Stereotactic Radiosurgery/TKIs Improves CNS Outcomes in EGFR/ALK+ NSCLC

“…In this multi-institutional cohort study, we found that the addition of up-front SRS to CNS-penetrant TKI improved time to CNS progression and local control, whereas no significant differences were observed in OS," according to the study authors.

Combining up-front stereotactic radiosurgery (SRS) with central nervous system (CNS)–penetrant tyrosine kinase inhibitors (TKIs) improved time to CNS progression and local control but did not prolong overall survival (OS) among patients with EGFR- or ALK-driven non–small cell lung cancer (NSCLC) and brain metastases, according to findings from the retrospective TURBO-NSCLC study published in Journal of Clinical Oncology.

The median OS was 41 months (95% CI, 35-not reached [NR]) in the TKI alone cohort vs 40 months (95% CI, 34-NR) in the TKI/SRS group (log-rank P = .5; multivariate HR, 0.96; 95% CI, 0.64-1.44; P = .8). Factors such as ALK driver alterations and a Karnofsky performance status of 90 to 100 correlated with improved OS (HR, 0.66; HR, 0.75, respectively) based on multivariate analysis; extracranial metastases were associated with worse OS outcomes (HR, 2.02).

After adjusting for baseline characteristics, combining SRS with TKIs conferred a significant improvement in time to CNS progression (HR, 0.63; 95% CI, 0.42-0.96; P = .033). Of note, the presence of brain metastases that were 1 cm or larger correlated with a shorter time to CNS progression (HR, 2.05; 95% CI, 1.28-3.20; P = .003). Investigators observed no differences in time to CNS progression outcomes when stratifying patients by EGFR-only or ALK-only disease.

The cumulative rate of local CNS progression at 12 months was 21% in patients who received TKIs alone vs 5% in the SRS/TKI group; the 24-month rates in each respective cohort were 25% vs 9% (P <.001). Combining SRS with TKIs was associated with improvements in local progression outcomes per multivariate analysis (HR, 0.30; 95% CI, 0.16-0.55; P <.001). The involvement of brain metastases that were 1 cm or larger conferred worse local progression outcomes (HR, 2.60; 95% CI, 1.36-4.96; P = .004).

“…In this multi-institutional cohort study, we found that the addition of up-front SRS to CNS-penetrant TKI improved time to CNS progression and local control, whereas no significant differences were observed in OS. In analyses stratifying patients by [brain metastases of 1 cm or larger], a greater benefit from up-front SRS was observed in patients with larger tumors,” Luke R.G. Pike, MD, DPhil, director of Brain Radiation Oncology and assistant attending radiation oncologist at Memorial Sloan Kettering Cancer Center, and coauthors wrote. “These data may better inform individualized treatment decisions for patients with [brain metastases] who are eligible for CNS-penetrant TKIs.”

Investigators of this retrospective study assessed data on patients who underwent treatment at 7 academic medical centers across the United States. The analysis included those with EGFR-mutated or ALK-rearranged NSCLC and intraparenchymal brain metastases who received prior treatment with CNS-penetrant TKIs with or without up-front SRS.

Demographic characteristics of interest included age, sex, smoking status, disease stage, Karnofsky performance status, number and size of brain metastases at presentation, and neurologic symptoms. The trial’s primary end points were time to CNS progression and OS, and secondary end points of interest included subtype of CNS progression, patterns of first progression, leptomeningeal progression, and neurologic mortality. Investigators employed the Fine and Gray method to conduct univariable and multivariate regression models for CNS and local progression as well as Cox regression to assess OS.

The analysis included a total of 317 patients who met inclusion criteria and underwent treatment with TKIs alone (n = 200) or TKIs plus SRS (n = 117). The median age at diagnosis was 62 years. In the TKI alone and TKI/SRS groups, respectively, most patients were female (66% vs 64%), had never smoked (75% vs 76%), stage IV disease (91% vs 88%), and EGFR driver alterations (78% vs 80%). Additionally, most patients in each group had extracranial metastases (91% vs 78%), a Karnofsky performance status of 80 or below (63% vs 52%), and no neurological resection before study treatment (91% vs 74%).

In the TKI-alone and TKI/SRS groups, respectively, the most common TKI therapies included osimertinib (Tagrisso; 78% vs 80%) and alectinib (Alecensa; 20% vs 18%). Additionally, 94% of patients in the TKI-alone cohort received no prior lines of systemic therapy compared with 89% in the TKI/SRS group.

Data showed a distant-only CNS progression rate of 16% in the TKI only group vs 25% in the TKI/SRS group; local failure as a component of CRS progression was reported in 25% and 12% of patients, respectively (P = .008). Investigators reported no significant differences in leptomeningeal progression, neurologic mortality, time to salvage whole-brain radiotherapy, or hospitalizations associated with CNS between these groups.

Reference

Pike LRG, Miao E, Boe LA, et al. Tyrosine kinase inhibitors with and without up-front Stereotactic radiosurgery for brain metastases from EGFR and ALK oncogene–driven non–small cell lung cancer (TURBO-NSCLC). J Clin Oncol. Published online July 24, 2024. doi:10.1200/JCO.23.02668