3. Selected studies investigating safety of combined RT and ICI in BM.

Authors	Study characteristics	Explore	RT-related toxicities
RT, radiotherapy; ICI, immune checkpoint inhibitor; BM, brain metastases; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery; PBI, partial brain irradiation; RN, radiation necrosis; SRT, stereotactic radiotherapy; CT, chemotherapy; TT, target therapy; AE, adverse event; TRIC, treatment-related imaging change.
Williams et al. (35)	Phase I study involving 16 patients with BM from melanoma	WBRT vs. SRS + ipilimumab	21 grade 1−2 neurotoxicities; no grade 4−5 toxicity or RN
Mathew et al. (81)	Retrospective study involving 58 patients with BM from melanoma	SRS ± ipilimumab	Intratumoral hemorrhage in 28.0% of patients receiving SRS + ipilimumab vs. 30.3% of patients receiving SRS.
Silk et al. (88)	Retrospective study involving 70 patients with BM from melanoma	RT (WBRT/SRS) ± ipilimumab	Intratumoral hemorrhage in 12.5% of patients receiving RT vs. 3.9% of patients receiving RT + ipilimumab; RN in 9.38% of patients receiving RT vs. none of patients receiving RT + ipilimumab
Chen et al. (89)	Retrospective study involving 260 patients with BM from melanoma, NSCLC, or RCC	SRS ± ICI	RN occurred in 3% of patients, this was not significantly different among patients who received SRS alone, SRS and non-concurrent ICI, and concurrent SRS and ICI.
Patel et al. (95)	Retrospective study involving 54 patients with BM from melanoma	SRS ± ipilimumab	RN in 21% of patients receiving SRS vs. 30% of patients receiving SRT + ipilimumab (P=0.078); intratumoral hemorrhage in 14.7% of patients receiving SRS vs. 15.0% of patients receiving SRT + ipilimumab (P=1.00)
Diao et al. (98)	Retrospective study involving 72 patients with BM from melanoma	SRS ± ipilimumab (concurrent: 59 lesions; nonconcurrent: 160 lesions; none: 91 lesions	RN in 3% of patients receiving concurrent therapy and 2% in those receiving nonconcurrent therapy; TRIC in 8% of patients receiving concurrent therapy and in 6% of those receiving nonconcurrent therapy; no patients receiving SRS alone had RN or symptomatic TRIC; the overall incidence of any lesion hemorrhage was 18%, nonconcurrent ipilimumab was associated with lower risk of lesion hemorrhage compared with concurrent ipilimumab
Fang et al. (99)	Retrospective study involving 137 patients with BM from melanoma	SRS + CT and/or ICI	RN in 27% of patients, including in 12.5% of patients receiving ipilimumab and 7.4% of patients receiving pembrolizumab.
Kaidar-Person et al. (100)	Retrospective study involving 58 patients with BM from melanoma	SRS ± ICI	RN in 28% of patients receiving SRS + ICI vs. none of patients receiving SRS alone.
Hubbeling et al. (102)	Retrospective study involving 163 patients with BM from NSCLC	RT (WBRT/SRS/PBI) vs. RT + ICI	RN occurred in only one patient (grade 4, RT cohort); the incidence of grade ≥3 AEs was 8%−13% across treatment groups, and did not differ significantly between RT + ICI and RT cohorts.
Skrepnik et al. (107)	Retrospective study involving 25 patients with BM from melanoma	SRS + ipilimumab	RN in 21% of patients
Martin et al. (131)	Retrospective study involving 480 patients with BM from melanoma, NSCLC, or RCC	SRS/SRT vs. SRS/SRT + ICI	Symptomatic RN in 7% of patients receiving SRS/SRT vs. 20% in patients receiving SRS/SRT + ICI
Colaco et al. (132)	Retrospective study involving 180 patients with BM from various tumor types	RT + ICI, CT, and/or TT	RN in 21.7% of patients including 16.9% in patients receiving RT + CT, 25.0% in patients receiving RT + TT, and 37.5% in patients receiving RT + ICI