Radiation therapy plus osimertinib vs osimertinib alone in epidermal growth factor receptor mutated non-small cell lung cancer: A systematic review

Table 1 Characteristics of the selected studies

Ref.	Design	Population	Patient characteristics	Intervention	Comparator	Primary outcome	Key findings
Soria et al[10], 2018 (FLAURA)	RCT (n = 556)	Treatment-naïve advanced NSCLC	Median age 64 years, 64% female, 62% Asian, PS 0-1	Osimertinib 80 mg daily	Erlotinib 150 mg or gefitinib 250 mg daily	PFS	mPFS: 18.9 months vs 10.2 months (HR: 0.46, P < 0.001)
Ramalingam et al[9], 2020 (FLAURA-OS)	RCT (n = 556)	Treatment-naïve advanced NSCLC	Same cohort as FLAURA	Osimertinib 80 mg daily	Erlotinib or gefitinib	OS	mOS: 38.6 months vs 31.8 months (HR: 0.80, P = 0.046)
Reungwetwattana et al[24], 2018	RCT (n = 144)	Treatment-naïve with CNS metastases	Median age 62 years, 69% female, 83% Asian, all with baseline BM	Osimertinib 80 mg daily	Erlotinib or gefitinib	CNS ORR	CNS ORR: 91% vs 68% (P = 0.0009)
Cho et al[25], 2019 (FLAURA Asian)	RCT (n = 357)	Asian treatment-naïve advanced NSCLC	100% Asian, median age 62 years, 62% female	Osimertinib 80 mg daily	Erlotinib or gefitinib	PFS	mPFS: 16.5 months vs 11.0 months (HR: 0.46, P < 0.001)
Wu et al[11], 2018 (AURA3-CNS)	RCT (n = 144)	T790M+ post-EGFR-TKI progression	Median age 61 years, 61% female, 73% Asian, all with BM	Osimertinib 80 mg daily	Platinum-pemetrexed	CNS ORR	CNS ORR: 70% vs 31% (P = 0.015)
Brown et al[14], 2020 (RTOG 0933)	RCT (n = 518)	Brain metastases	Median age 61 years, 48% female, mixed primary tumors	HA-WBRT + memantine	Historical WBRT controls	Cognitive function	HVLT-R decline: 7.0% vs 30% historical (P < 0.001)
Brown et al[13], 2017 (NCCTG N107C)	RCT (n = 194)	Resected brain metastases	Median age 60 years, 48% female, 85% NSCLC	Post-op SRS	Post-op WBRT	Cognitive function	Better cognitive preservation with SRS
Brown et al[15], 2016	RCT (n = 213)	1-3 brain metastases	Median age 60 years, 46% female, 84% NSCLC	SRS alone	SRS + WBRT	Cognitive function	Cognitive decline: 63.5% vs 91.7% (P < 0.001)
Jänne et al[26], 2024 (FLAURA2-CNS)	RCT (n = 557)	Treatment-naïve advanced NSCLC	Median age 64 years, 61% female, 48% Asian	Osimertinib + chemotherapy	Osimertinib alone	PFS	Enhanced CNS activity with combination
Li et al[19], 2023 (FLOWERS)	RCT (n = 200)	MET aberrant, EGFR+	Treatment-naïve with MET amplification/mutation	Osimertinib ± savolitinib	Osimertinib monotherapy	PFS	Ongoing trial design rationale
Shi et al[2], 2014 (PIONEER)	Cohort (n = 1482)	Asian adenocarcinoma	Median age 58 years, 58% female, 100% Asian	Observational	Not applicable	Mutation prevalence	EGFR mutations in 60.9% of adenocarcinomas
Gu et al[31], 2024	Cohort (n = 186)	Advanced adenocarcinoma with BM	Median age 58 years, 55% female, TP53 co-mutations	EGFR-TKI therapy	TP53 wild-type comparison	iPFS	TP53 co-mutation: Worse iPFS (7.1 months vs 14.8 months)
Rangachari et al[3], 2015	Cohort (n = 351)	EGFR+ vs ALK+ with BM	EGFR+: Median age 65 years, 76% female	Mixed therapy	ALK+ comparison	Survival patterns	BM in 25.4% EGFR+, mOS 19.9 months post-BM
Magnuson et al[27], 2016	Cohort (n = 351)	Treatment-naïve with BM	Median age 65 years, 76% female, PS 0-2	RT deferral analysis	Upfront RT comparison	OS	Comparable survival: 46 months vs 46 months (P = 0.95)
Ballard et al[8], 2016	Cohort (n = 189)	Preclinical + clinical BM	Mixed characteristics	Osimertinib activity	Historical EGFR-TKI comparison	Response rates	Superior CNS penetration and activity
Magnuson et al[28], 2017	Cohort (n = 351)	EGFR-TKI-naïve with BM	Median age 65 years, 76% female, multiple BM 68%	Combined vs EGFR-TKI alone	EGFR-TKI monotherapy	Intracranial control	12 months IC progression: 21% vs 47% (P = 0.014)
Chen et al[29], 2019	Cohort (n = 105)	Asymptomatic BM	Median age 59 years, 62% female, PS 0-1	RT + TKI vs EGFR-TKI alone	EGFR-TKI monotherapy	iPFS, OS	iPFS: 19.1 months vs 10.2 months; OS: 41.2 months vs 23.1 months
Miyawaki et al[30], 2020	Cohort (n = 180)	EGFR+ with BM	Median age 64 years, 59% female, 1-3 BM 48%	Sequencing analysis	Treatment sequence comparison	iPFS	1-3 BM: Comparable; ≥ 4 BM: Benefit from upfront RT
Iuchi et al[5], 2013	Cohort (n = 41)	Japanese with BM	Median age 65 years, 61% female, PS 0-2	Gefitinib monotherapy	Historical controls	Response rate	Intracranial ORR: 87.8%, mOS: 18.8 months
Eichler et al[4], 2010	Cohort (n = 82)	NSCLC with BM	Median age 58 years, 57% female	Survival comparison	EGFR wild-type	OS	EGFR+: 15 months vs 5 months wild-type (P = 0.003)
Yamamoto et al[33], 2017	Cohort (n = 1194)	Multiple BM	Median age 64 years, 58% female, 2-10 BM	SRS outcomes	Single BM comparison	Toxicity, cognition	Low toxicity rates, preserved cognition
Tatineni et al[32], 2023	Cohort (n = 267)	NSCLC with BM	Median age 66 years, 59% female, 2010-2019 era	EGFR-TKI + RT	Historical comparison	Survival outcomes	Improved outcomes with modern approaches
Yan et al[20], 2019	Cohort (n = 89)	Leptomeningeal metastases	Median age 57 years, 62% female, poor PS	WBRT analysis	Non-WBRT comparison	OS	WBRT did not improve survival
Hsu et al[6], 2025	Cohort (n = 127)	Baseline BM	Median age 64 years, 65% female, treatment-naïve	1st vs 2nd gen EGFR-TKI	Generation comparison	PFS	2nd gen: Modest improvement (11.2 months vs 8.7 months)
Zhong et al[21], 2025	Cohort (n = 42)	Leptomeningeal metastases	Median age 58 years, 64% female, poor prognosis	Intrathecal pemetrexed	Historical controls	Response	Feasible but limited efficacy
Pan et al[34], 2025	Cohort (n = 156)	EGFR+ with BM	Median age 61 years, 58% female, multiple BM	Brain RT analysis	Non-RT comparison	Efficacy	RT benefit in patients (> 3 brain metastases, ECOG 0-2, and moderate-severe symptoms)
Dohm et al[22], 2022	Cohort (n = 389)	NSCLC BM	Median age 63 years, 56% female, mixed treatments	SRS + systemic therapy	Treatment comparison	OS	Variable outcomes by systemic therapy type

RCT: Randomized controlled trial; NSCLC: Non-small cell lung cancer; CNS: Central nervous system; BM: Brain metastases; PS: Performance status; PFS: Progression-free survival; OS: Overall survival; ORR: Objective response rate; iPFS: Intracranial progression-free survival; IC: Intracranial; RT: Radiotherapy; TKI: Tyrosine kinase inhibitor; HA-WBRT: Hippocampal avoidance whole brain radiotherapy; SRS: Stereotactic radiosurgery; WBRT: Whole brain radiotherapy; HVLT-R: Hopkins Verbal Learning Test-Revised; mPFS: Median progression-free survival; mOS: Median overall survival; HR: Hazard ratio.

Table 2 Quality assessment for randomized controlled trials (Cochrane risk of bias)

Ref.	Randomization process	Deviations from interventions	Missing outcome data	Measurement of outcomes	Selection of results	Overall risk
Soria et al[10], FLAURA	Low	Some concerns	Low	Low	Low	Some concerns
Ramalingam et al[9], FLAURA-OS	Low	Some concerns	Low	Low	Low	Some concerns
Reungwetwattana et al[24]	Low	Some concerns	Low	Low	Low	Some concerns
Cho et al[25], FLAURA Asian	Low	Some concerns	Low	Low	Low	Some concerns
Wu et al[11], AURA3-CNS	Low	Low	Low	Low	Low	Low
Brown et al[14], RTOG 0933	Low	Low	Some concerns	Low	Low	Some concerns
Brown et al[13], NCCTG N107C	Low	Low	Low	Low	Low	Low
Brown et al[15], SRS study	Low	Low	Low	Low	Low	Low
Jänne et al[26], FLAURA2-CNS	Low	Some concerns	Low	Low	Low	Some concerns
Li et al[19], FLOWERS	Low	Some concerns	Some concerns	Low	Low	Some concerns

Risk of bias assessment based on Cochrane RoB 2 tool. "Some concerns" primarily related to open-label study design in targeted therapy trials.

Table 3 Quality assessment for observational studies (Newcastle-Ottawa scale)

Ref.	Selection (0-4)	Comparability (0-2)	Outcome (0-3)	Total score	Quality rating
Shi et al[2], PIONEER	4	2	3	9	High
Gu et al[31]	3	1	3	7	High
Rangachari et al[3]	4	2	2	8	High
Magnuson et al[27], 2016	3	2	3	8	High
Ballard et al[8]	3	1	2	6	Moderate
Magnuson et al[28], 2017	4	2	3	9	High
Chen et al[29]	3	2	3	8	High
Miyawaki et al[30]	3	2	3	8	High
Iuchi et al[5]	2	1	2	5	Moderate
Eichler et al[4]	3	2	2	7	High
Yamamoto et al[33]	4	1	3	8	High
Tatineni et al[32]	3	2	3	8	High
Yan et al[20]	2	1	2	5	Moderate
Hsu et al[6]	3	2	2	7	High
Zhong et al[21]	2	1	2	5	Moderate
Pan et al[34]	3	2	2	7	High
Dohm et al[22]	4	2	3	9	High

Newcastle-Ottawa Scale scoring: Selection (representativeness, selection of controls, ascertainment of exposure, outcome not present at baseline), Comparability (design and analysis), Outcome (assessment, follow-up length, adequacy). High quality: ≥ 7 points; Moderate quality: 5-6 points; Low quality: < 5 points.

Table 4 Grading of Recommendations Assessment, Development and Evaluation Evidence Quality Assessment

Outcome	Studies (design)	Participants	Effect estimate	Quality of evidence	Rationale for downgrading
Third-generation EGFR-TKIs vs first/second-generation
Progression-free survival	4 RCTs	1201	HR: 0.46 (0.38-0.56)	High	No serious limitations
CNS objective response rate	3 RCTs	644	OR: 4.2 (2.8-6.3)	High	No serious limitations
Overall survival	2 RCTs	913	HR: 0.80 (0.64-0.99)	Moderate	Wide confidence intervals
Combined EGFR-TKI + radiotherapy vs EGFR-TKI alone
Intracranial control	6 observational	1156	HR: 0.52 (0.38-0.71)	Low	Observational studies with inherent limitations and significant heterogeneity between studies (I² > 50%)
Overall survival	4 observational	892	HR: 0.68 (0.51-0.91)	Low	Observational studies with inherent limitations and wide confidence intervals
Stereotactic radiosurgery vs whole brain radiotherapy
Cognitive preservation	3 RCTs	925	OR: 5.8 (3.2-10.5)	Moderate	Mixed population studies with limited EGFR-mutant specific data
Local control	5 mixed studies	1689	OR: 1.8 (1.2-2.7)	Low	Observational studies with inherent limitations and significant heterogeneity between studies (I² > 50%)
Treatment sequencing
Upfront EGFR-TKI vs Combined	4 observational	567	Variable outcomes	Very low	Observational studies with inherent limitations, significant heterogeneity between studies (I² > 50%), and wide confidence intervals

RCTs: Randomized controlled trials; CNS: Central nervous system; HR: Hazard ratio; EGFR: Epidermal growth factor receptor; TKI: Tyrosine kinase inhibitor; OR: Odds ratio.