Integrating intracranial hypofractionated radiotherapy with immunotherapy for melanoma brain metastases: therapeutic impact and immune modulation.

Background: Combined radiotherapy and immunotherapy can enhance antitumor efficacy, but its effects on melanoma brain metastases (MBM) remain unclear.

Objectives: To evaluate the intracranial efficacy, safety, and exploratory immune biomarkers of zimberelimab combined with intracranial hypofractionated radiotherapy in patients with MBM.

Methods: Eligible patients were aged 18-75, had an Eastern Cooperative Oncology Group performance status of 0-2 and measurable brain metastases. Patients received 30-50 Gy/5-10 fractions intracranial hypofractionated radiotherapy and two cycles zimberelimab (240 mg every 3 weeks). The primary endpoint was the intracranial objective response rate (ORR). Secondary endpoints included the disease control rate, overall survival, progression-free survival (PFS), quality of life, safety and potential biomarkers. In addition, serum cytokines were profiled and linked to proteomics-based exploratory prognostic model constructed using the UK Biobank dataset.

Results: Between November 2022 and February 2025, 10 patients, with median age 60.5 years, completed the treatment, and their data were analyzed. The median intracranial metastatic lesion size was 2.4 cm (range 1.0-5.9 cm). The intracranial ORR was 70%, and intracranial disease control rate was 90%. The median overall survival and intracranial PFS were both 12 months, while the overall PFS was 10.5 months. The patients' quality of life improved, without grade ⩾3 treatment-related adverse events. Furthermore, post-treatment increases in selected immune-related biomarkers, such as CXCL9, were descriptively associated with treatment response, and baseline levels showed exploratory associations with survival outcomes.

Conclusion: HFRT plus zimberelimab demonstrated promising intracranial activity, quality of life improvement, and acceptable early safety in patients with MBM and may potentially induce an abscopal antitumor effect. Exploratory immune analyses suggest that baseline immune readiness and therapy-induced immune activation may be associated with treatment benefit.

Design: This was a prospective, single-arm, open-label phase II study.

Trial registration: ChiCTR, ChiCTR2200057001. Registered 25 February 2022 (https://www.chictr.org.cn/showproj.html?proj=153144).