Table 2.
Definitive immunoradiotherapy trials
| Trial, start year | Phase | N | Subsite and subtype | Basic scheme | Immunotherapy details | RT details | Main results |
|---|---|---|---|---|---|---|---|
| NCT02586207,117 2015 | I | 59 | LAHNSCC eligible for CRT (34 pts HPV + and 23 pts HPV-) | PEMBRO + CRT, followed by PEMBRO | PEMBRO on days -7 (before CRT), 15 and 36 (conc. with CRT), and adj. for 5 cycles | starting on day 1: CRT with IMRT 70 Gy (2Gy/fx) and LD-CDDP for 6 cycles | HPV + : 85% CR 12 weeks after CRT; HPV-: 78% CR 12 weeks after CRT; HPV + : 2-year OS 97% and PFS 93%; HPV-: 1-year OS 87% and PFS 73% |
| GORTEC 2015-01 “PembroRad” (NCT02707588),114 2016 | II, rand. | 133 | LAHNSCC ineligible for CDDP | arm A: CETUX + RT; arm B: PEMBRO + RT | arm A: CETUX during RT; arm B: PEMBRO during RT | IMRT (69.99Gy/33fx) | arm A: 94% grade 3 toxicity, 57% grade 3 mucositis, 86% received full RT; arm B: 78% grade 3 toxicity, 24% grade 3 mucositis, 88% received full RT |
| KEYNOTE-412 (NCT03040999),124 2017 | III, rand. | 780 | LAHNSCC eligible for CRT | arm A: PEMBRO + CRT, followed by PEMBRO; arm B: placebo + CRT, followed by placebo | arm A: priming dose of PEMBRO followed by 2x PEMBRO + CRT, followed by 14x maint. PEMBRO; arm B: placebo instead of PEMBRO | CRT (70Gy/35fx) and HD-CDDP | NA |
| NCT02759575,131 2016 | I/II | 47 | LAHNSCC of larynx | PEMBRO + CRT | PEMBRO starting 3 weeks before CRT, maximum 4x | CRT (70Gy/35fx) and HD-CDDP | NA |
| NCT02609503,116 2016 | II | 29 | LAHNSCC ineligible for CDDP | PEMBRO + RT, followed by PEMBRO | PEMBRO conc. with RT and 3 adj. cycles | IMRT (70Gy/35fx) | 2-year OS 75% and PFS 71%; 59% grade 3–4 lymphopenia |
| NCT02777385,130 2016 | II, rand. | 90 | LAHNSCC | arm A: PEMBRO + CRT; arm B: CRT followed by PEMBRO | arm A: 8x PEMBRO 1 week prior to RT; arm B: 8x PEMBRO beginning in week 10 | CRT with IMRT (70Gy/35fx) and LD-CDDP | NA |
| NCT03532737,132 2018 | II | 50 | LAHNSCC | PEMBRO + CRT or PEMBRO + CETUX + RT | PEMBRO starting 3 weeks before (C)RT and during CRT or during RT + CETUX | CRT with IMRT (66–70Gy/30–35fx) and HD-CDDP or conc. CETUX | NA |
| KEYCHAIN (NCT03383094),133 2018 | II, rand. | 114 | HPV + LAHNSCC | arm A: PEMBRO + RT; arm B: CRT | arm A: conc. and adj. PEMBRO for 20 cycles; arm B: CDDP-based CRT | IMRT (70Gy/33– 35fx) (arm A) and HD-CDDP in arm B | NA |
| PEACH (NCT02819752),134 2017 | I | 36 | LAHNSCC | PEMBRO + CRT, followed by PEMBRO | pre-loading dose of PEMBRO (dose-escalation trial, 100–200mg) and conc. CRT and PEMBRO and 4x adj. PEMBRO | standard CRT | NA |
| NCT04369937,127 2020 | II | 50 | IR HPV + HNSCC | HPV-16 vaccination (ISA101b) + PEMBRO + CRT | 3x ISA101b starting 1 week prior to PEMBRO and two weeks prior to CRT | CRT with IMRT (70Gy/35fx) and HD-CDDP | NA |
| RTOG 3504 (NCT02764593),120 2016 | I | 40 | IR-HR LAHNSCC | conc. and adj. NIVO added to each of 4 (C)RT cohorts | conc. NIVO starting 2 weeks before (C)RT and adj. NIVO starting 3 months after CRT | all cohorts: IMRT (70Gy/35fx); cohort 1: CRT with LD-CDDP; cohort 2: CRT with HD- CDDP; cohort 3: RT + CETUX; cohort 4: RT | adj. NIVO infeasible after HD-CDDP or in CDDP-ineligible pts; low rates of NIVO DLT |
| NCT03349710,125 2017 | III, rand. | 1046 | LAHNSCC | NIVO + RT vs. CETUX + RT vs. NIVO + CRT vs. CRT | Closed due to slow | accrual | |
| NCT03162731,121 2017 | I | 24 | HR LAHNSCC | NIVO + ipilimumab + RT | 17x NIVO and 6x ipilimumab, both starting 2 weeks before RT | IMRT (70Gy/35fx) | first 12 pts: grade 3 in-RT-field toxicity in 50% of pts, 3 pts discontinued therapy >3 months post-RT, 1 grade 3 colitis, 1 grade 5 bleeding, irAE in 50% of pts |
| NCT03894891,135 2019 | II | 70 | LAHNSCC of larynx and hypopharynx | induction docetaxel + CDDP + NIVO, followed by NIVO + RT | standard institutional dosing | standard institutional dosing | NA |
| NCT03829722,136 2019 | II | 40 | HR HPV + OP cancer | NIVO + CRT, followed by adj. NIVO | 4x NIVO before and conc. with CRT, followed by 4x NIVO | CRT (70Gy/35fx) and carboplatin + paclitaxel combination once per week | NA (temporarily suspended due to COVID-19) |
| NRG-HN005 (NCT03952585),126 2019 | II/III, rand. | 711 | early-stage HPV + OP cancer | arm A: NIVO + deescalated RT; arm B: CRT arm C: deescalated CRT | 6x NIVO, starting 1 week prior to RT | IMRT, CRT with HD- CDDP | NA |
| NCT03799445,137 2019 | II | 180 | low- intermediate volume HPV + OP cancer | NIVO + ipilimumab + RT | NIVO on days 1, 15, 29, and ipilimumab on day 1; for 2 cycles | IMRT 50–66Gy starting on day 1 of 2. cycle of NIVO + ipilimumab | NA |
| GORTEC 2017- 01 “REACH” (NCT02999087),138 2017 | III, rand. | 688 | LAHNSCC | Cohort 1 (fit for CDDP): CRT with CDDP (arm 1A), RT + AVEL + CETUX (arm 1B); Cohort 2 (unfit for CDDP); RT + CETUX (arm 2A), RT + AVEL + CETUX (arm 2B) | AVEL and CETUX starting 1 week prior to RT, followed by AVEL maint. for 12 months | IMRT 69.96Gy with either HD-CDDP or CETUX | first 82 pts: thresholds of the safety monitoring rule not crossed; trial continues |
| JAVELIN HEAD AND NECK 100 (NCT02952586),110 2016 | III, rand. | 697 | LAHNSCC | arm A: AVEL + CRT; arm B: placebo + CRT | AVEL starting 1 week prior to CRT, followed by maint. AVEL for 12 months | CRT with IMRT (70Gy/35fx) and HD-CDDP | preplanned interim analysis: unlikely to show improvement, terminated |
| NCT02938273,122 2017 | I | 10 | LAHNSCC ineligible for CDDP | AVEL + CETUX + RT | AVEL starting 1 week prior to RT, followed by maint. AVEL for 4 months; CETUX conc. | VMAT (70Gy/35fx) | tumour recurrence in 50% after a median follow up of 12months; transient and manageable irAE |
| DUCRO-HN (NCT03051906),139 2018 | I/II | 69 | LAHNSCC | DURVA + CETUX + RT | DURVA and CETUX, both conc. with RT, followed by adj. DURVA for 6 months | IMRT (69.9Gy/33fx) | NA |
| DURTRE-RAD (NCT03624231),115 2018 | II, rand. | 120 | HPV- LAHNSCC | arm A: DURVA + TREM + RT; arm B: DURVA + RT | DURVA started 2 weeks prior to RT and TREM started with RT, followed by DURVA for up to 9 cycles | RT (70Gy/35fx) | first 16 patients: in arm A 5/6 stopped treatment due to toxicity -> terminated; in arm B 1/10 patients stopped treatment |
| CheckRad-CD8 (NCT03426657),123 2018 | II | 120 | LAHNSCC | induction DURVA + TREM + CDDP + docetaxel and in case of increased CD8 + TILs compared to pre-treatment Bx -> DURVA + TREM + RT | after induction: DURVA with RT and TREM with RT, followed by DURVA for up to 12 cycles | RT (70Gy/35fx) | first 10pts after induction (re-biopsies): pCR in 8/10pts, 2 grade 3 + toxicities |
| NRG-HN004 (NCT03258554),113 2017 | II/III, rand. | 523 | LAHNSCC ineligible for CDDP | arm A: DURVA + RT; arm B: CETUX + RT | DURVA started 2 weeks prior to RT for 7 cycles; CETUX conc. | RT (70Gy/35fx) | lead-in trial, 10 pts: all received arm A treatment, all completed RT, 8/10 received all doses of DURVA |
| CITHARE (NCT03623646),140 2019 | II, rand. | 66 | early-stage HPV + OP cancer | arm A: DURVA + RT; arm B: CRT | DURVA conc. with RT | RT 70Gy with CDDP in arm B | NA |
| REWRITe (NCT03726775),129 2018 | II | 73 | HNSCC T1-2 or HNSCC T3-4 and not eligible for CRT/CETUX + RT | DURVA + RT, followed by additional 6 months of DURVA | DURVA conc. with RT, followed by 6 months of DURVA | RT to only primary tumour and immediately adjacent nodal level without extended neck irradiation | NA |
| NCT04405154,141 2020 | II | 32 | LAHNSCC | CRT + camrelizumab | camrelizumab conc. with CRT and after for total of 8 cycles | CRT with IMRT/VMAT (66–70Gy/33–35fx) and HD-CDDP | NA |
adj. = adjuvantly; AVEL = avelumab; CETUX = cetuximab; ,; CDDP = cisplatin; conc. = concurrently; CR = complete response; CRT = chemoradiotherapy; DLT = dose-limiting toxicity; DURVA = durvalumab; , fx = fractions; HD-CDDP = high dose cisplatin 100 mg/m2 every three weeks during RT; HR = high-risk; HPV+ = human papilloma virus associated cancer, HPV- = human papilloma virus negative cancer; IMRT = intensity modulated RT; IR = intermediate-risk; irAE – immune-related adverse effects; LAHNSCC = locally advanced head and neck squamous cell carcinoma; LD-CDDP = low dose cisplatin 40 mg/m2 every week during RT; maint. = maintenance; N = planned enrolment; NA = not available; NIVO = nivolumab; OP = oropharyngeal; OS = overall survival; PEMBRO = pembrolizumab; PFS = progression-free survival; RT = radiotherapy, TILs = tumour infiltrating lymphocytes; TREM – tremelimumab; VMAT = volumetric modulated arc therapy