Perioperative immunotherapy for esophageal squamous cell carcinoma: Now and future

Table 1 Reported clinical results of neoadjuvant immunotherapy for resectable esophageal squamous cell carcinoma

Drug & Ref.	Trial No.	Phase	Number of enrollments	Clinical stage	Design	Chemotherapy drugs	Chemotherapy cycles	Radiotherapy	Interval time to surgery	Primary outcome	Safety (rate of grade ≥ 3 trAEs)	Feasibility (therapy completion rate)	pCR	MPR	Surgical outcome (R0 rate)
Pembrolizumab[111]	Park et al[111] (NR)	NA	38	IA-IVA	Retrospective	5-FU + DDP/PTX + CBP	NA	41.4 Gy/23 f	6-8 wk	Operative risk	18.75% (3/16)	100% (16/16)	NA	NA	100%
Pembrolizumab[112]	Huang et al[112] (NR)	NA	54	II–IVA	Retrospective	DTX + NDP	2, Q3W		4-6 wk	pCR	13.04% (4/23)	NA	30.4% (7/23)	NA	100%
Pembrolizumab[113]	NCT02844075	II	28	IB-III	Single- arm	PTX + CBP	5, Q1W	41.4 Gy/23 f	5 wk	pCR	NA	92.9% (26/28)	46.1% (12/26)	NA	NA
Pembrolizumab[80]	Keystone-001/NCT04389177	II	50	IIIA-IIIB	Single-arm	PTX + DDP	3, Q3W		4-6 wk	pCR, MPR, safety	0	69.0% (29/42)	41.4% (12/29)	72.4% (21/29)	100%
Camrelizumab[114]	Qiao et al[114] (NR)	NA	254	IA-IVA	Retrospective	PTX, nab-PTX/DTX	2, Q3W		NA	pCR	6.25% (3/48)	NA	41.7% (20/48)	60.4 (29/48)	NA
Camrelizumab[74]	ChiCTR1900026240	II	60	IIIA-IVA	Single-arm	nab-PTX + CBP	2, Q3W		4-6 wk	pCR	56.7% (34/60)	85.0% (51/60)	39.2% (20/51)	NA	98.0%
Camrelizumab[115]	NCT04506138	I-II	46	II-IVA	Single-arm	nab-PTX + CBP			4-6 wk	pCR	15.2% (7/46)	82.6% (38/46)	21.6% (8/37)	48.6% (18/37)	80.4%
Camrelizumab[82]	GASTO1056/ChiCTR2000028900	II	23	II-III	Single-arm	nab-PTX + CBP	2, Q3W		3-6 wk	Safety	47.8%	87.0% (20/23)	25% (5/20)	50% (10/20)	100%
Camrelizumab[116]	Yang et al[116] (NR)	II	12	II-III	Single-arm	nab-PTX + S1	3, Q3W		3-6 wk	pCR	0	75.0% (9/12)	33.3% (4/12)	41.7% (5/12)	100%
Camrelizumab[75]	NIC-ESCC2019/NCT04225364	II	56	II-IVA	Single-arm	nab-PTX + DDP	2, Q3W		6 wk	pCR	10.7% (6/51)	91.1% (51/56)	35.3% (18/51)	23.5% (12/21)	100%
Camrelizumab[117]	ChiCTR1900023880	Ib	30	IC-IIIB	Single-arm	nab-PTX + NDP + Apatinib	2-4, Q3W		4-8 wk	Safety, feasibility	36.7% (11/30)	96.7% (29/30)	24.1% (7/29)	51.7% (15/29)	NA
Camrelizumab[118]	ESPRIT/ChiCTR2000033761	II	48	IIA-IIIB	Single-arm	PTX + NDP	2-4, Q3W		NA	pCR	4.2%	62.5% (30/48)	35.0% (7/20)	NA	NA
Camrelizumab[119]	NCT 03917966	II	40	IC-IVA	Single-arm	DTX + NDP	2, Q3W		4-6 wk	MPR	3%	70.6% (12/17)	25.0% (3/12)	41.6% (5/12)	100%
Camrelizumab[120]	ChiCTR2000039170	II	166	Locally advanced	Single-arm	nab-PTX + NDP	NA		NA	Safety	7.8% (13/166)	49.4% (82/166)	18.5% (15/81)	63.0% (51/81)	97.5% (79/82)
Sintilimab[121]	ChiCTR1900026593	II	47	II-IVA	Single-arm	PTX liposome + CBP	2, Q3W		3-6 wk	pCR	29.8% (14/47)	95.7% (45/47)	22.2% (10/45)	44.4% (20/45)	97.8% (44/45)
Sintilimab[81]	SIN-ICE study/ChiCTR2100048917	II	23	IC-IVA	Single-arm	Platinum	3, Q3W		4-6 wk	pCR, safety	30.4% (7/23)	73.9% (17/23)	35.3%, (6/17)	52.9% (9/17)	94.1% (16/17)
Sintilimab[73]	ESONICT-1/ChiCTR2100045659	II	30	IIB-IVA	Single-arm	DDP + nab-PTX	2, Q3W		4-6 wk	pCR, safety	3.3% (1/30)	76.6% (23/30)	21.7% (5/23)	52.2% (12/23)	100%
Sintilimab[88]	KEEP-G03/NCT03946969	II	30	IB-IVA	Single-arm	PTX liposom + DDP + S1	2, Q3W		Within 6 wk	Safety, feasibility	36.7%	100.0% (30/30)	20% (6/30)	50% (15/30)	100%
Toripalimab[122,123]	NCT03985670	II	30	II-IVA	Two-arm	PTX + DDP	2, Q3-4W		4-6 wk	pCR	8.33% (2/24)	80.0% (24/30)	20.8% (5/24)	NA	100%
Toripalimab[124]	ChiCTR1900025318	II	23	IIB-IVA	Single-arm	PTX + DDP	2, Q3W		4-6 wk	pCR, R0 rate	8.70% (2/23)	78.3% (18/23)	33.3% (6/18)	NA	100%
Toripalimab[77]	NCT04177797	II	20	IIIA-IVA	Single-arm	PTX + CBP	2, Q3W		4-6 wk	Safety, feasibility, MPR, pCR	20.0% (4/20)	80.0% (16/20)	18.8% (3/16)	43.8% (7/16)	87.5% (14/16)
Toripalimab[125]	ESONICT-2/ChiCTR2100052784	II	20	IIB-IVA	Single-arm	DTX + DDP	2, Q3W		4-6 wk	pCR, safety	15.0% (3/20)	60.0% (12/20)	16.7% (2/12)	41.7% (5/12)	100%
Toripalimab[126]	SCALE-1/ChiCTR2100045104	Ib	20	IIB-IVA	Single-arm	PTX + CBP	2, Q3W	30 Gy/12 f	4-7 wk	Safety	NA	87.0% (20/23)	55% (11/20)	80% (16/20)
Tislelizumab[76]	TD-NICE/ChiCTR2000037488	II	45	IIIA-IVA	Single-arm	CBP + nab-PTX	2, Q3W		3-6 wk	MPR	33.3% (15/45)	80.0% (36/45)	50% (18/36)	72% (26/36)	97.2% (35/36)
Multiple[127]	CHICTR2100045659		27	IC-IVA	Retrospectively, two-arm	Platinum+ PTX or platinum + 5-Fu	2, Q3w		4–8 wk	30-d major complications	11.1% (3/27)	NA	NA	NA	100%

NR: Not registered; NA: Not available; 5-FU: 5-fluorouracil; DDP: Cisplatin; PTX: Paclitaxel; DTX: Docetaxel; CBP: Carboplatin; NDP: Nedaplatin; nab-PTX: Albumin bound paclitaxel; S1: Tegafur (Gimeracil and Oteracil Potassium Capsules); pCR: Pathological complete response; MPR: Major pathological response; trAEs: Treatment-related adverse events.

Table 2 Ongoing clinical trials of neoadjuvant immunotherapy for resectable esophageal squamous cell carcinoma

Drug & target	Trial name/No./Ref.	Phase	Sample size	Clinical stage	Design	Chemotherapy drugs	Chemotherapy cycles	Radiotherapy	Interval to surgery	Primary endpoint	Start date
Nivolumab	FRONTiER/NCT03914443[67]	I	36	IC-IVA	Two-arm	5-FU + DDP	2, Q3W		12 wk	Incidence of dose-limiting toxicities	07-May-19
	NCT03987815	II	20	NA	Single-arm	NA				MPR	01-Aug-19
	NCT05213312	II-III	90	II-III	Two-arm	PTX/5-FU + DDP	2, Q3W		4-6 wk	pCR	01-Jun-22
Pembrolizumab	PALACE-1/NCT03792347[85]	I	20	IC-IVA	Single-arm	CBP + PTX	5, Q1W	41.4 Gy/23 f	4-6 wk	Safety	21-Jan-19
	PALACE-2/NCT04435197[84]	II	143	IC-IVA	Single-arm	CBP + PTX	5, Q1 W	41.4 Gy/23 f	4-6 wk	pCR	11-Aug-20
	NCT05302011	II	30	IIB/IIIB/IVA	Single-arm	CBP/DDP + DTX	4, Q3W			Tumor response, pCR	01-Jun-20
	NCT05281003	II	128	IC-IVA	Single-arm	PTX + DDP	4, Q4W			pCR	20-Feb-23
Camrelizumab	NCT04520035	II	60	IIB-IVA	Single-arm	PTX + DDP	2, Q3W			pCR	01-Aug-20
	NCT04767295	II	28	IA-IVA	Single-arm	nab-PTX + CBP	2, Q3W		5-8 wk	pCR	01-Mar-21
	NICE-2 Study/NCT 05043688[128]	II	204	Locally advanced	Three-arm	nab-PTX, CBP, PTX	2, Q3W	41.4 Gy/23 f	4-12 wk	pCR	14-Sep-21
	NCT05476380	II	39	IIIB-IVA	Single-arm	PTX + DDP	3, Q3W			pCR	19-Feb-21
	NCT05182944	II	130	IIB-IVA	Four-arm	nab-PTX + DDP	2, Q3W			pCR, 3-yr DFS	15-Jan-22
	NCT04937673	II	40	IIB-IVA	Two-arm	PTX/nab-PTX + DDP	3, Q3W		NA	Biomarkers related to pCR	01-Jul-21
	NCT05176002	I-II	26	II-IVA	Single-arm	NA	NA	Radiotherapy, NA	NA	Efficacy Safety	23-Sep-21
	NCT04666090	II	42	IIA-IVA	Single-arm	nab-PTX + NDP + Apatinib	2-3, Q2W		4-6wk	pCR	23-Nov-20
	NCT05355168	I-II	57	IC-IVA	Single-arm	Nimotuzumab + CRT	NA			pCR, MPR	01-Nov-21
	NCT03200691	II	21	IIA-III	Single-arm			40 Gy/20 f	2-4 wk	pCR	10-Aug-17
Sintilimab	NCT03940001	I	20	IIB-IVA	Single-arm	PTX + CBP	2, Q3W	41.4 Gy/23 f	NA	Unacceptable toxicity; pCR; MPR	01-May-19
	(NICCE)NCT05028231	NA	46	IIB-IVA	Single-arm	nab-PTX + DDP	2, Q3W			pCR	05-Jun-21
	NCT05357846	III	422	IIB-IVA	Two-arm	PTX + DDP	4, Q1W	40 or 45 Gy / 20 f	6-8 wk	OS	01-Nov-22
	NCT05244798	III	420	IC-IVA	Three-arm	nab-PTX + CBP	2, Q3	41.4 Gy/23 f	6-8 wk	pCR	01-Nov-22
Toripalimab	NCT04280822	III	400	IC-IVA	Two-arm	DDP + PTX	2, Q3W		2-3 wk	3 yr EFS; 5 yr EFS	21-Apr-20
	NCT04804696	II	53	NA	Single-arm	PTX + DDP	NA		NA	pCR	10-Feb-21
	NCT04177875	II	44	IC-IIIB	Single-arm	DTX/PTX + DDP	2, Q3W	40 Gy/20 f	NA	MPR; ORR	01-May-19
	NCT04888403	II	45	IIB-IVA	Single-arm	nab-PTX + NDP	5, Q1W	41.4 Gy/23 f	Within 7 wk	pCR	31-Dec-21
	NCT04644250	II	32	IIB-IVA	Single-arm	CBP + PTX liposome	5, Q1W	41.4 Gy/23 f	2-4 wk	pCR	01-Sep-20
	NCT04848753	III	632	IC-IVA	Two-arm	DDP + PTX	NA		NA	EFS	18-Jun-21
	NCT04006041	II	44	IIB-IVA	Single-arm	PTX + DDP	4, Q1W	44 Gy/20 f	6-8 wk	pCR	25-Jun-19
Tislelizumab	iCROSS/NCT04973306	II-III	176	II-III	Two-arm	CBP + PTX	5, Q1W	41.4 Gy/23 f	NA	pCR; OS	02-Mar-22
	NCT05323890	II	15	IIB-IVA	Single-arm	nab-PTX + DDP	5, Q1W	41.4 Gy/23 f	NA	MPR, pCR	20-Apr-22
	NCT04974047	II	70	IIB-IVA	Two-arm	PTX/5-FU + DDP	2, NA	40 or 45 Gy/20 fractions	NA	pCR	17-Aug-21
	NCT05189730	II	80	II-III	Single-arm	PTX + CBP	2, Q3W	40 Gy/20 f	4-6 wk	pCR, incidence of adverse events	01-Jul-21
Adebrelimab (PD-L1)	NATION1907II/NCT04215471	II	30	Resectable	Single-arm					ORR	01-Feb-20
Durvalumab	NCT04568200	II	60	IIB-IVA	Two-arm	CBP + PTX	4, Q3W	41.4 Gy/23 f		pCR	19-Jun-20
Pembrolizumab (+ Adjuvant)	KEYSTONE-002/NCT04807673[86]	III	342	IC-IIIB	Two-arm	PTX + DDP	3, Q3W	41.4 Gy/23 f	4-6 wk	EFS	01-Dec-21
PD-1 Inhibitor	REVO/NCT05007145	II	92	IB-IVA	Two-arm	nab-PTX + DDP	2-4, Q3W	40 Gy/20 f		pCR	15-Aug-21
Toripalimab (+ Adjuvant)	NCT 04437212	II	20	IIB-IVA	Single-arm	PTX/DDP	5, Q3W	41.4 Gy/23 f	6-8 wk	MPR	01-Jul-20

EFS: Events-free survival; DFS: Disease-free survival; OS: Overall survival; ORR: Objective response rate; NA: Not available; 5-FU: 5-fluorouracil; DDP: Cisplatin; PTX: Paclitaxel; DTX: Docetaxel; CBP: Carboplatin; NDP: Nedaplatin; nab-PTX: Paclitaxel for injection (albumin bound); pCR: Pathological complete response; MPR: Major pathological response.

Table 3 Clinical trials of adjuvant immunotherapy for resectable esophageal squamous cell carcinoma

Drug	Trial name/No.	Phase	Sample size	Clinical stage	Design	Chemotherapy drugs	Chemotherapy cycles	Radiotherapy	Interval time to surgery	Primary endpoint	Start date	Outcome
Nivolumab	CheckMate-577/NCT02743494	III	784 (ESCC29%)	NA	Two-arm	NA				DFS	Completed	22.1:11.0 mo
Toripalimab (+ Neoadjuvant)	NCT 04437212	II	20	IIB-IVA	Single-arm	PTX + DDP	5, Q3W	41.4 Gy/23 f	6-8 wk	MPR	Jul 1, 2020
Tislelizumab	AIRE/ChiCTR2100045651	III	110	High-risk resected locally advanced	Two-arm	Platinum-based doublets	2, Q3W			DFS	May 1, 2021
Tislelizumab	CRISEC/NCT04776590	II	30	NA	Single-arm	PTX + CBP	5, Q1W	41.4 Gy/23 f		pCR	Jan 28, 2021

DFS: Disease-free survival; NA: Not available; DDP: Cisplatin; PTX: Paclitaxel; CBP: Carboplatin; pCR: Pathological complete response; MPR: Major pathological response.