Ctim-03. long term follow-up of a prospective safety and toxicity study of immune checkpoint inhibitor therapy initiated 8 days prior to radiosurgery for melanoma brain or spine metastasis

Abstract We conducted a pilot study of checkpoint inhibitor (ICI) therapy followed in eight days(+/- 2) by initiation of SRS for brain or spine metastasis based on murine experiments of pre-SRS initiation of ICI. Alternative time intervals would be tested If there was >33% dose limiting toxicity(DLT) >Gr3 by CTCAE 4.0 within 12 weeks of treatment initiation (excluding Gr3 tumor flare, rash, immune reaction resolving to gr1 in <28 days). Initially ipilimumab was used, with protocol change to nivolumab as standard of care evolved. Treatment continued until DLT, progression, or clinical decision to end therapy. Dosing and timing of subsequent cycles were by institutional preference. Eligibility included melanoma with newly diagnosed unirradiated brain or spine metastasis, at least one >3 mm, no autoimmune diseases. Twenty-one patients enrolled, 17(81%) treated with nivolumab, 20(95%) had brain metastasis. The median baseline number of brain metastasis was 2(1-9). 7 subjects (33%) had only one brain met. Seven subjects(33%) were free of extra-CNS metastasis at baseline; 5(23%) had 1-5 systemic metastasis (oligometaststic), and 9 subjects(43%) had 6 or more systemic metastasis. Median number of cycles of checkpoint inhibitor therapy was 3 (1-37). The grade 3 toxicities (no grade 4 and 5) with possible, probable, or definite attribution to ipilimumab were colitis(4.8%), diarrhea(9.5%), fatigue(4.8%), muscle weakness (4.8%), and headache(4.8%). One subject had colitis as a DLT. No toxicity >3 or above was associated with nivolumab. Estimated median overall survival was 37.4 months, within minimum f/u of 8 surviving patients of 40 months (40-68). Three-year OS rate was 52%. Checkpoint inhibitor therapy initiated 8 days prior to SRS was safe and survival outcome is favorable. Peripheral blood Immune correlative studies are pending. Prospective data is needed to define optimal safety, timing, and outcome of concurrent checkpoint inhibitor therapy and radiosurgery for melanoma metastatic to the brain.