Table 1. Recruiting phase 3 trials combining radiotherapy and immunotherapy. Immunotherapy is prescribed concomitant and adjuvant for different cycles even up to more than 2 years, always in the absence of disease progression or unacceptable toxicity. The selected trials are divided into 3 categories of research interest and the use of IO: Induction [1], concomitant (concurrent) [2], and adjuvant (consolidation) [3] use of IO in combination with RT. Several combinations are possible.
| Disease | ClinicalTrials.gov identifier | Location | Category | Radiotherapy/chemotherapy | Immunotherapy | Randomization | Primary outcome |
|---|---|---|---|---|---|---|---|
| Glioblastoma | NCT02667587 | US | 2 | Standard RT 60 Gy (30×) + temozolomide | Nivolumab IV infusion; specified dose on specified days, start during CRT | C: CRT, E: CRT + IO | PFS + OS |
| Glioblastoma | NCT03548571 | EU | 3 | Standard RT: 60 Gy (30×) + concomitant + adjuvant temozolomide | Leukapheresis: before start of RT. Dendritic cell immunization starting first week after finalizing RT | C: CRT, E: CRT + sequential IO | PFS |
| High-risk neuroblastoma | NCT01704716 | EU | 2 | RT to the primary tumor. All different CT (vincristine, carboplatin, cisplatinum, etoposide, doxorubicin) | ch14.18/CHO antibody (Qarziba®) IV (total dose 100 mg/m2 over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) | C: CRT, E: CRT + IO | PFS |
| Glioblastoma | NCT02617589 | US | 2+3 | Standard RT + temozolomide | Nivolumab IV infusion, every 2 weeks, start during RT, consolidation every 4 weeks | C: CRT, E: CRT + IO | OS |
| Stage I−II oropharyngeal cancer | NCT03952585 | US | 1+2+3 | Standard RT: 5–6 fractions per week, for 5 weeks (25–30×) + cisplatin | Nivolumab 1 week prior to RT, IV on day 1, every 2 weeks for 6 cycles | C: CRT, E1: CRT↓ dose, E2: IO + CRT ↓ dose + IO | PFS + QoL |
| Stage II−III HPV oropharyngeal carcinoma | NCT03811015 | US | 3 | Standard RT: 5 fractions per week, for 7 weeks (35×) + cisplatin | Nivolumab IV once weekly, every 4 weeks for 12 months | C: CRT, E1: CRT + IO, E2: IO | PFS |
| Stage III HNSCC | NCT03700905 | EU | 1+3 | Post-operative radio(-chemo) therapy 56–66 Gy + chemotherapy cisplatin 100 mg/m2 on days 1, 22, 43 | Nivolumab neoadjuvant within 2 weeks before surgery 3 mg/kg IV on day 1, every 2 weeks within 6 weeks after end of RT; ipilimumab 1 mg/kg on day 1, every 6 weeks within 6 weeks after end of RT | C: surgery + CRT, E: IO + surgery + CRT + IO | DFS |
| Stage III HNSCC | NCT02999087 | EU | 2+3 | RT: 69.96 Gy (33×) over 6.5 weeks + cisplatin 100 mg/m2 | Cetuximab 250 mg/m2; avelumab 10 mg/kg, every 2 weeks during RT, maintenance phase: every 2 weeks for 12 months | C: CRT, E1-fit: CRT + IO, E2-unfit: CRT + IO, E3-unfit: CRT | PFS |
| Stage III HNSCC | NCT03258554 | US | 2+3 | RT 5 fractions per week, for 7 weeks (35×) + cetuximab | Durvalumab, start during RT; IV, every 4 weeks, for 7 cycles | C: CRT, E: RT + IO | PFS + OS |
| Stage III HPV negative HNSCC | NCT03673735 | EU | 1+3 | Standard CRT 6.5 weeks + cisplatin | Durvalumab IV, before CRT and for 6 months after CRT | C: CRT, E: IO + CRT + IO | DFS |
| Metastatic NSCLC | NCT03867175 | US | 2+3 | 3–10 treatments of SBRT | Pembrolizumab IV, every 3–4 weeks, for 1 year | E1: IO + SBRT + IO, E2: IO | PFS |
| (Metastatic) NSCLC | NCT03774732 | EU | 1+2+3 | 18 Gy (3×). Carboplatin, paclitaxel every 3 weeks for 4 cycles; or cisplatin, and pemetrexed | Pembrolizumab IV, every 3 weeks. Treatment may be continued aslong as patient is experiencing clinical benefit | C: CT + IO; E: IO + CT + SBRT+ IO | OS |
| (Metastatic) NSCLC | NCT03391869 | US | 1+3 | RT 14 days after completion of induction | Nivolumab IV on days 1, 15, and 29; ipilimumab IV on day 1; every 6 weeks, for 2 years | C: IO, E: IO + RT + IO | OS |
| Limited SCLC | NCT03811002 | US | 2+3 | Standard RT in +/−3 weeks, + etoposide/cisplatin | Atezolizumab IV, on day 1 or 2 of each chemotherapy every 3 weeks for 17 cycles (1 year) | C: RT + CT, E: RT + CT + IO | PFS + OS |
| Stage I−II NSCLC | NCT04214262 | US | 2+3 | SBRT | Atezolizumab IV on day 1, every 21 days for 8 cycles, start during RT | C: SBRT, E: SBRT + IO | OS |
| Stage III NSCLC | NCT03519971 | US | 2+3 | Standard CRT 6 weeks + cisplatin/etoposide | Durvalumab, IV every 4 weeks, start during RT | C: CRT, E: CRT + IO | PFS |
| Stage III NSCLC | NCT04092283 | US | 2+3 | Standard CRT 6 weeks + cisplatin/carboplatin | Durvalumab, IV on days 1+15; start during RT, repeats every 28 days for 12 cycles | C: CRT + sequential IO, E: CRT IO + sequential IO | OS |
| Stage III NSCLC | NCT02768558 | US | 2+3 | Standard CRT 6 weeks + cisplatin/etoposide | Nivolumab IV every 2 weeks for 1 year | C: CRT, E: CRT + IO | OS |
| Stage III or IV Hodgkin lymphoma | NCT03907488 | US | 1 | RT 5 fractions per week, for +/−4 weeks, starts after CT-IO. All different CT: dacarbazine, doxorubicin, vinblastine | E1: nivolumab IV on days 1 and 15 every 28 days for 6 cycles; E2: anti-CD30, on days 1 and 15 | E1: CT + IO + RT, E2: CT + IO + RT | PFS |
| Refractory or relapsed Hodgkin’s lymphoma | NCT00070187 | US | 3 | Hyperfractionated involved-field RT. All different CT: cyclosporine, etoposide | aldesleukin (IL-2) IV, once daily for 18 days | C: RT + CT, E: RT + CT + sequential IO | OS |
| Localized prostate cancer | NCT01436968 | US | 2+3 | Prostate RT | Prostatak®: 3× + AdV-tk injection + oral valacyclovir 1st injection 15 days before RT, 2nd injection 0–3 days before RT, 3rd injection 15–22 days after 2nd injection | C: RT, E: IO + RT | DFS |
| Stage II−III bladder cancer | NCT03775265 | US | 2+3 | Standard RT, 5 times a week, 7 weeks + chemotherapy based on physician’s choice | Atezolizumab IV on day 1 of chemotherapy, every 21 days for a total of 6 months (9×) | C: RT + CT, E: RT + CT + IO | Bladder intact free survival |
| Hepatocellular carcinoma | NCT04167293 | Asia | 3 | SBRT; 30–54 Gy in 3–6 fractions over 1–2 weeks | Sintilimab IV at 200 mg every 3 weeks for 1 year start within 4–6 weeks after completion of SBRT | C: SBRT, E: SBRT + IO | PFS |
| Pancreatic carcinoma | NCT01072981 | US | 2+3 | Standard CRT (gemcitabine + 5-FU) | HyperAcute-Pancreas IO Up to 18 immunizations of 300 million cells | C: CRT, E: CRT + IO | OS |
| Pancreatic carcinoma—unresectable | NCT01836432 | US | 1+ 2+3 | FOLFIRINOX on days 1, 15, 29, 43 & 57; days 71–80 5-FU or capecitabine plus radiation 50.4 Gy | Algenpantucel-L immunotherapy (HAPa) consisting of 300 million HAPa cells given by intradermal injection on days 8+22 for up to 18 doses; on days 1+15 with CRT, and consolidant | C: CT + CRT, E: CT + IO + CRT + IO | OS |
| Stage I−III Merkel cell | NCT03712605 | US | 2+3 | Standard RT within 14 days of day 1, cycle 1 | Pembrolizumab IV on day 1, start during RT, every 21 days, for 17 cycles | C: RT, E: IO + RT | OS + DFS |
| Stage III−IV melanoma | NCT01875653 | US | 2+3 | Patient specific RT | Dendritic cell subcutaneously, weekly for 3 weeks, start during RT, then monthly for 5 months | C: RT + GM-CSF, E: RT + IO | OS |
| Stage I−III triple-negative breast cancer | NCT02954874 | US | 3 | RT within 12 weeks of last breast cancer operation, use of neo-adjuvant CT (fluorouracil, epirubicin, cyclophosphamide, paclitaxel) | Pembrolizumab IV on days 1 and 22, start during RT, every 42 days for 1 year | C: RT, E: RT + IO | DFS |
| Stage I−IVa (gastro)esophageal adenocarcinoma | NCT03604991 | US | 2+3 | Standard chemo (carbo-paclitaxel) RT 5 weeks | Nivolumab IV on days 1+15, start during RT repeat every week for 5 weeks; ipilimumab IV on day 1, repeats every 2 weeks for 12 cycles | C: CRT, E1: CRT + IO, E2: IO 1, E3: IO 1+2 | pCR |
| Stage I−II uterine cancer | NCT04214067 | US | 1+2+3 | Standard RT 5–6 weeks + VBT | Pembrolizumab 7 days prior to the start, IV on day 1, every 3 weeks for up to 1 year (17 cycles) | C: RT, E: IO + RT + IO | RFS |
NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; SBRT, stereotactic body radiotherapy; RT, radiotherapy; CT, chemotherapy; CRT, chemoradiotherapy; IO, immunotherapy; IV, intravenously; PFS, progression-free survival; DFS, disease-free survival; OS, overall survival; HNSCC, head and neck squamous cell carcinoma; QoL; quality of life; pCR, pathologic complete response; HPV, human papillomavirus; AdV-tk, aglatimagene besadenovec; GM-CSF, granulocyte-macrophage colony stimulating factor; FOLFIRINOX, oxaliplatin-irinotecan-leucovorin-fluorouracil; C, control; E, experimental.