Safety and Efficacy of Stereotactic Radiosurgery with Concurrent Targeted Systemic Therapy for Brain Metastases

Abstract

Data describing the safety and efficacy of central nervous system (CNS)-active targeted systemic therapies in combination with stereotactic radiosurgery (SRS, 1 fraction) and/or radiotherapy (SRT, 3-5 fractions) for brain metastases are emerging but limited. We report rates of local and intracranial failure and radiation necrosis in patients receiving CNS-active targeted systemic therapy and SRS/SRT. We retrospectively identified patients with intact brain metastases at two institutions from 2009-2022 who were treated with SRS/SRT and CNS-active targeted systemic therapy in any sequence. Patients were followed for a minimum of 3 months after SRS/SRT with brain MRI. Patients typically stopped the targeted agent 2-4 days prior to radiation and resumed 2-4 days after. Targeted therapies included inhibitors of ALK/ROS1 (Alectinib, Ceritinib, Crizotinib, Lorlatinib), EGFR (Afatinib, Erlotinib, Gefitinib, Osimertinib), BRAF (Dabrafenib, Encorafenib, Vemurafenib), MEK (Binimetinib, Trametinib), CDK 4/6 (Abemaciclib, Palbociclib, Ribociclib), HER2 (Afatinib, Lapatinib, Neratinib, Pertuzumab, Trastuzumab, T-DM1, T-DXd, Tucatinib), KRAS (Adagrasib and Sotorasib), PARP (Niraparib, Olaparib), VEGF(R) (Axitinib, Bevacizumab, Ramucirumab), and less-selective tyrosine (receptor) kinase inhibitors (Bosutinib, Brigatinib, Entrectinib, Lenvatinib, Pazopanib, Sorafenib, Sunitinib). Local failure (LF) and radiation necrosis were determined radiographically with clinical impression (grade 2 (symptomatic) or higher (G2+)) and compared between different systemic agents. The study included 95 patients with 310 metastases (SRS 246, SRT 64 metastases). Most common primary histologies were non-small cell lung cancer (36% 34/95), breast cancer (28% 27/95), and melanoma (16% 15/95). Overall survival at 1 and 2 years was 80% (76/95) and 55% (52/95), respectively. Median follow-up was 16.6 (range 3-91) months. Median tumor size was 7mm (range 1-75mm). Median number of brain metastases per patient was 2.5 (range 1-12). The G2+ radiation necrosis rate was 5.8% (18/310) while the LF rate was 9.7% (30/310) per metastasis. There was no significant difference in G2+ radiation necrosis by class of targeted therapy. Sixty-two percent (59/95) of patients experienced distant intracranial failure. Median intracranial progression free survival (PFS) was 8.0 (range 0.4-61.4) months. Although heterogeneous, patients treated with SRS/SRT and ongoing CNS-active targeted systemic therapies have on average >6 month intracranial PFS and little evidence of significant toxicity. We observed <6% G2+ radiation necrosis for this cohort, and no particular class of agent was associated with a significantly higher rate of G2+ radiation necrosis.