1. Median overall survival was 41 months in the TKI-only group vs 40 months in the TKI-SRS group, with HR 0.96 (non-significant).
2. Time to CNS progression was improved in the TKI-SRS group with HR 0.63 (significant), and this was especially seen in patients with BM ≥1 cm, HR 0.60 (significant).
Evidence Rating Level: 2 (Good)
Study Rundown: Stereotactic radiosurgery (SRS) is the preferred radiation treatment for limited brain metastases (BM) in EGFR/ALK-mutated non-small cell lung cancer (NSCLC) however newer-generation tyrosine kinase inhibitors (TKIs) have shown promising CNS response rates. This retrospective study investigated the efficacy of TKIs with and without SRS in improving CNS control. The primary endpoints included time to CNS progression and overall survival (OS). Median OS was 41 months in the TKI-only group vs 40 months in the TKI-SRS group, with HR 0.96 (non-significant). Cumulative incidence of CNS progression at 12 months was 29% vs 17%, and at 24 months was 39% vs 34% for TKI-only and TKI-SRS groups, respectively. Time to CNS progression was improved in the TKI-SRS group with HR 0.63 (significant), and this was especially seen in patients with BM ≥1 cm, TKI-SRS had an HR 0.60 (significant). In a subset analysis, it was found that the cumulative incidence of CNS progression for patients with BM ≥1 cm was 41% vs 20% at 12 months and 51% vs 35% at 24 months for TKI-only vs TKI-SRS groups, however for patients with subcentimeter BM, there were no significant differences found. Cumulative incidence of local CNS progression was 21% vs 5% at 12 months and 25% vs 9% at 24 months in the TKI-only vs TKI-SRS group, with TKI-SRS having an HR 0.30 (significant). The TKI-SRS group had improved progression rates in both BM>1cm patients and subcentimeter BM. Distant CNS progression was seen at 8% vs 12% at 12 months and 14% vs 25% at 24 months in the TKI-only and TKI-SRS groups respectively. There was some trend to improved progression-free survival and event-free survival in the TKI-SRS group for patients with BM >1cm. There were no significant differences in CNS versus extra-CNS progression, rates of salvage brain radiation, leptomeningeal progression, neurologic mortality, time to salvage WBRT, or CNS-related hospitalizations between the treatment groups. The strength of this study included its sample size, and the limitations of this study included its methodology and non-balanced treatment arms. This study found that TKI with SRS showed some improvement with time to CNS progression and local control, especially in patients with larger brain metastases, though no significant difference in overall survival was observed.
Click to read the study in JCO
In-Depth [ retrospective cohort]: This multi-institutional retrospective cohort identified patients between January 2013 to June 2022 with EGFR/ALK mutated NSCLC with intraparenchymal BM treated with CNS-penetrant TKIs with (n=117) or without (n=200) up-front SRS. SRS had to be delivered within 8 weeks of initiating TKI. Among patients, 79% had EGFR mutations and 21% had ALK mutations. The most common TKI used was osimertinib (79%) followed by alectinib (19%), brigatinib (2%), and ensartinib (0.3%). Some differences observed between TKI-SRS vs TKI-only group included BM>1cm (77% vs 46%, p<0.001), pretreatment neurologic symptoms (52% vs 27%, p<0.001), neurosurgical resection (26% vs 9.5%, p<0.001), and extracranial mets (78% vs 91%, p<0.001), respectively. Median follow-up time was 23 months in the TKI-only group and 26 months in the TKI-SRS group. Median OS was 41 months (95%CI, 35-NR) in the TKI-only group vs 40 months (95%CI, 34-NR) in the TKI-SRS group, with HR 0.96 (95%CI, 0.64-1.44], p=0.8). There were no differences in OS when stratified by mutation. Cumulative incidence of CNS progression at 12 months was 29% vs 17%, and at 24 months was 39% vs 34% for TKI-only and TKI-SRS groups, respectively (p=0.12). Time to CNS progression was improved in the TKI-SRS group with HR 0.63 (95%CI, 0.42-0.96, p=0.033), and this was especially seen in patients with BM ≥1 cm, TKI-SRS had an HR 0.60 (95%CI, 0.37-0.97, p=.036). In a subset analysis, it was found that cumulative incidence of CNS progression for patients with BM ≥1 cm was 41% vs 20% at 12 months and 51% vs 35% at 24 months for TKI-only vs TKI-SRS groups (p=0.016), however for patients with subcentimeter BM, there were no significant differences found (p=0.2). Cumulative incidence of local CNS progression was 21% vs 5% at 12 months and 25% vs 9% at 24 months in the TKI-only vs TKI-SRS group (p<0.001), with TKI-SRS having an HR 0.30 (95%CI, 0.16-0.55, p<0.001). The TKI-SRS group had improved progression rates in both BM>1cm patients (p<0.001) and subcentimeter BM (p=0.025). Distant CNS progression was seen at 8% vs 12% at 12 months and 14% vs 25% at 24 months in the TKI-only and TKI-SRS groups respectively (p=0.09). There was some trend to improved progression-free survival and event-free survival in the TKI-SRS group for patients with BM >1cm. There were no significant differences in CNS versus extra-CNS progression, rates of salvage brain radiation, leptomeningeal progression, neurologic mortality, time to salvage WBRT, or CNS-related hospitalizations between the treatment groups. This study found that TKI with SRS showed some improvement with time to CNS progression and local control, especially in patients with larger brain metastases, though no significant difference in overall survival was observed.
Image: PD
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