Study | n | Design | Outcomes | Toxicities | Ref. |
---|---|---|---|---|---|
RS | 26 | Melanoma BMs treated with SRS or FSRT (16–30 Gy X 1–5 fractions) within 6 mo of nivolumab (1, 3, or 10 mg/kg every 2 weeks for 12 doses then every 12 weeks for 8 doses) | Median OS 11.8 mo (range 0.5–33.9) and 1-year OS 55% in unresected BMs; median OS not reached and 1-year OS 100% in resected BMs | 1 grade 2 headache relieved with steroids | [114] |
RS | 96 | Melanoma BMs treated with SRS (majority 24 Gy X 1 fraction) within 3 mo of nivolumab 3 mg/kg every 2 weeks, pembrolizumab 2 mg/kg every 3 weeks, or other systemic therapies | 6- and 12-mo distant BM control rate 61%/38% anti-PD-1, 26%/21% anti-CTLA-4, 53%/20% BRAF/MEK inhibitor, 15%/5% chemotherapy (p = 0.008); 6- and 12-mo OS 81%/66% anti-PD-1, 84%/50% anti-CTLA-4, 83%/75% BRAF/MEK inhibitor, 70%/15% chemotherapy (p = 0.004) | For anti-PD-1 therapy: 1 grade 2 headache managed with steroids | [113] |
RS | 24 | Melanoma and NSCLC BMs treated with SRS (median 20 Gy/fraction, IQR 16–21) within median 19 weeks (range 0–107) of nivolumab or pembrolizumab (median 5 cycles, IQR 3–6) | 6- and 12-mo OS 85 and 78%; median OS not reached; 6- and 12-mo distant brain progression rate 37 and 65% | 2 patients grade ≥ 3 CNS toxicity: 1 seizure and 1 symptomatic radionecrosis requiring surgery | [115] |
RS | 53 | Metastatic melanoma treated with extracranial RT/intracranial SRS (8–30 Gy X 1–10 fractions) or WBRT (median 30 Gy X10 fractions) and pembrolizumab 2 mg/kg every 3 weeks or nivolumab 3 mg/kg every 2 weeks as concurrent, sequential, or salvage (following progression on anti-PD-1 therapy) therapy | Medians OS 6.4 vs. 8.6 mo (p = 0.7672) for concurrent vs. sequential RT/SRS; ORR 31% vs. 36% (p = 1) for concurrent vs. sequential RT/SRS; lesional response rate 45% for 30 progressing lesions treated with salvage RT/SRS | For RT arm: 3 patients grade ≥ 3 rash, 1 grade ≥ 3 diarrhea, 2 grade ≥ 3 radiation dermatitis, 1 grade ≥ 3 radionecrosis; for WBRT arm: 1 grade ≥ 3 nausea, 1 grade ≥ 3 cognitive changes, 2 grade ≥ 3 rash | [116] |
RS | 75 | Melanoma BMs treated with SRS (median 20 Gy, range 12–24 Gy) within ±4 weeks (concurrent) of pembrolizumab 2 or 10 mg/kg every 2–3 weeks or nivolumab 3 mg/kg every 2–3 weeks or ipilimumab | Median % lesion volume reduction at 3 mo (− 83.0% vs. -52.8%, p < 0.0001) and 6 mo (− 94.9% vs. -66.2%, p < 0.0001) for concurrent vs. noncurrent; median % lesion volume reduction at 3 mo (− 89.3% vs. -66.2%, p < 0.0001) and 6 mo (− 95.1% vs. -75.9%, p = 0.0004) for anti-PD-1 vs. anti-CTLA-4 | NR | [117] |
RS | 21 | Metastatic NSCLC treated with RT (8–30 Gy X 1–10 fractions) while receiving anti-PD-1, anti-PD-L1, and/or anti-CTLA-4, or other immune therapy | 6- and 12-mo local control rates 91.7 and 85.2%; median time to systemic progression 2.3 mo (95% CI 1.0–4.5); median OS 7.2 mo (95% CI 4.2–11.1) | 1 grade 4 cerebral edema (WBRT) and 1 grade 3 pneumonitis | [118] |
RS | 25 | Unresectable melanoma treated with hypofractionated RT (1 weekly fraction over 4–5 weeks (84%) or 1 gammaknife RT for BMs (16%)) within 3 mo of anti-PD-1 (early) or > 3 mo after anti-PD-1 therapy (late) | CR, PR, SD, and PD rates for radiated sites 24, 8, 44, and 28% and for nonirradiated sites 29, 19, 19, and 33%, respectively; abscopal responses (CR or PR) in 56% for addition of late RT | No unusual AEs reported | [119] |
RS | 15 | Metastatic melanoma, RCC, NSCLC treated with palliative RT (total 8–36 Gy via 3–8 Gy fractions) within ±75 days of PD-1 inhibitor | Safety analysis | All-grade immune-related AEs in 3 patients (20%) and 1 RT-related AE (7%) of moderate mucositis; no cases of pneumonitis | [123] |
RS | 84 | Metastatic melanoma, NSCLC, and other solid tumors treated with thoracic RT (median total dose 3000 cGy (range 600–7400 X 10 fractions) within 1 month (concurrent) or up 6 months (sequential) of PD-1/PD-L1 and/or CTLA-4 blockade | No significant differences in toxicity rates between PD-1/PD-L1 and CTLA-4 inhibitors or concurrent and sequential treatment | For all-grade AEs: 6 patients with pneumonitis (7.2%, 1 grade ≥ 3); for grade ≥ 2 AEs: 14 fatigue, 9 rash, 10 GI toxicities, 12 infections, 8 thyroid dysfunction, 7 renal injury, and 9 other | [124] |
RS | 29 | Metastatic NSCLC treated with thoracic RT (10–70 Gy X 1–35 fractions) within 6 mo of PD-1/PD-L1 and/or CTLA-4 blockade | Median PFS and OS of 3.8 mo (95% CI 1.9–8) and 9.2 mo (95% CI 5.1-not reached) | Possible treatment-related AEs: 1 grade 5 pneumonitis and 2 grade 3 pneumonitis | [125] |
RS | 133 | Metastatic NSCLC, melanoma, and RCC treated with palliative RT (8–37.5 Gy X 1–15 fractions) within 180 days of PD-1 or CTLA-4 inhibitor | No significant difference in immune-related AEs between those receiving RT during/after checkpoint inhibitors and before checkpoint inhibitors (p = 0.053), receiving RT within 14 days or outside 14 days of checkpoint blockade (p = 0.06), and of site of irradiation | All-grade immune-related AEs: 20% dermatitis, 8% colitis, 5% transaminitis; grade ≥ 3 immune-related AEs: 4% colitis, 2% transaminitis, 2% hypophysitis | [127] |
RS | 137 | Metastatic NSCLC, melanoma, and RCC treated with WBRT (12–39 Gy), SRS (15–30 Gy), or extracranial RT (8–66 Gy) within a median 85 days (IQR 34–181) of anti-PD-1 therapy | Median OS 249 days (IQR 90–689) following PD-1 blockade; on multivariate analysis HR for death 3.1 (95% CI 1.7–5.9) for NSCLC and HR 3.2 (95% CI 1.2–7.9) for RCC vs. melanoma (p = 0.0008) | No grade 4–5 immune-related AEs | [120] |
RS | 17 | NSCLC BMs treated with SRS or FSRT (18–25 Gy X 1–5 fractions) within ±6 mo of nivolumab or durvalumab | Distant brain control rate 57% (RT during or before PD-1/PD-L1 blockade) vs. 0% (RT after, p = 0.05); median OS for SRS during/before PD-1/PD-L1 blockade vs. SRS after (HR 3.6, 95% CI 0.74–26.9, p = 0.11) on multivariate analysis | No neurologic/ cutaneous AEs with SRS and anti-PD-1/PD-L1 therapy (41% received prophylactic dexamethasone before SRS); 1 patient each discontinued PD-1/PD-L1 inhibitor due to colitis and pneumonitis | [128] |
RS | 137 | Melanoma BMs treated with SRS or WBRT (median 20 Gy, range 12–30) within 1 year of PD-1 or CTLA-4 blockade | Median OS 16.9 mo; for radionecrosis: 37 patients (27%); no difference in risk between ipilimumab and pembrolizumab (p = 0.549) or CTLA-4 and PD-1 (p = 0.86); 1-year OS 78.4% vs. 55.06% (without radionecrosis, p = 0.341) | See outcomes | [129] |
RS | 98 | Advanced NSCLC treated with palliative RT any time point before (median 9.5 mo, range 1–106) first cycle of pembrolizumab 2 or 10 mg/kg every 2–3 weeks | Any previous RT vs. no previous RT: median PFS 4.4 mo (95% CI 2.1–8.6) vs. 2.1 mo (95% CI 1.6–2.3, HR 0.56, 95% CI 0.34–0.91, p = 0.019); median OS 10.7 mo (95% CI 6.5–18.9) vs. 5.3 mo (95% CI 2.7–7.7, HR 0.58, 95% CI 0.36–0.94, p = 0.026) | All-grade treatment-related pulmonary toxicity in 3 patients (13%, with RT) vs. 1 (1% without RT, p = 0.046); grade ≥ 3 treatment-related pulmonary toxicity similar in both arms (1 each, p = 0.44) | [121] |
RS | 108 | Melanoma BMs treated with SRS and/or WBRT (dose NR) within ±6 weeks of various systemic therapies | In combination with RT: median OS 7.5 mo with CTLA-4 (95% CI 4.4–15.6), 20.4 mo PD-1 (95% CI 8.8-NA), and 17.8 mo BRAF ± MEK inhibitor (95% CI 11.8-NA) | 2 radiation necrosis (SRS + anti-PD-1) treated with surgery, steroids, and bevacizumab | [122] |