Osimertinib and Stereotactic Radiosurgery for Brain Metastases in EGFR-Mutated Lung Cancer: The STARLET Joint Analysis of OUTRUN and LUOSICNS Randomized Trials.

[INTRODUCTION] Clinical guidelines recommend upfront osimertinib monotherapy for asymptomatic brain metastases (BM) in EGFR-mutant NSCLC, despite a lack of randomized trial evidence. We conducted two randomized phase II trials, OUTRUN and LUOSICNS, to evaluate the efficacy and safety of upfront stereotactic radiosurgery (SRS) plus osimertinib versus osimertinib in this patient population.

[METHODS] Participants with up to ten BM amenable to SRS were randomized 1:1 to SRS followed by osimertinib (80 mg daily) or osimertinib monotherapy. SRS was delivered as a single or multi-fraction regimen. The primary end point was 12-month intracranial progression-free survival (ic-PFS). Key secondary end points include overall survival (OS), patterns of intracranial progression, and safety. Data from both trials were prospectively pooled for a joint analysis.

[RESULTS] Overall, 79 participants were randomized. At a median follow-up of 39.0 months, 12-month ic-PFS was not significantly different between SRS plus osimertinib (n = 39) than osimertinib monotherapy (n = 40) (11%, 95% CI: -10% to 32%, p = 0.31; median ic-PFS 21.9 mo versus 17.2 mo). Median OS was 46.1 versus 29.1 months. Among those with intracranial progression, 35% in the SRS plus osimertinib group and 57% in the osimertinib monotherapy group underwent SRS at progression. Grade 3/4 radionecrosis occurred in 5% of participants treated with SRS plus osimertinib.

[CONCLUSIONS] Adding upfront SRS to osimertinib did not significantly improve 12-month ic-PFS in EGFR-mutant NSCLC with BM. This represents the first randomized evidence supporting the use of osimertinib monotherapy as upfront therapy in minimally symptomatic patients with low-burden BM.

[GOV IDENTIFIER] OUTRUN: NCT03497767; LUOSICNS: NCT03769103.