Immune checkpoint inhibitors in the first-line treatment of esophageal squamous cell carcinoma: Minireview for a big shift

Table 1 Main results of randomized controlled trials investigating first-line treatment in advanced esophageal squamous cell carcinoma, focusing on the outcomes of the programmed death ligand 1 positive subgroups

	Phase	Experimental treatment	Enrollment	PD-L1 assay	PD-L1 cutoff	Median follow-up	Median OS PD-L1 positive subgroups	Median OS in overall population	Median PFS PD-L1 positive subgroups	Median PFS in overall population	ORR PD-L1 positive subgroups	ORR in overall population
KEYNOTE-590[8], n = 749	3	Pembrolizumab + 5FU + cisplatin	Global	22C3 assay	PD-L1 CPS ≥ 10 (n = 383)	22.6 months (IQR: 19.6-27.1)	13.5 months vs 9.4 months (HR = 0.62, 95%CI: 0.49-0.78, P < 0.0001)	12.4 months vs 9.8 months (HR = 0.73, 95%CI: 0.62-0.86, P < 0.0001)	7.5 months vs 5.5 months (HR = 0.51, 95%CI: 0.41-0.65, P < 0.0001)	6.3 months vs 5.8 months (HR = 0.65, 95%CI: 0.55-0.76, P < 0.0001)	51.1% vs 26.9%	45.0% vs 29.3%
CheckMate 648[24], n = 645	3	Nivolumab + 5FU + cisplatin	Global	28-8 assay	PD-L1 TPS ≥ 1% (n = 97)	13 months1	15.4 months vs 9.1 months (HR = 0.54, 95%CI: 0.37-0.80, P < 0.001)	13.2 months vs 10.7 months (HR = 0.74, 95%CI: 0.58-0.96, P = 0.002)	6.9 months vs 4.4 months (HR = 0.65, 95%CI: 0.46-0.92, P = 0.002)	5.8 months vs 5.6 months (HR = 0.81, 95%CI: 0.64-1.04, P = 0.04)	53% vs 20%	47% vs 27%
CheckMate 648[24], n = 649	3	Nivolumab + ipilimumab + 5FU + cisplatin	Global	28-8 assay	PD-L1 TPS ≥ 1% (n = 97)	13 months1	13.7 months vs 9.1 months (HR = 0.64, 95%CI: 0.46-0.90, P = 0.001)	12.7 months vs 10.7 months (HR = 0.78, 95%CI: 0.62-0.98, P = 0.01)	4.0 months vs 4.4 months (HR = 1.02, 95%CI: 0.73-1.43, P = 0.90)		35% vs 20%	28% vs 27%
ESCORT-1st[11], n = 596	3	Camrelizumab + paclitaxel + cisplatin	China	6E8 antibody	PD-L1 TPS ≥ 1% (n = 329)	10.8 months (IQR: 7.3-14.3)	15.3 months vs 11.5 months (HR = 0.59, 95%CI: 0.43-0.80, P = 0.32)	15.3 months vs 12.0 months (HR = 0.70, 95%CI: 0.56-0.88, P = 0.001)	6.9 months vs 5.6 months (HR = 0.51, 95%CI: 0.39-0.67, P = 0.38)	6.9 months vs 5.6 months (HR = 0.56, 95%CI: 0.46-0.68, P < 0.001)	74.1% vs 65.6%	72.1% vs 62.1%
ESCORT-1st[25], n = 596	3	Camrelizumab + paclitaxel + cisplatin	China	6E8 antibody	PD-L1 TPS ≥ 1% (n = 329)	24 months2	/5	15.6 months vs 12.6 months (HR = 0.70, 95%CI: 0.58-0.84, P = 0.0001)	/5	7.6 months vs 5.8 months (HR = 0.54, 95%CI: 0.45-0.65, P = 0.0001)	/5	/5
JUPITER-06[26], n = 514	3	Toripalimab + paclitaxel + cisplatin	China	JS311 assay	PD-L1 CPS ≥ 1 (n = 401)	7.1 months2	15.2 months vs 10.9 months (HR = 0.61, 95%CI: 0.44-0.87, P = 0.0056)	17 months vs 11 months (HR = 0.58, 95%CI: 0.43-0.78, P = 0.0004)	5.7 months vs 5.5 months (HR = 0.58, 95%CI: 0.44-0.75, P < 0.0001)	5.7 months vs 5.5 months (HR = 0.58, 95%CI: 0.46-0.74, P < 0.0001)		69.3% vs 52.1%
ORIENT-15[27], n = 659	3	Sintilimab + paclitaxel + cisplatin	Global (> 97% China)	22C3 assay	PD-L1 CPS ≥ 10 (n = 381)	16 months (IQR: 12.3-19.4)	17.2 months vs 13.6 months (HR = 0.64, 95%CI: 0.48-0.85, P = 0.002)	16.7 months vs 12.5 months (HR = 0.63, 95%CI: 0.51-0.78, P < 0.001)	8.3 months vs 6.4 months (HR = 0.58 95%CI: 0.45-0.75, P < 0.001)	7.2 months vs 5.7 months (HR = 0.56, 95%CI: 0.46-0.68, P < 0.001)	68% vs 49%	66% vs 45%
ASTRUM-007[29]	3	Serplulimab +5FU + cisplatin	China	/3	PD-L1 CPS ≥ 1 (n = 383)	14.9 months (IQR: 8.8-19.7)	15.3 months vs 11.8 months (HR = 0.68, 95%CI: 0.53-0.87, P = 0.0020)3	/3	5.6 months vs 5.3 months (HR = 0.60, 95%CI: 0.48-0.75, P < 0.0001)3	/3	57.6% vs 42.1%
RATIONALE 306[28], n = 645	3	Tislelizumab + cisplatin (or oxaliplatin) + capecitabine (or paclitaxel or 5FU)	Global	SP263 assay	PD-L1 TAP score ≥ 10% (n = 223)	16.3 months (IQR: 8.6-21.8)	16.6 months vs 10.0 months (HR = 0.62, 95%CI: 0.44-0.87, P = 0.0029)	17.2 months vs 10.6 months (HR = 0.66, 95%CI: 0.54-0.80, P < 0.0001)		7.3 months vs 5.6 months (HR = 0.62, 95%CI: 0.52-0.75, P < 0.0001)		63% vs 42%
SKYSCRAPER-08[30], n = 461	3	Tiragolumab + atezolizumab + paclitaxel + cisplatin	Asia	SP263 assay	PD-L1 TAP score ≥ 10% (n = 199)	14.6 months4	18.9 months vs 10.5 months (HR = 0.70, 95%CI: 0.49-1.01)	15.7 months vs 11.1 months (HR = 0.70, 95%CI: 0.55-0.88, P = 0.0024)		6.2 months vs 5.4 months (HR = 0.56; 95%CI: 0.45-0.70, P = 0.0001)		59.7% vs 45.5%
MORPHEUS-EC[31], n = 152	1/2b	Tiragolumab + atezolizumab + 5FU + cisplatin	Asia	SP263 assay	PD-L1 TAP score ≥ 10% (n = 40)	10.9 months4		16 months vs 9.9 months (HR = 0.64, 95%CI: 0.35-1.20)		6.9 months vs 4.1 months (HR = 0.52, 95%CI: 0.30-0.91)		67.7% vs 47.8%
MORPHEUS-EC[31], n = 152	1/2b	Atezolizumab + 5FU + cisplatin	Asia	SP263 assay	PD-L1 TAP score ≥ 10% (n = 40)	11.4 months4		13.1 months vs 9.9 months (HR = 0.75, 95%CI: 0.40-1.39)		6.8 months vs 4.1 months (HR = 0.75, 95%CI: 0.44-1.26)		53.8% vs 47.8%

¹Minimum follow-up; the median follow-up was not provided in the study.

²Data at the minimum follow-up period of 24 months.

³The overall population coincides with the programmed death ligand 1 combined positive score ≥ 1. The study does not specify the assay for the programmed death ligand 1 analysis.

⁴Unavailable confidence interval of the median follow-up.

⁵In the final analysis, with a median follow-up of 24 months, data on objective response rate in both the overall population and programmed death ligand 1-positive subpopulation and progression-free survival and overall survival in the programmed death ligand 1-positive subpopulation were not reported.

PD-L1: Programmed death ligand 1; OS: Overall survival; PFS: Progression-free survival; ORR: Objective response rate; 5FU: 5-fluorouracil; HR: Hazard ratio; CI: Confidence interval; CPS: Combined positive score; IQR: Interquartile range; TPS: Tumor proportion score; TAP: Tumor area positivity.