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Table 3 Prospective 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.
Phase I 4 solid tumors, 1 hematologic malignancy Atezolizumab 0.01–20 mg/kg every 3 weeks (dose-finding cohort) + local fractionated RT (dose NR) for mixed responses or asymptomatic PD Stabilization of systemic progression in all 5 patients (PR at systemic site in 1 patient) Transient grade 1–2 inflammatory AEs (fevers, flu-like symptoms) observed but no DLTs or serious immune-related AEs [134]
Phase I 9 advanced melanoma Nivolumab 0.3–10 mg/kg every 3 weeks X 21 weeks (induction) then every 12 weeks X 84 weeks (maintenance) ± ipilimumab 3 or 10 mg/kg every 3 weeks X 9 weeks (induction) then every 12 weeks X 84 weeks (maintenance) or combined nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks X 12 weeks then nivolumab 3 mg/kg every 2 weeks up to 96 weeks + RT (median 30 Gy X 5 fractions, range 21–37.5 Gy X 1–15 fractions) during induction or maintenance ORR 44% (4 PRs) as best response by WHO criteria; median OS 27 mo; 1- and 2-year OS rates of 89 and 78%, respectively 5 patients with non-laboratory grade ≥ 3 AEs, 2 RT-related grade ≥ 3 AEs (intracranial hemorrhage, diarrhea) [135]
Phase I/II 10 unresectable or metastatic solid tumors (≥5% PD-L1 expression) Durvalumab 10 mg/kg every 2 weeks + local RT (median 20 Gy, range 6–33 X median 5 fractions, range 1–10) given a median of 8.5 days (range 1–35) of last dose of durvalumab In-field ORR 60% (2/10 CRs, 4/10 PRs); median OS 11.5 mo (95% CI 8.8–13.7); median PSF 6.2 months (95% CI 4.5–12.4); out-of-field 10/14 SD, no responses or abscopal effects were seen 5 cases of (50%) RT-related grade 2 AEs (3 mucositis, 1 diarrhea, 1 vomiting) [136]
Phase I 24 metastatic pancreatic adenocarcinoma SBRT (8 Gy X 1 fraction or 25 Gy X 25 fractions) + durvalumab (dose NR) every 2 weeks or tremelimumab (dose NR) every 4 weeks X 6 doses then every 12 weeks for 3 doses or triple therapy SD as best ORR in 5 patients (21%) No DLTs observed; most common AE was grade 1–2 fatigue at dose level 2 [137]
Phase II 10 locally advanced NSCLC Weekly carboplatin (AUC 2) and weekly paclitaxel 50 mg/m2 + RT 5 days/week for 6–7 weeks (60–66 Gy over 30–33 fractions) followed by atezolizumab 1200 mg every 3 weeks + consolidation carboplatin (AUC 6) and paclitaxel 200 mg/m2 on days 1 and 22 for 2 cycles then atezolizumab alone up to 1 year Out of 7 patients receiving atezolizumab, 2 patients developed PD after 6 and 8 doses of atezolizumab 3 patients with potential immune-related AEs (1 grade 3 arthralgia, 1 grade 2 pneumonitis resolved with steroids, 1 grade 3 dyspnea) [138]
Phase III 709 stage III, locally advanced, unresectable NSCLC 2 or more cycles of platinum-based chemotherapy (defined by local practice) + concurrent definitive RT (54–66 Gy with mean dose to the lung < 20 Gy or volume of lung parenchyma receiving ≥20 Gy < 35%) followed by (within 1–42 days) durvalumab 10 mg/kg every 2 weeks up to 1 year or placebo if no PD during chemoradiation Median PFS 16.8 months (95% CI 13.0–18.1) vs. 5.6 months (95% CI 4.6–7.8) with placebo (HR 0.52, 95% CI 0.42–0.65, p < 0.001); median TTD or distant metastasis 23.2 months (95% CI 23.2-NE) vs. 14.6 months (95% CI 10.6–18.6) with placebo (HR 0.52, 95% CI 0.39–0.69, p < 0.001); ORR 28.4% vs. 16.0% with placebo (p < 0.001) Grade 3–4 AEs 29.9% vs. 26.1% (placebo); most common grade 3–4 AEs pneumonia (4.4% vs. 3.8%), pneumonitis (3.4% vs. 2.6%), and anemia (2.9% vs. 3.4%) in durvalumab vs. placebo arms [139]
  1. RT radiation therapy, NR not reported, PD progressive disease, PR partial response, DLT dose-limiting toxicity, AEs adverse events, Gy Gray, ORR overall response rate, PR partial response, WHO World Health Organization, CI confidence interval, SD stable disease, SBRT stereotactic body radiation therapy, NSCLC non-small cell lung cancer, AUC area under curve, CR complete response, PFS progression-free survival, HR hazard ratio, TTD time to death, NE not estimable or reached