Immune checkpoint inhibitors in esophageal cancer: Clinical development and perspectives

Figures & data

Figure 1. Mechanism of immune checkpoints and their blockade.

Table 1. Results of clinical trials in which an ICI was used as monotherapy in a third-line or later setting.

Trial	ICI	Phase	N (SCC [%])	All patients			SCC patients
				ORR (95% CI) (%)	mOS (95% CI) (m)	mPFS (95% CI) (m)	ORR (95% CI) (%)	mOS (95% CI) (m)	mPFS (95% CI) (m)
KEYNOTE-180	Pembrolizumab	II	121 (52)	9.9 (5.2–16.7)	5.8 (4.5–7.2)	2.0 (1.9–2.1)	14.3 (6.7–25.4)	6.8 (5.4–8.9)	2.1 (2.0–2.4)
ATTRACTION-1	Nivolumab	II	65 (100)	17 (10–28)	10.8 (7.4–13.3)	1.5 (1.4–2.8)	All patients were SCC

CI confidence interval, ICI immune checkpoint inhibitor, m months, mOS median overall survival, mPFS median progression-free survival, ORR objective response rate, SCC squamous cell carcinoma.

Table 2. Results of clinical trials that compared ICI monotherapy with chemotherapy in a second-line setting.

Trial	Phase	Arm	N (SCC[%]/PD-L1+[%])	All patients									Patients with SCC			Patients with PD-L1 +
				OS				PFS				ORR (%)	OS			OS
				Median (m)	HR (95% CI)	p-value		Median (m)	HR (95% CI)	p-value			Median (m)	HR (95% CI)	p-value	Median (m)	HR (95% CI)	p-value
KEYNOTE-181	III	Pembrolizumab	628 (63.9/35.4)	7.1	0.89 (0.75–1.05)	0.056		2.1	1.11 (0.94–1.31)	NA		13.1	8.2	0.78 (0.63–0.96)	0.0095	9.3	0.69 (0.52–0.93)	0.0074
		Chemotherapy		7.1				3.4				6.7	7.1			6.7
ATTRACTION-3	III	Nivolumab	419 (100/48.4)	10.9	0.77 (0.62–0.96)	0.019		1.7	1.08 (0.87–1.34)	NA		19	All patients were SCC			10.9	0.69 (0.51–0.94)	NA
		Chemotherapy		8.4				3.4				22				8.1
RATIONALE-302	III	Tislelizumab	512 (100/30.7)	8.6	0.7 (0.57–0.85)	0.0001		1.6	0.83 (0.67–1.01)	NA		20.3	All patients were SCC			10.3	0.54 (0.36–0.79)	0.0006
		Chemotherapy		6.3				2.1				9.8				6.8

HR hazard ratio, CI confidence interval, m months, NA not available, OS overall survival, PD-L1+ programmed cell death-1-positive, PFS progression-free survival, ORR objective response rate, SCC squamous cell carcinoma.

PD-L1 positivity was defined as CPS ≥10 in KEYNOTE-181, TPS ≥1 in ATTRACTION-3, and TAP score ≥10% in RATIONALE-302.

Table 3. Results of clinical trials than compared an ICI plus chemotherapy with chemotherapy alone in a first-line setting.

Trial	Phase	Arm	N (SCC[%]/PD-L1+[%])	All patients										Patients with SCC			Patients with PD-L1 +
				OS					PFS				ORR (%)	OS			OS
					Median (m)	HR (95% CI)	p-value		Median (m)	HR (95% CI)	p-value			Median (m)	HR (95% CI)	p-value	Median (m)	HR (95% CI)	p-value
KEYNOTE-590	III	Pembrolizumab+chemo	749 (73/51)		12.4	0.73 (0.62–0.86)	<0.0001		6.3	0.65 (0.55–0.76)	<0.0001		45	12.6	0.72 (0.60–0.88)	0.0006	13.5	0.62 (0.49–0.78)	<0.0001
		Chemo alone			9.8				5.8				29.3	9.8			9.4
CheckMate-648	III	Nivolumab+chemo	970 (98/48.8)		13.2	0.74 (0.58–0.96)	0.002		5.8	0.81 (0.65–1.04)	0.04		47	NA			15.4	0.54 (0.37–0.80)	<0.001
		Nivolumab+ipilimumab			12.7	0.78 (0.62–0.98)	0.01		NA	NA	NA		28				13.7	0.64 (0.46–0.90)	0.001
		Chemo alone			10.7	-	-		5.6	-	-		27				9.1	-	-
RATIONALE-306	III	Tislelizumab+chemo	649 (100/36.3)		17.3	0.66 (0.54–0.80)	<0.0001		7.3	0.62 (0.52–0.75)	<0.0001		63.5	All patients were SCC			16.8	0.61 (0.44–0.85)	0.0017
		Chemo alone			10.6				5.6				42.4				10
ESCORT-1st	III	Camrelizumab+chemo	596 (100/55.2)		15.3	0.70 (0.56–0.88)	0.001		6.9	0.56 (0.46–0.68)	<0.001		72.1	All patients were SCC			15.3	0.59 (0.43–0.80)	0.32
		Chemo alone			12				5.6				62.1				11.5
ORIENT-15	III	Sintilimab+chemo	659 (100/57.8)		16.7	0.63 (0.51–0.78)	<0.001		7.2	0.56 (0.46–0.68)	<0.001		66	All patients were SCC			17.2	0.64 (0.48–0.85)	0.002
		Chemo alone			12.5				5.7				45				13.6
JUPITER-06	III	Toripalimab+chemo	514 (100/41.2)		17	0.58 (0.43–0.78)	<0.0001		5.7	0.58 (0.46–0.74)	<0.0001		69.3	All patients were SCC			17	0.64 (0.40–1.03)	0.0618
		Chemo alone			11				5.5				52.1				10.9

Chemo chemotherapy, CI confidence interval, HR hazard ratio, ICI immune checkpoint inhibitor, m months, NA not available, ORR objective response rate, OS overall survival, PD-L1+ programmed cell death-1-positive, PFS progression-free survival, SCC squamous cell carcinoma.

PD-L1 positivity was defined as CPS ≥10 in KEYNOTE-590, ORIENT-15, and JUPITER-06, as TPS ≥1 in CheckMate-648 and ESCORT-1st, and as TAP score ≥10% in RATIONALE-306.

Chemotherapy consisted of fluoropyrimidine plus platinum in KEYNOTE-590 and CheckMate-648, taxane plus platinum in ESCORT-1st and JUPITER-06, and fluoropyrimidine/taxane plus platinum in RATIONALE-306 and ORIENT-15.