New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer

Table 1 Ongoing clinical trials of stereotactic ablative radiotherapy and immune checkpoint inhibitors combination in early-stage non-small cell lung cancer

Ref.	Phase	n	Stage	SABR dose	ICI agent	ICI sequence	Status
NCT03833154[38]	III randomized	706	I-II	NM; 3-8 fx	Durvalumab	Sequential	Recruiting
NCT04214262[39]	III randomized	460	I-II	NM; 3-5 fx	Atezolizumab	Concurrent	Recruiting
NCT03110978[40]	II randomized	140	I-IIA	50 Gy/4 fx; 70 Gy/10 fx	Nivolumab	Concurrent	Recruiting
NCT03446547[41]	II randomized	216	I	NM; 3-4 fx	Durvalumab	Sequential	Recruiting
NCT03148327[42]	I-II randomized	105	I-IIA	54 Gy/3 fx; 50 Gy/4 fx; 65 Gy/10 fx	Durvalumab	Concurrent	Recruiting
NCT03050554[43]	I-II	56	I	48 Gy/4 fx; 50 Gy/5 fx	Avelumab	Concurrent	Not recruiting
NCT03383302[44]	I-II	31	I-II	54 Gy/3 fx; 55 Gy/5 fx	Nivolumab	Sequential	Recruiting
NCT02599454[45]	I	33	I	50 Gy/4 fx; 50 Gy/5 fx	Atezolizumab	Induction	Not recruiting

SABR: Stereotactic ablative body radiotherapy; ICI: Immune checkpoint inhibitor; Gy: Gray; NM: Not mentioned.

Table 2 Ongoing clinical trials of radiotherapy and immune checkpoint inhibitors combination in locally advanced stage non-small-cell lung cancer in the neoadjuvant setting

Ref.	Phase	Design	No.ofpatients	Tumor stage	RT	ICI agent	Sequence	Status
CASE4516, NCT02987998[72]	1	Neoadjuvant CRT (CDDP-etoposide) + ICI followed by surgery and consolidative ICI	20	Resectable IIIA	45 Gy/25 fx (1.8 Gy/fx)	Pembroli zumab	Concomitant (neoadjuvant) + adjuvant ICI	Active, not recruiting
NCT03237377[73]	2	Neoadjuvant RT-ICI followed by surgery +/-adjuvant CT	32	Resectable IIIA	45 Gy/25 fx (1.8-2 Gy/fx)	Durvalumab ± tremelimumab	Concomitant(neoadjuvant)	Recruiting
NCT04245514, SAKK 16/18[74]	2 3 RT arms	Neoadjuvant RT-ICI followed by surgery	90	Resectable IIIA	Randomized 1:1:1; A: 20 × 2 Gy; B: 5 × 5 Gy; C: 3 × 8 Gy (non -consecutive days)	Durvalumab	Concomitant (neoadjuvant)	Recruiting
INCREASE, NL8435[75]	2 single arm	Neoadjuvant CRT (platinum doublet) + ICI followed by surgery	29	Resectable IIB-III (T3-4 N0-1)	50 Gy/25 fx	Ipilimumab + Nivolumab	Concomitant (neoadjuvant)	Recruiting
NCT02904954[76]	2 randomized	Neoadjuvant ICI +/- SBRT followed by surgery and adjuvant maintenance ICI	60	Resectable I-IIIA	SBRT 24 Gy/3 fx	Durvalumab	Concomitantneoadjuvant + adjuvant ICI	Active, not recruiting
NCT03871153[77]	2 single arm	Neoadjuvant CRT (Carbo-taxol) + ICI followed by surgery and adjuvant ICI	25	Resectable IIIA N2	45-61.2 Gy (25-34 fx a 1.8-2 Gy/fx)	Durvalumab	Concomitant (neoadjuvant) + adjuvant ICI	Recruiting
CHIO3, NCT04062708[78]	2single arm	Concomitant neoadjuvant CT (platinum doublet + ICI followed by surgery + adjuvant RT followed by ICI	55	Resectable IIIA-IIIB	54 Gy	Durvalumab	Concomitant CT-ICI (neoadjuvant) + adjuvant ICI (after adjuvant RT)	Not yet recruiting
NCT03102242[79]	2singlearm	Induction ICI followed by definitive CRT (Carbo-Taxol followed by consolidation CT-ICI	63	Unresectable IIIA-IIIB	60 Gy/30 fx	Atezolizumab	Neoadjuvant + consolidative ICI	Active, notrecruiting
NCT02572843[80]	2	Neoadjuvant CT (platinum + docetaxel) + ICI followed by surgery +/-RT + ICI	68	Resectable IIIA N2	Convenional RT if R1-R2 and before adjuvant ICI	Durvalumab	Neoadjuvant + adjuvant	Active, not recruiting

RT: Radiotherapy; CRT: Chemoradiotherapy; CT: Chemotherapy; ICI: Immune checkpoint inhibitor; Gy: Gray.

Table 3 Ongoing clinical trials of radiotherapy and immune checkpoint inhibitor combination in locally advanced stage non-small cell lung cancer in the adjuvant/consolidation setting

Ref.	Phase	Design	No.of patients	Tumor stage	RT	ICI agent	Sequence	Status
BTCRC-LUN16-081, NCT03285321[50]	2 randomized	Concomitant definitive CRT followed by consolidative ICI (3 CT regimens: CDDP-VP16 vs Carbo-Taxol vs Cisplatin- Pemetrexed)	108	Unresectable IIIA-IIIB	59.4-66.6 Gy	Nivolumab +/-Ipilimumab	Consolidation afterdefinitive treatment	Recruiting
NCT03589547[81]	2	CRT followed by consolidative ICI and SABR	25	III	60 Gy followed by SBRT 20 Gy/2-3 fx	Durvalumab	Consolidation after definitive treatment (ICI prior to SABR)	Recruiting
PACIFIC 6, NCT03693300[82]	2	ICI after sequential CRT	150	Unresectable III	Conventional RT; 60 Gy/30 fx	Durvalumab	Consolidation after definitive treatment (within 28 d after RT)	Active, not recruiting
MK-3475, NCT03379441[83]	2	Maintenance ICI after definitive CRT	126	Unresectable IIIA-IIIB	Conventional RT	Pembrolizumab	Consolidation afterdefinitive treatment	Not recrutiing
DUART,NCT 04249362[84]	2 single arm	RT followed by ICI	150	Unresectable III	Conventional RT 60 Gy Hypofractionated RT 40-54 Gy	Durvalumab	Consolidation after RT (no CT)	Recruiting
PACIFIC 5, NCT03706690[47]	3 randomized, doube-blinded	Consolidative ICI vs placebo after definitive CRT radical (concomitant or sequential)	360	Unresectable III	Conventional RT	Durvalumab	Consolidation after definitive treatment	Recruiting

RT: Radiotherapy; CRT: Chemoradiotherapy; CT: Chemotherapy; ICI: Immune checkpoint inhibitor; Gy: Gray.

Table 4 Ongoing clinical trials of radiotherapy and immune checkpoint inhibitor combination in locally advanced stage non-small cell lung cancer in the concomitant setting

Ref.	Phase	Design	No.of patients	Tumor stage	RT	ICI agent	Sequence	Status
ARCHON-1, NCT03801902[85]	1; 2 RT arms	ICI + RT	24	Unresectable II-III	Conventional RT (60 Gy/30 fx); Hypofractionated RT (60 Gy/15 fx)	Durvalumab	Concomitant with definitive RT	Recruiting
PARTICLE-D, NCT03818776[86]	1; 2 RT arms (proton beam therapy	ICI + RT	27	Unresectable III	RT 60 Gy/20 fx; RT 63 Gy/23 fx	Durvalumab	Concomitant with definitive RT	Recruiting
NCT04013542[87]	1	ICI + RT	20	II-III	Conventional RT	Ipilimumab + Nivolumab	Concomitant with definitive RT and consolidation (nivolumab)	Recruiting
NCT03663166[88]	1; 2	Concomitant CRT + ICI +/- consolidative ICI	50	Unresectable III	60 Gy/30 fx	Ipilimumab +/-Nivolumab	Concomitant definitive treatment +/- consolidative ICI	Recruiting
SPRINT,NCT03523702[54]	2	ICI + RT (if PD-L1 ≥ 50%) ; CRT (if PD-L1 < 50%)	63	Unresectable III	Conventional RT	Pembrolizumab	Concomitant with definitive RT	Recruiting
KEYNOTE-799, NCT03631784[89]	2	Concomitant ICI + CRT (platinum doublet) followed by ICI	216	Unresectable III	60 Gy/30 fx	Pembrolizumab	Concomitante and consolidative	Active, not recruiting
NCT04092283[90]	3 randomized	Concomitant CRT + ICI vs CRT followed by ICI (CT: Cisplatin + VP16/ Taxol + Carboplatin/ Cisplatin + Pemetrexed)	660	Unresectable III	60 Gy/30 fx	Durvalumab	Concomitant with definitive treatment vs adjuvant ICI	Recruiting
PACIFIC 2, NCT03519971[91]	3 randomized, double-blinded	ICI vs placebo concomitant to CRT (CDDP-VP16 vs Carbo-Taxol vs Cisplatin or Carbo + Pemetrexed)	328	Unresectable III	Conventional RT (60 Gy in 30 fx)	Durvalumab	Concomitant +/- consolidative	Active, not recruiting
NCT04026412[92]	3 randomized	ICI (nivolumab) + CRT followed by ICI (nivolumab + ipilimumab) vs ICI (nivolumab) + CRT followed by ICI (nivolumab) vs CRT followed by durvalumab	1400	Unresectable/inoperable III	Conventional RT	Nivolumab; Ipilimumab; Durvalumab	Concomitant + 2 consolidation regimens vs consolidation after CRT	Recruiting

RT: Radiotherapy; CRT: Chemoradiotherapy; CT: Chemotherapy; ICI: Immune checkpoint inhibitor; Gy: Gray.

Table 5 Ongoing clinical trials involving radiotherapy and immunotherapy in stage IV non-small cell lung cancer

Ref.	Phase	ICI agent	RT dose	Design	Primary endpoints
NCT03158883[93]	I	Avelumab	50 Gy/5 fx	ICI + SABR	ORR
NCT03224871[94]	I	Nivolumab; Pembrolizumab; Intratumor IL-2	8 Gy/3 fx	ICI + IL-2 + RT	MTD
NCT03436056, PRIMING[95]	I	Pembrolizumab	SABR 30 Gy-3 fx SABR 54 Gy/3 fx	ICI + SABR	MTD
NCT03812549[96]	I	Sintilimab	SABR 30 Gy/3 fx; LD (low dose)-RT: 2 Gy/1 fx or 4 Gy/2 fx or 10 Gy/5 fx	ICI + SABR; ICI + LD-RT	MTD
NCT03223155, COSINR[69]	I	Nivolumab; Ipilimumab	SABR 3-5 fx, 2-4 sites	ICI + SABR	MTD
NCT02639026[97]	I	Durvalumab; Tremelimumab	HFRT 24 Gy/3 fx, 17 Gy/1 fx	ICI + HFRT	MTD
NCT03275597[98]	I	Durvalumab; Tremelimumab	SABR 30-50 Gy/5 fx	ICI + SABR	MTD
NCT03168464[99]	I-II	Nivolumab; Ipilimumab	RT 30 Gy/5 fx	ICI + RT	ORR
NCT02239900[100]	I-IIR	Ipilimumab	SABR 50 Gy/4 fx or 60 Gy/10 fx; 1-4 lesions	ICI + SABR	MTD
NCT02444741[101]	I-IIR	Pembrolizumab	SABR 4 fx or IMRT, PBRT, 3D-CRT 15 fx	ICI + SABR or IMRT, PBRT, 3D-CRT	MTD, ORR
NCT03176173, RRADICAL[102]	II	Nivolumab; Pembrolizumab; Atezolizumab	SABR 1-10 fx	ICI +/- SABR	PFS
NCT03965468, CHESS[103]	II	Durvalumab	SABR 1-10 fx	ICI + SABR + CT	PFS
NCT03044626, FORCE[104]	II	Nivolumab	RT 20 Gy/5 fx	ICI + RT	ORR
NCT02221739[105]	II	Ipilimumab	IMRT or 3D-CRT 30 Gy/5 fx	ICI + RT	ORR
NCT02658097[106]	II	Pembrolizumab	RT 8 Gy/1 fx	ICI + RT	ORR
NCT03391869, LONESTAR[107]	III	Nivolumab; Ipilimumab	LCT	ICI +/- SABR	OS
NCT03867175[108]	III	Pembrolizumab	SABR 3-10 fx	ICI +/- SABR	PFS
NCT03774732, NIRVANA-LUNG[109]	III	Pembrolizumab	SABR or 3D-CRT 18 Gy/3 fx	ICI + RT + CT	OS

ICI: Immune checkpoint inhibitors; Fx: Fraction; SABR: Stereotactic ablative radiotherapy; RT: Radiotherapy; LD-RT: Low dose radiotherapy; HFRT: Hypofractionated radiotherapy; IMRT: Intensity modulated radiotherapy; PBRT: Proton beam radiation therapy; 3D-CRT: 3D conformal radiation therapy; LCT: Local consolidation therapy; CT: Chemotherapy; ORR: Overall response rate; MTD: Maximum tolerated dose.