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Table 2 Retrospective clinical studies with available results on the antitumor activity of combined radiation therapy and PD-1/PD-L1 blockade

From: Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination

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]
  1. RS retrospective study, BMs brain metastases, SRS stereotactic radiosurgery, FSRT fractionated stereotactic RT, Gy Gray, OS overall survival, NSCLC non-small cell lung cancer, IQR interquartile range, CNS central nervous system, RT radiotherapy, WBRT whole brain radiation therapy, ORR overall response rate, NR not reported, CI confidence interval, CR complete response, PR partial response, SD stable disease, PD progressive disease, AEs adverse events, RCC renal cell carcinoma, GI gastrointestinal, HR hazard ratio, PFS progression-free survival, NA not applicable