Table 1. Reports of retrospective studies evaluating of extracranial radiotherapy combined with immune checkpoint blockade in patients with melanoma.

Study	N	Patient description	Treatment groups	End point(s)	Outcomes		Safety
					Clinical	Correlative
Postow et al.¹⁴^‡	1	Patient with metastatic melanoma receiving SBRT to paraspinal metastasis	Ipi+28.5Gy in 3 fractions Ipi dosing: 3mg/kg or 10mg/kg every three weeks	RR, abscopal response	Marked decrease in SBRT treated site as well as non-irradiated thoracic and splenic metastases 4 months post treatment	Combined ipi and RT resulted in anti-tumor immune activation increased titers of anti-NY-ESO antibodies increase in CD4+ ICOS^high cells decrease in myeloid derived suppressor cells	Asymptomatic hypothyroidism requiring thyroid hormone supplementation
Hiniker et al.³³^‡	1	Patient with melanoma receiving SBRT to liver metastasis	Ipi+ 54Gy in 3 fractions	RR, abscopal response	Complete radiographic resolution of all non-irradiated liver metastases with combined ipi and SBRT after having experienced POD on ipi alone	Not reported	Autoimmune hypophysitis treated with prednisone
Stamell et al.¹⁵^‡	1	Patient with metastatic melanoma receiving electron beam radiotherapy to scalp primary	Ipi+24Gy in 3 fractions Ipi dosing: 3mg/kg or 10mg/kg every three weeks	RR, abscopal response	Resolution of all non-irradiated in-transit metastases 8 months following initial therapy	When patient recurred and was treated with SRS, anti-melanoma antigen A3 (MAGEA3) antibodies were observed, implying radiation-induced immune activation	Not reported
Barker et al.¹⁷	29	Metastatic melanoma irradiated for extracranial metastases	Ipi+RT (median dose 30 Gy in 5 fractions) Ipi dosing ranged from 3mg/kg to 10mg/kg every three weeks for four doses	OS, safety	Median survival: RT during induction/maintenance Ipi: 9mo/39mo Differences likely due to selection bias	Decrease in absolute lymphocyte count noted in most patients after radiotherapy	Ir-AEs in10mg/kg versus 3mg/kg ipi dose: 25% versus 7% (p=0.005) RT related adverse events higher with EQD2 of >100Gy (α/β = 0.6)
Schiavone et al.¹⁶^‡	4	Mucosal melanoma of vagina (n=3) and cervix (n=1)	Ipi+RT (6Gy × 5) (n=3) Ipi+RT (2.15Gy × 28) (n=1) Ipi dosing: 3mg/kg or 10mg/kg every three weeks	RR	3 patients taken to post-RT surgery, 1 exhibited pCR, all exhibited complete radiographic response	Not reported	CTCAE grade 3 colitis and rash in 2 patients
Qin et al.¹⁸	88	Unresectable stage III or IV melanoma irradiated for extracranial metastases	Ipi +/- RT (variable dose/fractionation) Ipi dose: not reported	OS, PFS, RR	Median Survival: Ipi : 24.8 mo Ipi + RT: 17.9 mo Irradiated tumor response improved if Ipi administered prior to RT (74.7%) versus (44.8%) at 12 mo (P=0.01). No differences in ablative or conventional RT	Not reported	No differences in toxicities across treatment groups
Theurich et al.¹⁹	127	Stage IIIC and IV melanoma with cranial and extracranial metastases	Ipi +/- local peripheral therapy (radiation or electrochemotherapy) Ipi dosing: 3mg/kg or 10mg/kg every three weeks	OS, PFS, safety, immune response	Median survival: 13.8 mo Ipi : 10.5 mo Ipi + local peripheral therapy: 23.3 mo (P = 0.0028)	On multivariable analysis, local peripheral therapy associated with statistically significant survival benefit (P=0.05)	Ir-AEs not increased with combination treatment

^‡

Denotes case report/series; CR: complete response; PR: partial response; SD: stable disease; POD: progression of disease; LC: local control; LF: local failure; OS: overall survival; RR: response rate; pCR: pathological complete response; ipi: ipilimumab; nivo: nivolumab; SRS: stereotactic radiosurgery; NS: not significant; AE: adverse event ir-AE: immune related adverse events (ir-AE); RT: radiotherapy