Hyperprogressive disease during PD-1 blockade in patients with advanced pancreatic cancer

Figures & data

Figure 1. Flowchart of patient selection.

Note Abbreviations: PC, pancreatic cancer; PD-1, programmed cell death-1; CT, computed tomography; MRI, magnetic resonance imaging.

Figure 2. Case study of a patient with PC with HPD during treatment with a PD-1 inhibitor.

Note Magnetic resonance imaging before baseline (a), at baseline about 6-8 weeks later (b), and during PD-1 inhibitor therapy 6-8 weeks later (c) in a man in his mid-30s with stage IV (liver and retroperitoneal lymph node metastases) PD-L1 expression positive pancreatic cancer treated with PD-1 inhibitor, nab-paclitaxel and gemcitabine in the fifth line. After 2 administrations, there was evidence of significant liver lesion progression. Abbreviations: PC, pancreatic cancer; HPD, hyperprogressive disease; PD-1, programmed cell death-1; PD-L1, programmed death ligand-1.

Table 1. Characteristics of patients with advanced PC.

Characteristics	No. of Patients (n = 104)	Percentage (%)
Age (years)
≥60	35	33.7
<60	69	66.3
Sex
Male	73	70.2
Female	31	29.8
Smoking history
Smoke	37	35.6
Never smoke	67	64.4
Surgical history
Yes	39	37.5
No	65	62.5
Histological differentiating degree
Low differentiation	59	56.7
Moderate and high differentiation	45	43.3
Metastatic sites
0–2	90	86.5
>2	14	13.5
Liver metastasis
Present	45	43.3
Absent	59	56.7
Abx BA21
Yes	7	6.7
No	97	93.3
Hb level (g/L)
<110	25	24.0
≥110	79	76.0
dNLR
>3	36	62.5
≤3	65	34.6
Missing	3	2.9
Lactate dehydrogenase level
≤Upper limit of normal	91	87.5
˃Upper limit of normal	7	6.7
Missing	6	5.8
PD-L1 status
Negative	30	28.8
Positive	32	30.8
Missing	42	40.4
Combined with other drugs
Yes	95	91.3
No	9	8.7
PD-1 inhibitor therapy line
≤2	97	93.3
>2	7	6.7
Hyperprogressive Disease
Yes	10	9.6
No	94	90.4

Abbreviations: PC, pancreatic cancer; Abx B21, antibiotic therapy within 21 days before immunotherapy; Hb, hemoglobin; dNLR, derived neutrophil-to-lymphocyte ratio; LDH, lactate dehydrogenase; PD-1, programmed cell death-1; programmed death ligand-1(PD-L1); HPD, hyperprogressive disease.

Table 2. Differences of patients’ characteristics between the non-HPD group and the HPD group.

Characteristics	No. of Patients (%)		p value
	Non-HPD(n = 94)	HPD(n = 10)
Age (years)			.797
≥60	32(34.0)	3(30.0)
<60	62(66.0)	7(70.0)
Sex			.476
Male	65(69.1)	8(80.0)
Female	29(30.9)	2(20.0)
Smoking history			.017
Smoke	30(31.9)	7(70.0)
Never smoke	64(68.1)	3(30.0)
Surgical history			.059
Yes	38(40.4)	1(10.0)
No	56(59.6)	9(90.0)
Histological differentiating degree			.373
Low differentiation	52(55.3)	7(70.0)
Moderate and high differentiation	42(44.7)	3(30.0)
Metastatic sites			.010
0–2	84(89.4)	6(60.0)
>2	10(10.6)	4(40.0)
Liver metastasis			<.010
Present	35(37.2)	10(100.0)
Absent	59(62.8)	0(0.0)
Abx BA21			<.010
Yes	3(3.2)	4(40.0)
No	91(96.8)	6(60.0)
Hb level (g/L)			<.010
<110	18(19.1)	7(70.0)
≥110	76(80.9)	3(30.0)
dNLR			.762
>3	32(35.2)	4(40.0)
≤3	59(64.8)	6(60.0)
Missing	3	0
Lactate dehydrogenase level			.096
≤Upper limit of normal	5(5.7)	2(20.0)
˃Upper limit of normal	83(94.3)	8(80.0)
Missing	6	0
PD-L1 status			.738
Negative	28(50.0)	2(33.3)
Positive	28(50.0)	4(66.7)
Missing	38	4
Combined with other drugs			.179
Yes	87(92.6)	8(80.0)
No	7(7.4)	2(20.0)
PD-1 inhibitor therapy line			<.010
≤2	93(98.9)	4(40.0)
>2	1(1.1)	6(60.0)

Abbreviations: HPD, hyperprogressive disease; Abx B21, antibiotic therapy within 21 days before immunotherapy; Hb, hemoglobin; dNLR, derived neutrophil-to-lymphocyte ratio; LDH, lactate dehydrogenase; PD-1, programmed cell death-1; programmed death ligand-1(PD-L1).

Figure 3. Overall survival for HPD compared with PD without HPD in patients with immunotherapy.

Abbreviations: HPD, hyperprogressive disease; PD, progressive disease.

Figure 4. ROC curves of baseline CA19-9 predicting the occurrence of HPD during treatment with PD-1 inhibitors in patients with advanced PC.

Abbreviations: ROC, receiver operating characteristic; HPD, hyperprogressive disease; PD-1, programmed cell death-1; PC, pancreatic cancer.

Table 3. Data related to ROC analysis of baseline CA19-9 predicted HPD.

Baseline tumor marker	Cut-off values	AUC	sensitivity	specificity	Youden index	p value
CA19-9(U/ml)	1279.0	0.729	66.7%	87.1%	0.537	.024

Abbreviations: ROC, receiver operating characteristic; HPD, hyperprogressive disease; AUC, area under the curve.

Figure 5. ROC curves of the first month’s increase in CA19-9 predicting the occurrence of HPD during treatment with PD-1 inhibitors in patients with advanced PC.

Abbreviations: ROC, receiver operating characteristic; HPD, hyperprogressive disease; PD-1, programmed cell death-1; PC, pancreatic cancer.

Table 4. Data associated with the ROC analysis of the first month’s increase in CA19-9 predicted HPD.

Tumor marker	Cut-off values	AUC	sensitivity	specificity	Youden index	p value
CA19-9	56.31%	0.892	87.5%	83.1%	0.706	.000

Abbreviations: ROC, receiver operating characteristic; HPD, hyperprogressive disease; AUC, area under the curve.

Figure 6. Comparison of OS between high and low CA19-9 levels in PC patients receiving immunotherapy.

Abbreviations: OS, overall survival; PC, pancreatic cancer.