Unmasking immune checkpoint resistance in esophageal squamous cell carcinoma: Insights into the tumor microenvironment and biomarker landscape

Table 1 Summary of clinical studies on immunotherapy for esophageal squamous cell carcinoma

Line of therapy	Study	Therapy/intervention	Sample size	Study design	Primary outcomes	Key findings	Treatment combination (if any)
Neoadjuvant	ChiCTR2000040034[14]	Camrelizumab + nabpaclitaxel + cisplatin; camrelizumab + paclitaxel + cisplatin; paclitaxel + cisplatin	391 (132/130/129)	Multicenter, randomized, open-label, 3arm trial	pCR rate; EFS	EFS: PCR: 28.0% (camrelizumab + nabpaclitaxel) & 15.4% (camrelizumab + paclitaxel) vs 4.7% (paclitaxel); both P < 0.01; grade ≥ 3 TRAEs: 29%-34%; EFS immature	PD-1 inhibitor + doublet chemotherapy
	NCT04389177[108]	Pembrolizumab + paclitaxel + Cisplatin (neoadjuvant; adjuvant PD-1 if non-pCR)	47	Single-arm, single-center, open-label, phase II	MPR; safety	Results pending (protocol)	PD-1 inhibitor + doublet chemotherapy
	NCT04215471[73]	Adebrelimab	30	Phase Ib, single-arm	Safety, feasibility, pCR	pCR: 8%; major pathologic response: 24%; 2-year OS: 92%; acceptable safety profile with no grade ≥ 3 adverse events	PD-L1 inhibitor monotherapy
	ChiCTR2100045104[109]	Toripalimab + paclitaxel/carboplatin + radiotherapy	23	Phase Ib, single-arm	MPR & pCR	pCR: 55%; 2-year PFS: 63.8%; 2-year OS: 78%; manageable safety profile	PD-1 inhibitor + doublet chemotherapy + radiotherapy
Adjuvant	NCT02743494[72]	Nivolumab vs placebo	794 (532 nivolumab, 262 placebo)	Phase III, randomized, double-blind	DFS	Median DFS significantly improved with nivolumab (22.4 months vs 11.0 months, HR = 0.69, P < 0.001). Acceptable safety profile	PD-1 inhibitor monotherapy
Firstline	NCT03748134[9]	Sintilimab + cisplatin + paclitaxel (or cisplatin + 5-FU)	659 (327/332)	Multicenter, randomized, double-blind, phase III	OS & PFS	OS: 16.7 months vs 12.5 months (HR = 0.63, P < 0.001); PFS: 7.2 months vs 5.7 months (HR = 0.56, P < 0.001); grade ≥ 3 TRAEs: 60% vs 55%	PD-1 inhibitor + doublet chemotherapy
	NCT03829969[8]	Toripalimab + paclitaxel + cisplatin	514 (257/arm)	Multicenter, randomized, double-blind, placebo-controlled, phase III	PFS; OS	PFS: HR = 0.58 (95%CI = 0.46-0.74; P < 0.0001); OS: HR = 0.58 (95%CI = 0.43-0.78; P = 0.0004); grade ≥ 3 TEAEs: Similar between arms	PD-1 inhibitor + doublet chemotherapy
	NCT04187352[10]	Sugemalimab + cisplatin + 5 fluorouracil	540 (360/180)	Multicenter, randomized, double-blind, phase III	PFS; OS; ORR	PFS: 6.2 months vs 5.4 months (HR = 0.67, P = 0.0002); OS: 15.3 months vs 11.5 months (HR = 0.70, P = 0.0076); ORR: 60.1% vs 45.2%; grade ≥ 3 TRAEs: 51.3% vs 48.4%	PD-L1 inhibitor + doublet chemotherapy
	NCT03143153[11]	Nivolumab + chemo/nivolumab + ipilimumab vs chemo	970 (321/325/324)	Phase III, randomized, open-label, 3-arm	OS, PFS	OS: 15.4 months (nivolumab + chemo) vs 10.7 months (chemo); HR = 0.54, P < 0.001; OS: 13.7 months (nivolumab + ipilimumab) vs 10.7 months; HR = 0.64; PFS and ORR also improved	PD-1 inhibitor ± CTLA-4 inhibitor + chemo
	NCT03691090[12]	Camrelizumab + paclitaxel + cisplatin vs paclitaxel + cisplatin	596 (298/298)	Phase III, randomized, open-label	OS	OS: 15.3 months vs 12.0 months; HR = 0.70, P < 0.001; PFS and ORR also improved; acceptable safety profile	PD-1 inhibitor + doublet chemotherapy
Second-line	NCT02564263[6]	Pembrolizumab	387	Phase III, randomized, controlled trial	OS; HRQoL	No significant difference in HRQoL between pembrolizumab and chemotherapy; stable global health, symptom scores in both groups	PD-1 inhibitor monotherapy
	NCT02569242[7]	Nivolumab vs chemotherapy	419 (210 nivolumab, 209 chemotherapy)	Phase III, randomized, open-label	OS	Median OS significantly improved with nivolumab (10.9 months vs 8.4 months, HR = 0.77, P = 0.019). Favorable safety profile compared to chemotherapy	PD-1 inhibitor monotherapy
	NCT03852251[90]	Cadonilimab (anti-PD-1/CTLA-4 bispecific antibody)	22 (ESCC cohort)	Phase Ib/II, multicenter, open-label	ORR, safety	ORR: 18.2% in ESCC cohort; manageable safety profile	PD-1/CTLA-4 inhibitor monotherapy
	NCT03736863[95]	Camrelizumab + apatinib	52	Single-arm, open-label	ORR	ORR: 34.6%; manageable safety profile	PD-1 inhibitor + VEGFR2 inhibitor
	NCT03736863 (rechallenge)[96]	Camrelizumab + apatinib	49	Single-arm, open-label	ORR	ORR: 10.2%; DCR: 69%; median PFS: 4.6 months; manageable grade ≥ 3 AEs in 35%	PD-1 inhibitor + VEGFR2 inhibitor

pCR: Pathologic complete response; EFS: Event-free survival; TRAE: Treatment-related adverse event; MPR: Major pathologic response; OS: Overall survival; PFS: Progression-free survival; DFS: Disease-free survival; ORR: Overall response rate; HRQoL: Health-related quality-of-life; PD-1: Programmed death-1; ESCC: Esophageal squamous cell carcinoma; PD-L1: Programmed death-ligand 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4.