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

StudynDesignOutcomesToxicitiesRef.
Phase I4 solid tumors, 1 hematologic malignancyAtezolizumab 0.01–20 mg/kg every 3 weeks (dose-finding cohort) + local fractionated RT (dose NR) for mixed responses or asymptomatic PDStabilization 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 I9 advanced melanomaNivolumab 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 maintenanceORR 44% (4 PRs) as best response by WHO criteria; median OS 27 mo; 1- and 2-year OS rates of 89 and 78%, respectively5 patients with non-laboratory grade ≥ 3 AEs, 2 RT-related grade ≥ 3 AEs (intracranial hemorrhage, diarrhea)[135]
Phase I/II10 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 durvalumabIn-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 seen5 cases of (50%) RT-related grade 2 AEs (3 mucositis, 1 diarrhea, 1 vomiting)[136]
Phase I24 metastatic pancreatic adenocarcinomaSBRT (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 therapySD as best ORR in 5 patients (21%)No DLTs observed; most common AE was grade 1–2 fatigue at dose level 2[137]
Phase II10 locally advanced NSCLCWeekly 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 yearOut of 7 patients receiving atezolizumab, 2 patients developed PD after 6 and 8 doses of atezolizumab3 patients with potential immune-related AEs (1 grade 3 arthralgia, 1 grade 2 pneumonitis resolved with steroids, 1 grade 3 dyspnea)[138]
Phase III709 stage III, locally advanced, unresectable NSCLC2 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 chemoradiationMedian 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]

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