.0587	0.0079-38.4
Margin dose (Gy)			19.0	6.0-25.0
Maximal dose (Gy)			29.7	12.0-36.4
Isodose level (%)			70	50-95
WBRT protocol
Total dose (Gy)			30	20-30
Fraction			11	10-12
Site of first progression	35	92.1	29	93.5
Only intracranial	8	21.1	8	25.8
Both (intra- and extracranial)	14	36.8	7	22.6
Intracranial	22	57.9	15	48.4
Only extracranial	13	34.2	14	45.2

Abbreviations: TKI, tyrosine kinase inhibitor; FU, follow-up; mo, month; KPS, Karnofsky performance status; mets, metastases; cc, cubic centimeter; Gy, Gray; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; GKRS. Gamma-knife radiosurgery; WBRT, whole brain radiotherapy; CI, confidence interval.

A total of 567 tumors were analyzed in terms of intracranial local tumor control, and the KM curve between cohorts demonstrated a statistically significant difference (p<0.001). The control rates in the TKI-alone cohort were as follows: 61%, 54%, and 23% for the TKI-alone cohort, while the rates were 92%, 83%, and 77% for the TKI+RT cohort at 12, 24, and 36 months, respectively (Fig. 1a). The median duration of intracranial local tumor control in the TKI-alone cohort was 24.9±1.8 months, and was not reached in the TKI+RT cohort.

The 567 tumors were also analyzed in terms of intracranial distant tumor control, and the KM curve between cohorts demonstrated a statistically significant difference (p<0.001) based on events weighted by the number of local tumors (Fig. 1b). The control rates were 29%, 9%, and 4% for the TKI-alone cohort, while the rates for the TKI+RT cohort were 65%, 43%, and 14% at 12, 24, and 36 months, respectively. The median duration of intracranial distant tumor control in the TKI-alone cohort was 8.7±0.2 months, and the median duration for the TKI+RT cohort was 23.2±1.5 months. In terms of overall survival, we did not observe a significant difference (p=0.271) between the two cohorts in KM curves. The median survial duration in the TKI-alone cohort was 20.4±1.0 months, and the median duration for the TKI+RT cohort was 26.1±2.5 months (Fig. 1c).

Predictors of tumor control and survival are listed in Table 2. The number of brain metastases (HR=3.018, p=0.007) was negatively correlated with intracranial local tumor control, whereas T790M point mutation (HR=0.359, p=0.008), and intracranial RT (WBRT or GKRS) within three months of initiating osimertinib (HR=0.396, p=0.010) were positively correlated with intracranial local tumor control. The number of brain metastases was negatively correlated with intracranial distant tumor (HR=2.253, p=0.034) and OS (HR=2.049, p=0.019). KPS were positively correlated with OS (HR=0.308, p=0.003).

Table 2. Univariate and multivariate analysis of tumor control and overall survival

Factors	Intracranial Local Tumor Control						Intracranial Distant tumor control						Overall Survival
Factors	Univariate			Multivariate			Univariate			Multivariate			Univariate			Multivariate
	HR	95%CI	p	HR	95%CI	p	HR	95%CI	p	HR	95%CI	p	HR	95%CI	p	HR	95%CI	p
Age≥65	0.757	0.354-1.616	0.471				1.166	0.594-2.288	0.655				1.040	0.565-1.915	0.900
Gender	1.139	0.547-2.373	0.729				1.132	0.578-2.218	0.717				1.222	0.655-2.282	0.529
Smoking	0.722	0.314-1.662	0.444				0.869	0.400-1.888	0.723				0.940	0.455-1.941	0.867
Number of brain mets at TKI (>6)	2.292	1.163-4.516	0.017	3.018	1.344-6.779	0.007	2.306	1.232-4.318	0.009	2.253	1.063-4.776	0.034	2.338	1.303-4.197	0.004	2.049	1.123-3.739	0.019
Max dimension of brain mets (>2cm)	1.899	0.954-3.780	0.068	1.737	0.803-3.755	0.161	1.779	0.919-3.442	0.087	1.889	0.909-3.925	0.088	1.486	0.733-2.856	0.235
Symptom from brain mets	1.104	0.575-2.118	0.766				1.114	0.608-2.041	0.726				1.182	0.669-2.091	0.565
Leptomeningeal seeding	0.765	0.268-2.187	0.617				1.410	0.615-3.234	0.417				1.641	0.784-3.435	0.189	1.213	0.524-2.806	0.652
KPS≥80	1.678	0.510-5.525	0.395				1.086	0.420-2.804	0.865				0.240	0.116-0.496	<0.001	0.308	0.142-0.668	0.003
Pre-systematic therapy	0.822	0.288-2.343	0.714				0.580	0.224-1.505	0.263				5.185	0.714-37.643	0.104	3.149	0.409-24.282	0.271
Craniectomy for brain mets	2.476	1.110-5.525	0.027	2.744	1.020-7.380	0.046	1.856	0.848-4.065	0.122	1.629	0.631-4.206	0.314	0.622	0.223-1.738	0.365
GKRS 3 months before using osimertinib	1.439	0.664-3.120	0.356				1.063	0.498-2.273	0.874				0.932	0.482-1.801	0.834
WBRT 3 months before using osimertinib	1.762	0.840-3.695	0.134	2.787	1.115-6.969	0.028	2.328	1.208-4.487	0.012	1.95	0.930-4.092	0.077	2.063	1.134-3.755	0.018	1.826	0.968-3.446	0.063
Exon 19 deletion	0.755	0.385-1.478	0.412				0.566	0.301-1.062	0.076	0.713	0.360-1.410	0.331	1.441	0.812-2.556	0.212
T790M point mutation	0.610	0.310-1.200	0.152	0.359	0.168-0.769	0.008	0.970	0.521-1.805	0.924				1.537	0.826-2.860	0.174	1.198	0.628-2.287	0.584
L858R point mutation	1.001	0.519-1.931	0.998				1.394	0.762-2.551	0.281				0.888	0.504-1.566	0.682
RT (WBRT or GKRS) within 3 months of using osimertinib	0.504	0.256-0.993	0.048	0.396	0.195-0.802	0.010	0.553	0.296-1.031	0.062	0.533	0.284-1.001	0.051	0.719	0.398-1.299	0.274

Abbreviations: HR, hazard ratio; CI, confidence interval; TKI, tyrosine kinase inhibitor; mets, metastases; cm, centimeter; KPS, Karnofsky performance status; GKRS, Gamma-knife radiosurgery; WBRT, whole brain radiotherapy; RT, radiotherapy.

The efficacy of osimertinib in controlling brain metastases in cases of NSCLC has prompted interest in whether the efficacy of this treatment could be enhanced by including intracranial RT. Our objective in this study was to clarify the role of intracranial RT in this patient population. We obtained convincing evidence that augmenting osimertinib treatment with intracranial RT can enhance intracranial local and distant tumor control; however, these benefits did not translate into improved OS.

The efficacy of third generation TKIs in controlling NSCLC brain metastases has been linked to its ability to pass the BBB. In one positron emission tomography (PET) study of cynomolgus monkeys, osimertinib achieved a brain-to-plasma ratio value of 2.59, far exceeding those of gefitinib (0.25), erlotinib (0.09), and afatinib (0.17) [16]. In a PET 11C-osimertinib study involving eight healthy volunteers, osimertinib was shown to pass through the intact BBB, resulting in a brain-to-blood ratio of 3.8 (3.3-4.1) [17]. By contrast, Yang et al. reported that the brain-to-blood ratio of osimertinib was only 16% based on real world data, which is far lower than estimates based on laboratory data [22]. Researchers have hypothesized that radiation can have synergistic effects on BBB permeability for drugs such as osimertinib. One study reported a significant increase in the vascular permeability of tumors at two to four weeks after WBRT (30 Gray/10 fractions or 37.5 Gray/15 fractions) or single-session stereotactic radiosurgery (24, 18 or 15 Gray based on maximum tumor dimensions) [23]. One case report revealed that WBRT dramatically increased the concentration of non-BBB penetrant crizotinib at weeks 2 and 3 [24]. Researchers have hypothesized that the BBB can be damaged by radiotherapy, thereby facilitating the transport of drugs across the BBB to lesions in the brain parenchyma. Jost et al. reported that TKIs, such as osimertinib, can significantly enhance the radiosensitivity of tumors [25]. They reported that combining osimertinib with radiotherapy had synergistic effects in vivo and in vitro, including a shortening of radiation-induced G2/M-phase cell cycle arrest, delays in deoxyribonucleic acid (DNA) damage repair, inhibited cell proliferation, and inducing apoptosis [26, 27]. Osimertinib is meant to block the EGFR pathway, and radiotherapy generates free radicals via ionizing radiation, which causes DNA damage and induces cytotoxic effects. GKRS has also been shown to destroy small blood vessels and lead indirectly to the deterioration of the tumor microenvironment [28]. To summarize, the synergistic effects of combining osimertinib with intracranial radiotherapy are expected to promote brain metastases control.

Table 3: Literature review of studies examining osimertinib combined with other therapies versus osimertinib alone in EGFR-mutated NSCLC patients

Author, year	No.	Osimertinib+other therapy vs. Osimertinib-alone	EGFR status	Intracranial PFS (median, mo)	PFS (median, mo)	OS (median, mo)	Other parameter (median, mo)
Zheng et al., 2020³²	108	14 (1 SRS/2WBRT/3surgery /8 extracranial RT) vs. 94	Exon 19 (48%); L858R (47%); Other (5%)	-	NR vs. 12.8 (p=0.01)	85.8 vs. 77.1 (p=0.58)
Yu et al., 2021¹⁹	205	48 (24 SRS/24 WBRT) vs. 157	Exon 19 (50%); L858R (44%); Other (6%)	24.1 vs. 17.7 (p=0.160)	12.9 vs. 11.3 (p=0.410)	27.8 vs. 24.5 (p=0.930)	Subgroup of oligo-BM*: Intracranial PFS: 29 vs. 16 (p=0.001) PFS: 19 vs. 12.4 (p=0.033) OS: 40.1 vs. 24.5 (p=0.026)
Zhai et al., 2021³¹	61	21 (2 SRS/19 WBRT) vs. 40	Exon 19 (49%); L858R (51%); T790M (84%)	16.7 vs. 13.5 (p=0.836)	9.0 vs. 10.9 (p=0.467)	29.2 vs. 26.1 (p=0.826)	Subgroup of Exon 19 deletion: OS: 16.6 vs. NR (p=0.011) Subgroup of L858R: OS: 29.2 vs. 18.8 (p=0.046) Subgroup of leptomeningeal mets: OS: NR vs. NR (p=0.762)
Thomas et al., 2022¹⁸	95	43 (34 SRS/9 WBRT) vs. 52	Exon 19(55%); L858R (41%); T790M (23%); Other (9%)	20.5 vs. 14.8 (p=0.51)	6.9 vs. 8.5 (p=0.13)	44 vs. NR† (p=.092)	Treatment failure: 8.6 vs. 13.8 (p=0.26)
Dohm et al., 2022³⁰	92	34 (17 SRS/17 WBRT) vs. 58	NA	Local (1yr): 93.1 vs. 99.6% (p=0.31) Distant (1yr): 68.7 vs. 84.9% (p=0.80)	-	1yr: 73.5 vs. 66% (p=0.)
Zhao et al., 2022²⁹	102	48 (24 SRS or neurosurgery /22 WBRT) vs. 56	Exon 19 (39%); L858R (41%); Other (20%)	-	-	NA (p=0.358)	Subgroup of SRS/neurosurgery vs. alone§ OS: 38.9 vs. 26.7 (p=0.041) Subgroup of WBRT vs. alone§: OS: HR=1.27 (p=0.588)
Our study	69	31 (25 SRS/6 WBRT) vs. 38	Exon 19 (45%); L858R (48%); T790M (65%); Other (7%)	Local (3 yr): 77 vs. 23% Distant (median): 23.2 vs. 8.7 mo	-	26.1 vs. 20.4 (p=0.271)

Abbreviations: No, Case number; EGFR, epidermal growth factor receptor; mo, months; PFS, progression-free survival; OS, overall survival; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy; RT, radiotherapy; NR, not reached; mets, metastases; NA, not available; yr, year; HR, hazard ratio. *Subgroup of 16 patients with oligo-BM (Oligo-brain metastases) was defined as the state of having 1 to 3 brain metastases with a maximal size of ≦3 cm, and was in comparison with 28 patients receiving non-upfront cranial RT groups in a matched cohort. †OS was only calculated in subgroup of osimertinib used as first line. (Osimertinib alone:21 patients; Osimertinib+RT:21 patients) §Subgroup of upfront neurosurgery/SRS and upfront WBRT were compared with patients without upfront cranial local treatment, respectively.

The advent of TKIs provided a novel approach to the treatment of NSCLC with brain metastases; however, there has been a lack of evidence indicating the role of intracranial radiotherapy when combined with advanced TKIs. A literature review of osimertinib alone versus osimertinib plus other treatments is listed in Table 3 [18, 19, 29-32]. Thomas et al. reported no difference (p=0.51) between osimertinib+RT and osimertinib-alone in terms of intracranial progression in EGFR-mutant NSCLC patients. Note however that they calculated intracranial progression on a per-patient basis and combined distant lesions with local lesions, which didn’t preclude the identification of paradoxical effects, such as the general regression of local lesions in conjunction with the appearance of only one new distant lesion or persistence of single local lesion [18]. Dohm et al. reported that the effects of osimertinib+RT were similar to those of osimertinib-alone in terms of distant intracranial control (p=0.80) or local control (p=0.31); however, the details of that study are not available [30]. Hui et al. reported that among 37 patients (284 brain metastases) treated with osimertinib, 14% (95% CI 9.9-17.9%) of the patients had intracranial local tumor recurrence within a short-term follow up (one year) [33]. Our results suggest that over a 3-year follow up, the combination of intracranial RT with osimertinib provides robust intracranial tumor control, exceeding the efficacy of osimertinib alone (77% vs. 23%, p<0.001). The inclusion of intracranial RT was shown to improve distant tumor control (median survival: 23.2±1.5 vs. 8.7±0.2 months, p<0.001); however, the effects did not appear durable, resulting in marginally significant differences (HR=0.533, p=0.051) in multivariable cox regression analysis. The intracranial distant tumor control is likely to be attributed to the abscopal effect. Furthermore, our findings did not translate into improved OS, which suggests that a higher number of brain metastases (HR=2.049, p=0.019) and lower KPS (HR=0.308, p=0.003) were associated with poorer OS. Control over primary lesions appears to play an important role in the prognosis of OS. Several case examples are illustrated in Fig 2.

Our assessment of intracranial tumor control on a per-tumor basis provides another perspective to evaluate the efficacy of osimertinib alone versus osimertinib plus intracranial radiotherapy. This study was subject to a number of limitations, which should be considered in generalizing these findings. We observed imbalances in some genes between the two cohorts. Due to the retrospective nature of this study, the treatment prior to osimertinib exhibited notable heterogeneity. We were unable to confirm our pathological findings directly via biopsy of brain lesions, which necessitated a reliance on images based on biopsy from lung or lymph nodes. The sample size in the current study was too small to perform score matching. Intracranial distant tumor control was calculated and weighted on a per-intracranial-local-tumor basis, such that the effect of patients with a larger number of brain metastases at osimertinib initiation would be overestimated. The treatment plans implemented by physicians were prone to selection bias, due to an absence of consensus regarding which patients should receive osimertinib, WBRT, or GKRS and the scheduling of treatment delivery. This study was also subject to detection bias, which is highly dependent on the interpretation of radiologists. The adverse effects of WBRT (e.g., neurocognitive decline and leukoencephalopathies) were reported, but we were unable to assess them, due to difficulties in dealing with medical records. A standardized protocol based on randomization and a prospective cohort would provide clear results. Note that results of four clinical trials comparing osimertinib and osimertinib plus GKRS (NCT03535363, NCT05033691, NCT03497767 and NCT03769103) are pending.

A combined treatment of osimertinib with intracranial radiotherapy was shown to outperform osimertinib alone in terms of intracranial local and distant tumor control among NSCLC patients with brain metastases and EGFR mutation. Intracranial local tumor control remained robust over a period of 3 years, while intracranial distant tumor control did not. Note however that these radiographic findings did not translate into improvements in OS. The benefits of augmenting osimertinib treatment with intracranial radiotherapy will need to be verified in a prospective, randomized study.

Tyrosine kinase inhibitor (TKI), blood-brain barrier (BBB), non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), radiotherapy (RT), gamma-knife radiosurgery (GKRS), whole brain radiotherapy (WBRT), hazard ratio (HR), cerebrospinal fluid (CSF), progression-free survival (PFS), magnetic resonance imaging (MRI), Karnofsky Performance Scale (KPS), Kaplan-Meier curve (KM curve), positron emission tomography (PET)

Acknowledgements: This work was supported by the Ministry of Science and Technology, Taiwan (MOST 110-2314-B075-038-MY2).

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No competing interests reported.

Combined BBB-penetrant tyrosine kinase inhibitor and intracranial radiotherapy versus BBB-penetrant tyrosine kinase inhibitor alone for the treatment of EGFR-mutated non-small cell lung cancer patients with brain metastases

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