Table 1.

Ongoing trials evaluating combinations of ICIs and radiation in the management of recurrent/metastatic HNSCC.

NCT#	Title	Inclusion criteria	Treatment arms	Timing	Phase
NCT03539198	Study of Proton SBRT and Immunotherapy for Recurrent/Progressive Locoregional or Metastatic Head and Neck Cancer	Recurrent/metastatic HNSCC, ≥2 metastatic sites	1: nivolumab given every 2 weeks, with proton SBRT to one metastatic site administered with cycle 3	concurrent	n/a
NCT03283605	Immunotherapy and SBRT for Metastatic Head and Neck Carcinomas	Metastatic HNSCC, ≥2 metastatic sites	1: durvalumab + tremelimumab for four cycles (4 weeks each), SBRT between cycles 2 and 3	concurrent	1/2
NCT03844763	CONFRONT: Targeting the Tumor Microenvironment in R/M SCCHN	Recurrent/metastatic HNSCC	1: avelumab, cyclophosphamide, and radiation (8 Gy/1 fx) to a single site 1 week after first dose of avelumab	concurrent	1/2
NCT03522584	Durvalumab, Tremelimumab and Hypofractionated Radiation Therapy in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma	Recurrent/metastatic HNSCC; progression through prior PD-1/PD-L1 inhibitor	1: durvalumab + tremelimumab for four cycles (4 weeks each) followed by durvalumab alone for nine cycles; SBRT during week 3 in three fractions, every other day	concurrent	1/2
NCT03474497	UCDCC#272: IL-2, Radiotherapy, and Pembrolizumab in Patients Refractory to Checkpoint Blockade	Recurrent/metastatic HNSCC; progression through prior PD-1/PD-L1 inhibitor	1: one cycle of pembrolizumab, then SBRT (24 Gy/3 fx) and intratumoral injection of interleukin-2 during cycle 2, then additional pembrolizumab	concurrent	1/2
NCT03317327	REPORT: REirradiation and Programmed Cell Death Protein 1 (PD-1) Blockade on Recurrent Squamous Cell Head and Neck Tumors	Recurrent HNSCC after prior radiation or second primary HNSCC	1: nivolumab with re-irradiation to 60 Gy (in 1.5 Gy bid fx), followed by nivolumab for up to 12 months	concurrent	1/2
NCT04340258	Trial Combining Pembrolizumab and Cesium 131 Brachytherapy With Salvage Surgery in HNSCC	Resectable recurrent HNSCC after prior surgery or radiation	1: one dose of pembrolizumab, then salvage surgery with implantation of Cesium-131 brachytherapy seeds (60–70 Gy), followed by adjuvant pembrolizumab for 6 months	concurrent	1/2
NCT04454489	Quad Shot Radiotherapy in Combination With Immune Checkpoint Inhibition	Recurrent/metastatic HNSCC	1: pembrolizumab given every 3 weeks; quad-shot radiation (14.8 Gy in 4 bid fx) between cycles 2 and 3	concurrent	2
NCT03313804	Priming Immunotherapy in Advanced Disease With Radiation	Recurrent/metastatic HNSCC	1: nivolumab, pembrolizumab, or atezolimuab, with either SBRT (BED > 100 Gy) or 30 Gy fractionated RT	concurrent	2
NCT03386357	Radiotherapy With Pembrolizumab in Metastatic HNSCC	Recurrent/metastatic HNSCC, ≥2 metastatic sites, progression through platinum-based therapy	1: radiation to 1–3 metastases (36 Gy/12 fx), with pembrolizumab starting between fraction 3 and 4	concurrent	2
			2: pembrolizumab alone
NCT03511391	CHEERS: CHEckpoint Inhibition in Combination With an Immunoboost of External Body Radiotherapy in Solid Tumors	Recurrent/metastatic HNSCC, progression through platinum-based therapy	1: 2 cycles of nivolumab, then SBRT to 1–3 metastases (24 Gy/3 fx) prior to cycle 3	concurrent	2
			2: nivolumab alone
NCT03085719	Targeting PD-1 Therapy Resistance With Focused High or High and Low Dose Radiation in SCCHN	Metastatic HNSCC, progression through prior PD-1 inhibition, ≥3 metastatic sites	1: pembrolizumab and high dose SBRT (3 fx) to one metastatic site	concurrent	2
			2: pembrolizumab and high dose SBRT (3 fx) to one metastatic site, and low dose radiation (2 fx) to another site
NCT03546582	KEYSTROKE: SBRT +/− Pembrolizumab in Patients With Local-Regionally Recurrent or Second Primary Head and Neck Carcinoma	Recurrent HNSCC after prior radiation or second primary HNSCC	1: reirradiation with SBRT over 2 weeks, then pembrolizumab every 3 weeks for up to 2 years	sequential	2
			2: reirradiation with SBRT over 2 weeks
NCT03521570	Intensity-Modulated Radiation Therapy & Nivolumab for Recurrent or Second Primary Head & Neck Squamous Cell Cancer	Recurrent HNSCC after prior radiation or second primary HNSCC	1: one dose of nivolumab, then radiation with concurrent nivolumab, then adjuvant nivolumab for 5 months	concurrent + sequential	2
NCT02289209	Reirradiation With Pembrolizumab in Locoregional Inoperable Recurrence or Second Primary Squamous Cell CA of the Head and Neck	Unresectable recurrent HNSCC after prior radiation or second primary HNSCC	1: pembrolizumab with re-irradiation to 60 Gy (in 1.2 Gy bid fx), followed by pembrolizumab for 3 months	concurrent + sequential	2
NCT02684253	Screening Trial of Nivolumab With Image Guided, Stereotactic Body Radiotherapy (SBRT) Versus Nivolumab Alone in Patients With Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)	Metastatic HNSCC, ≥2 metastatic sites	1: one cycle of nivolumab, then SBRT (27 Gy/3 fx) with the 2nd cycle, followed by additional nivolumab	concurrent	2
			2: nivolumab alone

BED, biologically effective dose; bid, twice a day; fx, fraction; HNSCC, head and neck squamous cell carcinoma; ICIs, immune checkpoint inhibitors; SBRT, stereotactic body radiotherapy.