Table 3 Prospective clinical studies with available results on the antitumor activity of combined radiation therapy and PD-1/PD-L1 blockade
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] |