Table 2.
Immune checkpoint inhibitors used in combination with RT in recent clinical trials
| Trial/author | Site | Year | Metastatic vs curative intent | Number of patients | Phase of study | Sequencing of treatment | Dose of RT | Endpoints and results | Toxicity |
|---|---|---|---|---|---|---|---|---|---|
| Atezolizumab | |||||||||
| Qin 19 | Metastatic NSCLC | 2020 | Metastatic | 12 | Phase 2 | Concurrent | 3 × 8 Gy or 5 × 6 Gy | ORR = 25%. OS = 6.9 months | 5/12 had a grade 3 immune‐related adverse event |
| Van den ende (PERFECT) 20 | In resectable oesophageal adenocarcinoma | 2021 | Curative | 40 | Phase 2 | Concurrent | CROSS regimen combined with five cycles of atezolizumab | pCR in 25%. Baseline expression of an established IFNγ signature was higher in responders than non‐responders | 6/40 had any grade immune‐related adverse events |
| Avelumab | |||||||||
| Kwan (ICE‐PAC) 21 | Prostate | 2021 | Metastatic | 31 | Phase 2 | SABR was administered to one or two disease sites within 5 d before the first and second avelumab treatments | 20 Gy in one fraction | 48% achieved CR or PR, or SD for ≥6 months | Grade 3–4 treatment‐related adverse events occurred in six patients (16%), with three (10%) requiring high‐dose corticosteroid therapy |
| Shamseddine 22 | Rectal | 2020 | Curative | 13 | Phase 2 | Preop short‐course radiation followed by six cycles of FOLFOX with avelumab in locally advanced rectal cancer patients | 25 Gy in five fractions | 3/13 achieved pCR, and another 3/13 had near pCR | The protocol regimen was well‐tolerated, with no reported serious adverse events of grade 4 |
| Lee 23 | Head and neck SCC | 2021 | Curative | 697 | Phase 3 | Concurrent CRT +/− 2 weekly avelumab | 70 Gy in 35 fractions | Median PFS not reached in both groups | Serious treatment‐related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group |
| Ipilimumab | |||||||||
| Chicas‐Sett 24 | Melanoma | 2018 | Metastatic | 451 | Systematic review | Various | Various | The median reported abscopal effect and OS were 26.5% and 19 months, respectively | The median toxicity ≥ Grade 3 was 18.3%, ranged from 10% to 20% |
| Formenti 25 | NSCLC | 2018 | Metastatic | 39 | Phase 2 | Concurrent | RT to one metastasis (palliative dose, 6 Gy × 5 or 9 Gy × 3) | ORR in 18% with 2 CR and 5 PR | Adverse events were consistent with ipilimumab‐induced side effects, and the addition of RT did not modify them |
| Fizazi 26 | Prostate | 2014 | Metastatic | 799 | Phase 3 | Concurrent | 8 Gy single fraction to one or more bone metastases | OS rates were higher in the ipilimumab versus placebo arms at 2 years (25.2% vs 16.6%), 3 years (15.3% vs 7.9%), 4 years (10.1% vs 3.3%), and 5 years (7.9% vs 2.7%) | In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long‐term safety signals were identified |
| Nivolumab | |||||||||
| Masini (Nives) 27 | Renal | 2021 | Metastatic | 69 | Phase 2 | Concurrent | 30Gy in three fractions | The ORR was 17%. The median PFS was 5.6 months, no evidence better than nivolumab alone | No new safety concerns arose |
| Peters (ETOP NICOLAS) 28 | Lung | 2021 | Curative | 79 | Phase 2 | Concurrent nivolumab and CRT | 66 Gy in 33 fractions | OS of 38.8 months and a 2‐year survival rate of 63.7% (numerically higher than other studies for the same population) | Nine (11.7%) pneumonitis events of grade ≥3 occurred among the 79 patients. All happened within 1‐year of follow‐up. Half of all patients experienced adverse events |
| McBride 29 | Head and neck | 2021 | Metastatic | 62 | Phase 2 randomised | Nivolumab alone vs Concurrent | SABR to metastasis 9 Gy X 3 fractions | ORR in non‐irradiated lesions was 34.5 vs 29%. | Grade 3–5 toxicities were similar (13.3% v 9.7%; P = 0.70) |
| Sundahl 30 | Melanoma | 2019 | Metastatic | 20 | Phase 2 | Concurrent | SABR 8 Gy × 3 | ORR in non‐irradiated lesions of 45% was noted with three complete and six partial responses. Three patients experienced stable disease, and 7 had progressive disease as best response | Three patients experienced grade 3 AEs (lymphopenia, gastroenteritis, and bullous pemphigoid). No grade 4 to 5 AEs occurred |
| Voorwerk (TONIC) 31 | Triple‐negative breast cancer | 2019 | Metastatic | 67 | Phase 2 randomised to five arms | Concurrent | 8 Gy X3 | ORR was higher in the cisplatin (ORR23%) and doxorubicin (ORR 35%) and not the RT group | Not reported |
| Pembrolizumab | |||||||||
| Liniker 32 | Melanoma | 2016 | Metastatic | 53 | Retrospective | Mixed sequential or concurrent. | Various | Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (P = 0.448) | There was no excessive anti‐PD‐1 or RT toxicity observed in patients receiving extracranial RT |
| Ho 33 | Triple‐negative breast cancer | 2020 | Metastatic | 17 | Phase 2 | Concurrent | 30 Gy in five fractions | 3/17 achieved CR. 17.6% had a reduction in tumour outside the treated area | 29% experienced grade 1 or 2 dermatitis. 4/17 had a grade 3 adverse event |
| Shaverdian 34 | NSCLC | 2017 | Metastatic | 98 | Retrospective analysis of a phase 3 trial | Radiotherapy prior to immunotherapy | Various | OS 10.7 months vs 5.3 months (P = 0.034) | 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy |
| Zhu 35 | Pancreatic | 2021 | Post‐operative locally recurrent pancreatic cancer. | 170 | Phase 2 randomised | Concurrent. | 35–40 Gy in five fractions | OS was 24.9 months vs 22.4 months P = 0.0012 | 22% vs 14% had a severe adverse event with and without immunotherapy |
| Rahma 36 | Rectal cancer | 2021 | Curative preoperative | 185 | Phase 2 randomised | Concurrent | 50.4 Gy in 28 fractions | pCR rate was 31.9% vs 29.4% (P = 0.75) | Grade 3 to 4 adverse events were slightly increased 48.2% vs 37.3% |
| Li (PALACE‐1) 37 | Oesophageal | 2021 | Curative preoperative | 20 | Phase 2 | Concurrent | 41.4 Gy in 23 fractions | pCR in 55.6% | Grade 3 + AEs 13/20, 65%, and one patient had a grade 5 AE |
| Fukushima 38 | Bladder | 2020 | Metastatic | 98 | Retrospective | History of radiotherapy to the primary tumour. | Various. | OS 77% vs 50% at 12 months; P = 0.02. | Not reported. |
| Tree (PLUMMB) 39 | Bladder | 2018 | Mixed | 5 | Phase 1 | Concurrent | 36 Gy in six fractions | Stopped early after five patients due to toxicity | 3 grade 3, 1 grade 4 |
| Siva (RAPPORT) 40 | Renal | 2021 | Metastatic | 30 | Phase 1/2 | Sequential (5 days after radiotherapy) | 20 Gy single fraction SABR (or, if not feasible, 10 fractions of 3 Gy) was given to all metastatic sites | Local control at 2 years was 92%. ORR was 63%, and DCR was 83%. Estimated 1‐ and 2‐yr OS were 90% and 74%, respectively, and PFS was 60% and 45% | Four patients (13%) had grade 3 treatment‐related AEs |
| Durvalumab | |||||||||
| Antonia (PACIFIC) 17 | Stage 3 NSCLC | 2017 | curative | 713 | Phase 3 | Sequential | 60 Gy in 30 fractions | 18‐month PFS was 44.2% versus 27.0% | Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of placebo |
| Xie. 41 | Pancreatic cancer | 2020 | metastatic | 59 | Phase 1 | Sequential | SABR 8 Gy in one fraction or 25 Gy in five fractions | The ORR was 5.1% | No dose‐limiting toxicities were seen |
CR, complete response; ORR, overall response rate; OS, median overall survival; pCR, pathological complete response; PFS, progression‐free survival; PR, partial response.