Abstract
BACKGROUND
Brain metastases may affect 30% of patients with metastatic cancer and are a major cause for morbidity and mortality. Treatment approaches include neurosurgical interventions, various approaches of radiotherapy, notably radiosurgery, and systemic pharmacotherapy. Encouraging response rates and response duration have been observed in patients with melanoma and non-small cell lung cancer (NSCLC) and asymptomatic or oligo-symptomatic brain metastasis treated with novel systemic therapies including immune checkpoint inhibitors and targeted therapy, challenging the need for immediate radiosurgery and introducing a change into clinical practice not supported by data from controlled clinical trials.
METHODS
ETOP 19-21 USZ-STRIKE (NCT05522660) is a randomized phase III study conducted by the ETOP IBCSG Partners Foundation. Patients with brain metastases from melanoma or NSCLC are treated systemically with the most appropriate pharmacotherapy. Randomization determines whether they receive pharmacotherapy alone or in combination with radiosurgery. The primary endpoint is CNS-specific progression-free survival (PFS), locally assessed per iRANO criteria. Secondary endpoints include CNS-specific PFS per tumor cohort, objective CNS response rate, duration of CNS response, pattern of CNS-specific progression, extra-CNS progression, incidence of radionecrosis and pseudoprogression, overall survival, neurocognitive function, quality of life and functional independence, and toxicity. We assume that the addition of radiosurgery to systemic treatment increases median CNS specific PFS by 62% from a median of 4 and 8 months for melanoma and NSCLC, respectively, corresponding to a hazard ratio 0.62 for time to CNS failure. According to the log-rank test, at a one-sided significance level of 5%, 138 observed events yield 88% power, for a sample size of 190 patients. The trial is supported by philanthropic funds from the USZ foundation and conducted at 11 sites in four countries. Accrual is slower than predicted mostly because of equipoise and patient, caregiver and notably physician bias.