World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Original Article

Volume 13, Number 3, June 2022, pages 126-135

Surrogate Endpoints for Overall Survival in Immune-Oncology Trials of Advanced Gastro-Esophageal Carcinoma

Figure 1. Study flow chart. PD-1: programmed death-1; ASCO: American Society of Clinical Oncology; ESMO: European Society for Medical Oncology; OR: odds ratio; HR: hazard ratio; OS: overall survival.

Figure 2. Performance of PFS as surrogate endpoint for OS in immuno-oncology trials of advanced gastro-esophageal carcinoma. (a) Correlation between PFS and OS at arm-level. Each dot represents one of the experimental arms of the phase 3 clinical trials, with size of the dot being proportional to the sample size. (b) Correlation between HRs for PFS and OS at trial-level. Size of dots is proportional to weighted sample size. The blue line represents the upper and lower 95% confidence intervals of the regression line (red line). Trials are colored based on whether the endpoint results were statistically significant. Nivo: nivolumab; Pembro: pembrolizumab; Ipi: ipilimumab; C: chemotherapy; GC: gastric carcinoma; ESCA: esophageal carcinoma; HR: hazard ratio; OS: overall survival; PFS: progression-free survival; NS: not significant; R: weighted Pearson correlation coefficient.

Figure 3. Leave-one-out cross-validation analysis of the prediction of OS by treatment effect on PFS. Predicted HRs for OS (blue circles) with 95% prediction intervals (vertical grey lines) were calculated from the observed HR on PFS of that particular trial and the surrogate model built on the remaining trials. Observed HRs are shown for OS (red squares). Nivo: nivolumab; Pembro: pembrolizumab; Ipi: ipilimumab; C: chemotherapy; HR: hazard ratio; OS: overall survival; PFS: progression-free survival.

Figure 4. Correlation between PFS and OS at different cut-off time points. (a) Correlation between PFS and OS at arm-level. Bottom right: PFS at 6 months to predict OS at 12 months. (b) Correlation between HRs for PFS and OS at trial-level. Bottom right: HRs for PFS at 6 months to predict HRs for OS at 12 months. Nivo: nivolumab; Pembro: pembrolizumab; Ipi: ipilimumab; C: chemotherapy; GC: gastric carcinoma; ESCA: esophageal carcinoma; HR: hazard ratio; OS: overall survival; PFS: progression-free survival; NS: not significant; R: weighted Pearson correlation coefficient.

**Table 1.** Characteristics of the Included Trials
Studies	Population	Line of treatments	Study phase	Primary endpoint	Treatment arms	N	DCR (%)	ORR (%)	OS	PFS
Patients with CPS ≥ 10 were included. Patients with CPS ≥ 5 were included. All randomly assigned patients were included. Patients with CPS ≥ 1 were included. ***Patients with CPS ≥ 1 were included. G: gastric; EGJ: esophagogastric junction; ESCA: esophageal carcinoma; Nivo: nivolumab; Ipi: ipilimumab; NIVO3: nivolumab 3 mg/kg; NIVO1 + IPI3: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; NIVO3 + IPI1: NIVO3 plus ipilimumab 1 mg/kg; NR: not reported; CPS: combined positive score; TPS: tumor positive score; ORR: objective response rate; DCR: disease control rate; OS: overall survival; PFS: progression-free survival; HR: hazard ratio.
ATTRACTION-2 [12]	G/EGJ carcinoma	≥ 3	3	OS	Nivo; placebo	330; 163	40; 25	11; 0	5.26; 4.14	0.63 (0.51 - 0.78)	1.61; 1.45	0.60 (0.49 - 0.75)
JAVELIN Gastric 300 [32]	G/EGJ carcinoma	≥ 2	3	OS	Avelumab; chemotherapy	185; 186	22.2; 44.1	2.2; 4.3	4.6; 5.0	1.1 (0.90 - 1.40)	1.4; 2.7	1.73 (1.40 - 2.20)
KEYNOTE-061 [33]	G/EGJ carcinoma	2	3	OS; PFS	Pembrolizumab; paclitaxel	196; 199	59.5; 29.5	16; 14	9.1; 8.3	0.82 (0.66 - 1.03)	1.5; 4.1	1.27 (1.03 - 1.57)
ATTRACTION-3 [13]	ESCA	2	3	OS	Nivo; chemotherapy	210; 209	37; 66	19; 22	10.9; 8.4	0.77 (0.62 - 0.96)	1.7; 3.4	1.08 (0.87 - 1.34)
ATTRACTION-4 [34]	G/EGJ carcinoma	1	3	OS; PFS	Nivo + chemotherapy; placebo + chemotherapy	362; 362	71.8; 68.5	57.5; 47.8	17.45; 17.15	0.90 (0.75 - 1.08)	10.45; 8.34	0.68 (0.51 - 0.90)
ESCORT [14]	ESCA	2	3	OS	Camrelizumab; chemotherapy	228; 220	44.7; 34.5	20.2; 6.4	8.3; 6.2	0.71 (0.57 - 0.87)	1.9; 1.9	0.69 (0.56 - 0.86)
KEYNOTE-590 [18]	ESCA	1	3	OS; PFS	Pembrolizumab + chemotherapy; placebo + chemotherapy	373; 376	79.3; 75.6	45; 29.3	12.4; 9.8	0.73 (0.62 - 0.86)	6.3; 5.8	0.65 (0.55 - 0.76)
KEYNOTE-181 [15]*	ESCA	2	3	OS (CPS ≥ 10)	Pembrolizumab; chemotherapy	107; 115	49.5; 47.0	21.5; 6.1	9.3; 6.7	0.69 (0.52 - 0.93)	2.6; 3.0	0.73 (0.54-0.97)
CheckMate 649 [16, 36]**	G/EGJ carcinoma	1	3	OS; PFS (CPS ≥ 5)	Nivo + chemotherapy; chemotherapy; Nivo + ipi; chemotherapy	473; 482; 234; 239	88; 79; 54; 83	60; 45; 27; 47	14.4; 11.1; 11.2; 11.6	0.71 (0.59 - 0.86); 0.89 (0.71 - 1.10)	7.7; 6.0; 2.8; 6.3	0.68 (0.56 - 0.81); 1.42 (1.14 - 1.76)
JAVELIN Gastric 100 [37]***	G/EGJ carcinoma	1	3	OS (all patients or TPS ≥ 1)	Avelumab; chemotherapy	249; 250	50.2; 61.2	13.3; 14.4	10.4; 10.9	0.91 (0.74 - 1.11)	3.2; 4.4	1.04 (0.85 - 1.28)
KEYNOTE-062 [35]****	Gastric carcinoma	1	3	OS; PFS (CPS ≥ 1 or ≥ 10)	Pembrolizumab + chemotherapy; pembrolizumab; chemotherapy	257; 256; 250	78; 42; 79	49; 15; 37	13.9; 10.6; 11.1	0.85 (0.70 - 1.03); 0.91 (0.74 - 1.10)	6.9; 2.0; 6.4	0.84 (0.70 - 1.02); 1.66 (1.37 - 1.51)
RATIONALE 302 [38]	ESCA	2	3	OS	Tislelizumab; chemotherapy	256; 256	47; 41.8	20.4; 9.8	8.6; 6.3	0.70 (0.57 - 0.85)	1.6; 2.1	0.83 (0.67 - 1.01)
CheckMate 648 [31]*****	ESCA	1	3	OS; PFS (CPS ≥ 1)	Nivo + chemotherapy; Nivo + ipi; chemotherapy	158; 158; 157	78; 63; 66	53; 35; 20	15.4; 13.7; 9.1	0.54 (0.37 - 0.80); 0.64 (0.46 - 0.90)	6.9; 4.0; 4.4	0.65 (0.46 - 0.92); 1.02 (0.73 - 1.43)
ESCORT-1st [17]	ESCA	1	3	OS; PFS	Camrelizumab + chemotherapy; chemotherapy	298; 298	91.3; 88.9	72.1; 62.1	15.3; 12.0	0.70 (0.56 - 0.88)	6.9; 5.6	0.56 (0.46 - 0.68)
ORIENT-15 [39]***	ESCA	1	3	OS (CPS ≥ 10 and all patients)	Sintilimab + chemotherapy; chemotherapy	327; 332	NR	66.1; 45.5	16.7; 12.5	0.63 (0.51 - 0.78)	7.2; 5.7	0.56 (0.46 - 0.68)
ORIENT-16 [40]***	G/EGJ carcinoma	1	3	OS (CPS ≥ 5 and all patients)	Sintilimab + chemotherapy; chemotherapy	327; 323	NR	58.2; 48.4	15.2; 12.3	0.76 (0.63 - 0.94)	7.1; 5.7	0.64 (0.53 - 0.77)
JUPITER-06 [41]	ESCA	1	3	OS; PFS	Toripalimab + chemotherapy; chemotherapy	257; 257	NR	NR	17.0; 11.0	0.58 (0.43 - 0.78)	5.7; 5.5	0.58 (0.46 - 0.74)

Table 1. Characteristics of the Included Trials

Studies

Population

Line of treatments

Study phase

Primary endpoint

Treatment arms

DCR (%)

ORR (%)

PFS

Median

*Patients with CPS ≥ 10 were included. **Patients with CPS ≥ 5 were included. ***All randomly assigned patients were included. ****Patients with CPS ≥ 1 were included. *****Patients with CPS ≥ 1 were included. G: gastric; EGJ: esophagogastric junction; ESCA: esophageal carcinoma; Nivo: nivolumab; Ipi: ipilimumab; NIVO3: nivolumab 3 mg/kg; NIVO1 + IPI3: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; NIVO3 + IPI1: NIVO3 plus ipilimumab 1 mg/kg; NR: not reported; CPS: combined positive score; TPS: tumor positive score; ORR: objective response rate; DCR: disease control rate; OS: overall survival; PFS: progression-free survival; HR: hazard ratio.

ATTRACTION-2 [12]

G/EGJ carcinoma

≥ 3

Nivo; placebo

330; 163

40; 25

11; 0

5.26; 4.14

0.63 (0.51 - 0.78)

1.61; 1.45

0.60 (0.49 - 0.75)

JAVELIN Gastric 300 [32]

G/EGJ carcinoma

≥ 2

Avelumab; chemotherapy

185; 186

22.2; 44.1

2.2; 4.3

4.6; 5.0

1.1 (0.90 - 1.40)

1.4; 2.7

1.73 (1.40 - 2.20)

KEYNOTE-061 [33]

G/EGJ carcinoma

OS; PFS

Pembrolizumab; paclitaxel

196; 199

59.5; 29.5

16; 14

9.1; 8.3

0.82 (0.66 - 1.03)

1.5; 4.1

1.27 (1.03 - 1.57)

ATTRACTION-3 [13]

ESCA

Nivo; chemotherapy

210; 209

37; 66

19; 22

10.9; 8.4

0.77 (0.62 - 0.96)

1.7; 3.4

1.08 (0.87 - 1.34)

ATTRACTION-4 [34]

G/EGJ carcinoma

OS; PFS

Nivo + chemotherapy; placebo + chemotherapy

362; 362

71.8; 68.5

57.5; 47.8

17.45; 17.15

0.90 (0.75 - 1.08)

10.45; 8.34

0.68 (0.51 - 0.90)

ESCORT [14]

ESCA

Camrelizumab; chemotherapy

228; 220

44.7; 34.5

20.2; 6.4

8.3; 6.2

0.71 (0.57 - 0.87)

1.9; 1.9

0.69 (0.56 - 0.86)

KEYNOTE-590 [18]

ESCA

OS; PFS

Pembrolizumab + chemotherapy; placebo + chemotherapy

373; 376

79.3; 75.6

45; 29.3

12.4; 9.8

0.73 (0.62 - 0.86)

6.3; 5.8

0.65 (0.55 - 0.76)

KEYNOTE-181 [15]*

ESCA

OS (CPS ≥ 10)

Pembrolizumab; chemotherapy

107; 115

49.5; 47.0

21.5; 6.1

9.3; 6.7

0.69 (0.52 - 0.93)

2.6; 3.0

0.73 (0.54-0.97)

CheckMate 649 [16, 36]**

G/EGJ carcinoma

OS; PFS (CPS ≥ 5)

Nivo + chemotherapy; chemotherapy; Nivo + ipi; chemotherapy

473; 482; 234; 239

88; 79; 54; 83

60; 45; 27; 47

14.4; 11.1; 11.2; 11.6

0.71 (0.59 - 0.86); 0.89 (0.71 - 1.10)

7.7; 6.0; 2.8; 6.3

0.68 (0.56 - 0.81); 1.42 (1.14 - 1.76)

JAVELIN Gastric 100 [37]***

G/EGJ carcinoma

OS (all patients or TPS ≥ 1)

Avelumab; chemotherapy

249; 250

50.2; 61.2

13.3; 14.4

10.4; 10.9

0.91 (0.74 - 1.11)

3.2; 4.4

1.04 (0.85 - 1.28)

KEYNOTE-062 [35]****

Gastric carcinoma

OS; PFS (CPS ≥ 1 or ≥ 10)

Pembrolizumab + chemotherapy; pembrolizumab; chemotherapy

257; 256; 250

78; 42; 79

49; 15; 37

13.9; 10.6; 11.1

0.85 (0.70 - 1.03); 0.91 (0.74 - 1.10)

6.9; 2.0; 6.4

0.84 (0.70 - 1.02); 1.66 (1.37 - 1.51)

RATIONALE 302 [38]

ESCA

Tislelizumab; chemotherapy

256; 256

47; 41.8

20.4; 9.8

8.6; 6.3

0.70 (0.57 - 0.85)

1.6; 2.1

0.83 (0.67 - 1.01)

CheckMate 648 [31]*****

ESCA

OS; PFS (CPS ≥ 1)

Nivo + chemotherapy; Nivo + ipi; chemotherapy

158; 158; 157

78; 63; 66

53; 35; 20

15.4; 13.7; 9.1

0.54 (0.37 - 0.80); 0.64 (0.46 - 0.90)

6.9; 4.0; 4.4

0.65 (0.46 - 0.92); 1.02 (0.73 - 1.43)

ESCORT-1st [17]

ESCA

OS; PFS

Camrelizumab + chemotherapy; chemotherapy

298; 298

91.3; 88.9

72.1; 62.1

15.3; 12.0

0.70 (0.56 - 0.88)

6.9; 5.6

0.56 (0.46 - 0.68)

ORIENT-15 [39]***

ESCA

OS (CPS ≥ 10 and all patients)

Sintilimab + chemotherapy; chemotherapy

327; 332

66.1; 45.5

16.7; 12.5

0.63 (0.51 - 0.78)

7.2; 5.7

0.56 (0.46 - 0.68)

ORIENT-16 [40]***

G/EGJ carcinoma

OS (CPS ≥ 5 and all patients)

Sintilimab + chemotherapy; chemotherapy

327; 323

58.2; 48.4

15.2; 12.3

0.76 (0.63 - 0.94)

7.1; 5.7

0.64 (0.53 - 0.77)

JUPITER-06 [41]

ESCA

OS; PFS

Toripalimab + chemotherapy; chemotherapy

257; 257

17.0; 11.0

0.58 (0.43 - 0.78)

5.7; 5.5

0.58 (0.46 - 0.74)

**Table 2.** Subgroup Analysis of the Correlation Between PFS and OS as Trial Level
Subgroup analysis	No. of comparisons	Weighted correlation coefficients, R (95% CI)	P value
G: gastric; EGJ: esophagogastric junction; ESCA: esophageal carcinoma; CI: confidence interval.
Tumor type
ESCA [13-15, 17, 18, 31, 38, 39, 41]	10	0.47 (0.00 - 0.99)	0.174
G/EGJ cancer [12, 16, 32-37, 40]	10	0.71 (0.22 - 0.99)	0.021
Trials line
First-line [16-18, 31, 34-37, 39-41]	13	0.57 (0.08 - 0.99)	0.043
≥ 2 lines [12-15, 32, 33, 38]	7	0.96 (0.72 - 0.99)	< 0.001
Treatment strategy
Monotherapy [12-15, 32, 33, 35, 37, 38]	9	0.89 (0.56 - 0.99)	0.001
Combinational therapy [16-18, 31, 34-36, 39-41]	11	0.41 (0.00 - 0.99)	0.215
Median follow-up
≥ 10 months [13, 16-18, 31, 32, 34-37, 39, 40]	14	0.71 (0.31 - 0.99)	0.005
< 10 months [12, 14, 15, 33, 38, 41]	6	0.91 (0.51 - 0.99)	0.011

Table 2. Subgroup Analysis of the Correlation Between PFS and OS as Trial Level

Subgroup analysis

No. of comparisons

Weighted correlation coefficients, R (95% CI)

P value

G: gastric; EGJ: esophagogastric junction; ESCA: esophageal carcinoma; CI: confidence interval.

Tumor type

ESCA [13-15, 17, 18, 31, 38, 39, 41]

0.47 (0.00 - 0.99)

0.174

G/EGJ cancer [12, 16, 32-37, 40]

0.71 (0.22 - 0.99)

0.021

Trials line

First-line [16-18, 31, 34-37, 39-41]

0.57 (0.08 - 0.99)

0.043

≥ 2 lines [12-15, 32, 33, 38]

0.96 (0.72 - 0.99)

< 0.001

Treatment strategy

Monotherapy [12-15, 32, 33, 35, 37, 38]

0.89 (0.56 - 0.99)

0.001

Combinational therapy [16-18, 31, 34-36, 39-41]

0.41 (0.00 - 0.99)

0.215

Median follow-up

≥ 10 months [13, 16-18, 31, 32, 34-37, 39, 40]

0.71 (0.31 - 0.99)

0.005

< 10 months [12, 14, 15, 33, 38, 41]

0.91 (0.51 - 0.99)

0.011