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. Author manuscript; available in PMC: 2018 Jan 1.
Published in final edited form as: Cancer J. 2017 Jan-Feb;23(1):32–39. doi: 10.1097/PPO.0000000000000236

Table 2. Reports of retrospective trials evaluating of brain radiotherapy combined with immune checkpoint blockade in patients with melanoma.

Study N Treatment groups End point(s) Outcome Safety
Clinical Correlative
Knisely et al.20 77 Ipi +/- SRS (some also received WBRT or repeat SRS; doses not reported)
Ipi dose: not reported		 OS Median survival

  • SRS 4.9 mo

  • SRS+ ipi 21.3 mo


No difference in survival noted whether ipi given pre- or post-SRS		 Not reported Not reported
Bot et al.34‡ 1 Ipi+WBRT (4Gy × 5) for leptomeningeal disease
Ipi dose: 3mg/kg every 3 weeks for a planned four doses		 OS, RR 1.5 year survival
Complete radiographic response to CNS metastases		 Decrease in size of abscopal lung metastases following WBRT Not reported
Du Four et al.35‡ 3 Ipi + RT (3 patients had Stereotactic RT and 2 had WBRT; all had >1 RT course)
Ipi dose: 3mg/kg every 3 weeks for a planned four doses		 RR, AE First report of radionecrosis in patients treated with Ipi and radiotherapy Not reported Focal radiation necrosis noted
Silk et al.21 70 WBRT (30–37.5 Gy in 10–13) or SRS (14–24 Gy in 1–5 fractions)+/- Ipi
Ipi dose: 3 mg/kg every 3 weeks for a planned four doses		 OS, RR, AE Median survival

  • WBRT: 3 mo

  • SRS: 18.3 mo

  • SRS+ipi: 19.9 mo


Subset analysis showed SRS+ipi associated with improved overall survival (p=0.009)		 More patients with PR or SD in patients receiving ipi before RT Intratumoral hemorrhage with RT
Mathew et al.22 58 SRS (mean 20Gy) +/- Ipi
Ipi dose: 3 mg/kg every 3 weeks for a planned four doses		 OS, LC, freedom from new metastasis, AE Median survival:

  • SRS: ∼5mo

  • SRS+ipi: ∼7mo (NS)


Local control and freedom from new metastases not different between SRS and SRS+ipi		 No differences noted in outcomes based on when ipi was administered relative to RT No differences in intracranial hemorrhage
Du Four et al.36‡ 4 Ipi + RT (SRS or WBRT+SRS) (3-20Gy per 1-10 fractions)
Ipi dose: 3 mg/kg every 3 weeks for a planned four doses (n=3; dose blinded for 1 patient)		 RR, AE Time to histopathologically confirmed radionecrosis (six metastases total) following ipi and RT was 15 mo and 11 mo, respectively Not reported Symptomatic radiation necrosis in all patients
Tazi et al.23 10 SRS (dose not reported)+
IpiIpi dose: not reported		 OS, AE Median survival: 29.3 mo
Disease-specific graded prognostic assessment (DS-GPA) estimated mean survival was 9.1 months		 Not reported One patients with grade 3 GI toxicity
One with hypopituitarism
Patel et al. 24 54 SRS (15-21Gy in 1 fractions or hypofractionated in 3-5 fractions if cavity >40mm) +/- Ipi (within 4 months of SRS)
Ipi dose: not reported		 OS, LC, AE Median survival†:

  • SRS: 8mo

  • SRS+ipi: 8mo


Local control rates similar in both groups		 No differences noted in outcomes based on when ipi was administered relative to RT Radiation necrosis and intracranial hemorrhage not different in both groups
Schoenfeld et al.37 16 WBRT (median 36Gy) or SRS (median 22 Gy) + Ipi
Ipi dose: 3mg/kg (n=14) or 10mg/kg Ipi (n=2)		 OS, abscopal response, ir-AE Median survival: 14.4mo

  • SRS before ipi: 26mo

  • SRS after ipi: 6mo


(p < 0.001)		 63% of patients receiving cranial RT and ipi within 3mo demonstrated a size decrease in non-irradiated extracranial index metastasis No significant ir-AEs
Gerber et al.25 13 WBRT (median 30Gy in 10 fractions)+ Ipi
Ipi dose: 3 mg/kg (n=12), 10 mg/kg (n=1)		 OS, RR, AE Median survival: 4mo
4/9 evaluable patients demonstrated PR or SD by Modified WHO criteria		 5/9 evaluable patients demonstrated PR and SD by immune-related criteria Grade 3 cognitive change (n=1); All evaluated patients demonstrated new or increased intratumoral hemorrhage (n=10)
Kiess et al.38 46 SRS (median 21 Gy in 1 fraction) + Ipi
Ipi dose: 3 mg/kg (n=25) or 10 mg/kg (n= 21) every three weeks for 4 doses (induction), then maintenance every 3 mo (n=13)		 OS, LC, AE Median survival: 12.4 mo
OS: significantly worse in the SRS after Ipi cohort (P=0.008)
LC: no differences based on timing of Ipi before, during or after SRS		 Treated tumors increased to >150% pre-SRS size in 50% in SRS before or during Ipi versus 13% in patients treated with SRS after Ipi
1 patient demonstrated abscopal responses in pelvic and lung metastases		 Grade 3/4 toxicities occurred in 20% of patients
Intracranial hemorrhage in 40% of patients treated with SRS during Ipi
Shen et al39 193 (36 melanoma primary) SRS (15-24Gy in 1 fraction, 21-24 in 3 fractions, 25Gy in 5 fractions) + systemic therapy (including 20 with immunotherapy) OS, RR, AE Median survival for patients with melanoma brain metastasis:

  • SRS : 11.3 mo

  • SRS+ any systemic therapy: 25.2 mo (P<0.05)


Patients with metastatic melanoma treated with SRS were not specifically characterized		 Not reported Higher CNS toxicity with combined SRS and immune therapy
Ahmed et al.26 26 (73 metastases) +/- resection + nivo + SRS (most common 21 or 24 Gy in 1 fraction) within 6 mo of nivo
Analysis of subset of patients within larger trials NCT01176461 and NCT01176474 		OS, LC, LF, AE Median Survival: approximately 12 months from treatment start Not reported Hemorrhage and edema noted in failures
‡

Denotes report/series;

†

obtained from Kaplan-Meier curve; 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