Predictive Nomogram for Hyperprogressive Disease During Anti-PD-1/PD-L1 Treatment in Patients with Advanced Non-Small Cell Lung Cancer

Figures & data

Figure 1 Flowchart of our study.

Table 1 Baseline Clinical Features of LC Patients with ICI Therapy

Characteristic	Primary Cohort (n=176)				Validation Cohort (n=85)
	Total	HPD (n=17, 9.66%)	Non-HPD (n=159, 90.34%)	P value (Fisher’s Exact test)	Total	HPD (n=9, 10.59%)	Non-HPD (n=76, 89.41%)	P value (Fisher’s Exact test)
Age, years, n (%)
≥65	37	5(13.51)	32(86.49)	0.268	17	1(5.88)	16(94.12)	0.481
<65	139	12(8.63)	127(91.37)		68	8(11.76)	60(88.24)
Sex, n (%)
Male	137	14(10.22)	123(89.78)	0.239	62	9(14.52)	53(85.48)	0.053
Female	39	3(7.69)	36(92.31)		23	0(0.00)	23(100.00)
Smoke, n (%)
Past/Current	90	11(12.22)	79(87.78)	0.228	47	6(12.77)	41(87.23)	0.791
Never	86	6(6.98)	80(93.02)		28	3(10.71)	25(89.29)
Alcohol, n (%)
Past/Current	35	5(14.29)	30(85.71)	0.268	19	1(5.26)	18(94.74)	0.392
Never	141	12(8.51)	129(91.49)		66	8(12.12)	58(87.88)
BMI, kg/m^2, n (%)
≥24	62	6(9.68)	56(90.32)	0.927	35	3(8.57)	32(91.43)	0.088
≥18.5 and<24	96	10(10.42)	86(89.58)		45	4(8.89)	41(91.11)
<18.5	14	1(7.14)	13(92.86)		5	2(40.00)	3(60.00)
Histology, n (%)
Adenocarcinoma	113	12(9.17)	101(90.83)	0.816	48	4(8.33)	44(91.67)	0.278
Squamous cell carcinoma	62	5(8.06)	57(91.94)		29	5(17.24)	24(82.76)
Sarcomatoid carcinoma	1	0(0.00)	1(100.00)		8	0(0.00)	8(100.00)
PD-L1 status
Negative	58	5(8.62)	53(91.38)	0.268	52	9(17.31)	43(82.69)	0.136
Positive	20	1(5.00)	19(95.00)		11	0(0.00)	11(100.00)
Stage, n (%)
III	13	0(0.00)	13(100.00)	0.219	27	6(22.22)	21(77.78)	0.017
IV	163	17(10.49)	145(89.51)		58	3(5.17)	55(94.83)
No. of metastatic sites, n (%)
<2	94	5(7.37)	88(92.63)	0.010	47	6(12.77)	41(87.23)	0.468
≥2	68	12(19.40)	54(80.60)		38	3(7.89)	35(92.11)
Brain metastasis, n (%)
Absent	135	13(9.63)	122(90.37)		71	9(19.23)	62(80.77)	0.159
Present	25	4(16.00)	21(84.00)	0.207	14	0(0.00)	14(100.00)
Liver metastasis, n (%)
Absent	147	12(8.16)	135(91.84)	<0.001	74	9(12.68)	65(87.84)	0.221
Present	13	5(38.46)	8(61.54)		11	0(0.00)	11(100.00)
Molecular status, n (%)
EGFR mutation	6/94	1/6(1.06)	5/6(5.32)	0.814	16/75	1/9(11.11)	8/9(88.89)	0.949
ALK rearrangement	1/94	0/1(0.00)	1/1(1.06)		1/75	0/1(0.00)	1/1(1.33)
KRAS mutation	6/94	0/6 (0.00)	6/6(6.38)		5/75	0/5(0.00)	5/5(66.67)
C-met rearrangement	3/94	0/3 (0.00)	3/3(3.18)		1/75	0/1(0.00)	1/1(66.67)
TP53 mutation	2/94	0/2(0.00)	2/2(2.12)		5/75	0/5(0.00)	5/5(3.13)
PTEN mutation	2/94	0/2(0.00)	2/2(2.12)		1/75	0/1(0.00)	1/1(1.33)
HER2 mutation	2/94	0/2(0.00)	2/2(2.12)		5/75	0/5(0.00)	5/5(66.67)
FGFR2 amplification	1/94	0/1(0.00)	1/1(1.06)		1/75	0/1(0.00)	1/1(1.33
Previous ICI treatment, n (%)
No treatment	4	0(0.00)	4(100.00)	0.306	31	3(9.67)	28(90.32)	0.969
Chemotherapy	135	16(11.85)	119(88.15)		50	5(10.00)	45(90.00)
Radiotherapy	30	7(23.33)	23(76.67)		14	2(14.29)	12(85.71)
Target therapy	59	7(11.86)	52(88.14)		18	2(11.11)	16(88.88)
Type of inhibitor, n (%)
PD-1 inhibitor	171	17(9.94)	154(90.06)	0.001	78	9(11.54)	69(88.46)	0.342
PD-L1 inhibitor	5	0(0.00)	5(100.00)		7	0(0.00)	7(100.00)

Abbreviations: HPD, hyperprogressive disease; ICIs, immune checkpoint inhibitors; LC, lung cancer; BMI, body mass index; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; KRAS, Kirsten rat sarcoma viral oncogene homolog; TP53, tumor protein 53; PTEN, phosphate and tension homology; HER2, human epidermal growth factor receptor 2; FGFR2, fibroblast growth factor receptor-2; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1.

Table 2 Hematological Examination Biomarkers of LC Patients with ICI Therapy in the Primary Cohort

Various (Median, IQR)	Total (n=176)	HPD (n=17, 9.66%)	Non-HPD (n=159, 90.34%)	P value (Mann–Whitney U-Test)
Routine Blood Test
WBC (10^9/L)	7.21 (5.65–9.11)	5.98 (3.72–8.72)	7.35 (5.68–89.15)	0.070
NEU (10^9/L)	4.60 (3.50–6.17)	3.80 (2.22–6.15)	4.60 (3.60–6.20)	0.162
LYM (10^9/L)	1.40 (1.07–1.96)	1.10 (0.90–1.60)	1.46 (1.10–2.00)	0.022
MO (10^9/L)	0.60 (0.43–0.76)	0.60 (0.40–0.70)	0.60 (0.43–0.80)	0.695
EO (10^9/L)	0.15 (0.10–0.30)	0.10 (0.00–0.30)	0.17 (0.10–0.30)	0.374
BASO (10^9/L)	0.00 (0.00–0.10)	0.00 (0.00–0.10)	0.02 (0.00–0.10)	0.280
NLR	3.28 (2.13–4.84)	3.50 (2.59–4.85)	3.18 (2.05–4.92)	0.528
dNLR	1.93 (1.45–2.64)	2.09 (1.63–2.99)	1.91 (1.44–2.61)	0.475
LMR	2.33 (1.71–3.55)	1.88 (1.50–2.79)	2.50 (2.54–3.67)	0.052
PLR	175.76 (126.78–256.74)	191.43 (158.33–320.92)	173.67 (123.33–249.47)	0.195
RBC (10^12/L)	4.20 (3.62–4.56)	3.97 (3.38–4.30)	4.20 (3.64–4.59)	0.107
HGB (g/L)	122.00 (109.00–134.00)	112.00 (106.00–127.50)	125.00 (110.00–134.00)	0.077
HCT (%)	38.10 (33.95–41.58)	34.30 (33.30–39.65)	38.50 (34.30–41.90)	0.076
MCV (fL)	92.95 (88.53–96.55)	92.70 (89.00–98.05)	93.00 (88.50–96.40)	0.802
PLT (10^9/L)	257.00 (205.25–332.25)	220.00 (155.50–346.00)	258.00 (207.00–230.00)	0.358
Coagulation Test
PT (sec)	11.70 (11.20–12.13)	11.70 (11.40–12.45)	11.60 (11.15–12.10)	0.340
APTT (sec)	25.95 (23.40–29.20)	30.10 (27.75–32.00)	25.70 (23.25–28.20)	0.000
FBG (g/L)	4.18 (3.26–4.91)	5.01 (3.76–5.83)	4.12 (3.15–4.85)	0.105
TT (sec)	17.50 (16.57–18.03)	17.30 (16.30–18.55)	17.50 (16.65–18.00)	0.824
Liver Function Test
ALT (U/L)	17.85 (12.20–24.15)	21.30 (12.90–30.35)	17.70 (12.15–23.85)	0.435
AST (U/L)	20.05 (16.63–25.83)	23.70 (17.05–35.70)	19.60 (16.00–25.05)	0.083
TBA (umol/L)	2.80 (1.90–4.88)	2.80 (1.65–5.20)	2.80 (1.90–4.88)	0.994
ALP (U/L)	81.75 (67.33–99.38)	78.70 (58.18–117.68)	82.50 (67.78–99.38)	0.681
GGT (U/L)	40.00 (27.70–63.75)	47.80 (25.25–100.60)	39.55 (27.78–59.63)	0.353
LDH (U/L)	210.50 (179.50–286.75)	206.5 (170.68–446.10)	210.50 (181.30–280.50)	0.633
TP (g/L)	73.70 (69.89–78.18)	73.61 (67.38–80.24)	73.70 (70.30–78.01)	0.856
ALB (g/L)	41.60 (38.78–44.12)	40.30 (38.10–45.70)	41.60 (38.80–44.05)	0.806
GLB (g/L)	32.05 (28.93–36.17)	31.06 (28.04–34.76)	32.10 (28.97–36.24)	0.529
TBIL (umol/L)	6.20 (8.05–10.50)	7.50 (5.55–10.00)	8.10 (6.25–10.50)	0.387
DBIL (umol/L)	2.50 (1.90–3.30)	2.50 (1.60–3.50)	2.50 (1.90–3.28)	0.754
Renal Function Test
BUN (mmol/L)	4.90 (3.89–5.90)	4.90 (3.97–6.55)	4.90 (3.85–5.90)	0.584
CREA (umol/L)	71.15 (58.58–83.63)	74.60 (69.15–91.55)	70.30 (58.50–83.20)	0.187
UA (umol/L)	352.70 (295.55–414.35)	350.80 (269.15–431.60)	354.60 (294.10–412.80)	0.632
CYSC (mg/L)	0.93 (0.79–1.13)	0.93 (0.93–1.24)	0.93 (0.79–1.12)	0.907
Blood Lipid Test
CHO (mmol/L)	4.92 (4.10–5.63)	4.42 (3.90–5.21)	4.95 (4.15–5.65)	0.153
TG (mmol/L)	1.29 (0.94–1.79)	1.34 (0.90–1.83)	1.29 (0.95–1.79)	0.916
HDL (mmol/L)	1.18 (0.98–1.41)	1.14 (0.90–1.83)	1.18 (0.98–1.42)	0.210
LDL (mmol/L)	3.11 (2.48–3.80)	2.89 (2.35–3.82)	3.11 (2.54–3.80)	0.457
APOA1 (g/L)	1.28 (1.15–1.46)	1.22 (1.08–1.30)	1.31 (1.16–1.46)	0.071
APOB (g/L)	1.00 (0.86–1.22)	0.98 (0.86–1.21)	1.00 (0.86–1.22)	0.758
Inflammation Test
CRP (mg/L)	12.73 (3.22–28.71)	14.74 (2.18–45.57)	11.63 (3.36–28.20)	0.736
CK (U/L)	62.50 (45.00–86.75)	63.00 (43.00–86.00)	62.00 (45.00–90.00)	0.816
SAA (mg/L)	30.15 (9.53–129.60)	128.90 (19.00–147.10)	26.20 (9.00–117.10)	0.133
Thyroid Function Test
FT3 (pmol/L)	4.63 (4.08–5.01)	4.25 (3.86–5.67)	4.63 (4.11–5.01)	0.535
FT4 (pmol/L)	16.64 (14.97–18.28)	17.35 (14.70–19.54)	16.62 (15.02–18.23)	0.766
TSH (uIU/mL)	1.80 (1.18–3.20)	2.68 (1.37–5.83)	1.78 (1.11–2.95)	0.111
A-TPO (U/mL)	14.03 (10.71–19.70)	11.29 (9.32–20.34)	14.13 (10.96–19.70)	0.352
TG (ng/mL)	8.81 (5.52–19.18)	10.09 (8.28–24.70)	8.48 (5.23–18.37)	0.230
Lymphocyte Subsets Exam
CD3+ T cells (%)	69.50 (62.35–76.67)	77.00 (66.30–81.65)	69.19 (60.75–75.88)	0.026
CD3+CD4+ T cells (%)	37.10 (29.25–37.10)	40.30 (34.55–48.20)	36.75 (28.13–42.38)	0.061
CD3+CD8+ T cells (%)	25.40 (21.15–34.50)	25.00 (23.65–36.05)	25.70 (20.93–34.48)	0.841
CD19+ B cells (%)	7.60 (5.70–10.78)	7.80 (3.55–10.10)	7.55 (5.80–10.88)	0.671
CD3-CD16+CD56+ NK cells (%)	18.24 (12.95–23.30)	13.30 (9.15–17.85)	19.41 (13.63–24.23)	0.046
CD4+CD25+CD127-low Treg cells (%)	25.20 (17.50–34.75)	38.10 (27.10–42.45)	23.85 (17.08–32.80)	0.002
CD8+CD25+ T cells (%)	5.60 (3.05–8.65)	5.20 (3.50–9.15)	5.60 (3.03–8.68)	0.584

Abbreviations: WBC, White blood cells; NEU, Neutrophils; LYM, Lymphocytes; MO, Monocytes; EO, Eosinophils; BASO, Basophils; PLT, Platelets; NLR, Neutrophils/Lymphocytes rate; LMR, Lymphocytes/Monocytes rate; PLR, Platelets/Lymphocytes rate; RBC, Red blood cells; HGB, Hemoglobin; HCT, Hematocrit; MCV, Mean red blood cell volume; PT, Prothrombin time; APTT, Activated partial thromboplastin time; FBG, Fibrinogen; TT, Thrombin time; ALT, Alanine aminotransfease; AST, Aspartic acid aminotransferase; TBA, Total bile acid; ALP, Alkaline phosphatase; GGT, γ-glutamyl transpeptadase; LDH, Lactate dehydrogenase; TP, Total protein; ALB, Albumin; GLB, Globulin; TBIL, Total bilirubin; DBIL, Direct bilirubin; BUN, Blood urea nitrogen; CREA, Creatinine; UA, Uric acid; CYSC, Cystatin C; CHO, Cholesterol; TG, Triglycerides; HDL, High density lipoprotein; LDL, Low density lipoprotein; APOA1, Apolipoprotein-A1; APOB, Apolipoprotein-B; CRP, C reactive protein; CK, Creatine kinase; SAA, serum amyloid A protein; FT3, Free triiodothyronine; FT4, free thyroxine; TSH, Thyroid-stimulating hormone; A-TPO, Thyroid peroxidase antibody; TG, Thyroglobulin; CD, cluster of differentiation. Number in bold was considered statistically significant.

Table 3 Multivariate Logistic Regression Analysis Between Features and HPD in Advanced NSCLC

Characteristic	P value (Multivariate Analysis)	OR	95% CI
No. of metastatic sites	0.049	1.868	0.284–12.291
Liver metastasis	0.048	2.737	0.393–19.084
Type of inhibitor	1.000	0.000	0.000
LYM	0.114	0.199	0.027–1.474
APTT	0.004	12.576	2.232–70.847
CD3+ T cells	0.212	4.457	0.467–42.496
NK cells	0.816	1.307	0.137–12.504
Treg cells	0.003	10.386	2.265–47.621

Note: Number in bold was considered statistically significant.

Abbreviations: HPD, hyperprogressive disease; LYM, Lymphocytes; APTT, Activated partial thromboplastin time.

Figure 2 Kaplan–Meier survival curves in NSCLC patients according to HPD status, response categories and nomogram. (A) OS according to HPD. (B) PFS according to HPD. (C) OS according to response categories. (D) PFS according to response categories. (E) OS according to the nomogram. (F). PFS according to the nomogram. “HPD=0” indicates patients without HPD, while “HPD=1” indicates patients with HPD. “SD” indicates patients with stable disease, “PR” indicates patients with partial reaction, “PD” indicates patients with progressive disease but no HPD, and “HPD” indicates patients with hyperprogressive disease. “Low” indicates patients in the low-risk group according to the nomogram, while “High” indicates patients in the high-risk group according to the nomogram.

Figure 3 Pretherapy levels of APTT and Treg cells between HPD and non-HPD NSCLC patients. (A) The difference in serum levels of APTT in the primary cohort. (B) The difference in the levels of Treg cells in the primary cohort. (C) The difference in serum levels of APTT in the validation cohort. (D) The difference in the levels of Treg cells in the validation cohort.

Figure 4 Kaplan–Meier survival curves in NSCLC patients according to the factors in the nomogram. (A) OS according to liver metastasis (P<0.05). (B) OS according to more than two metastatic sites (P>0.05). (C) OS according to APTT (P<0.05). (D) OS according to Treg cells (P<0.05).

Figure 5 Development and validation of the prediction nomogram in the primary cohort. (A) Nomogram to predict HPD in patients with ICI therapy. The nomogram is valued to obtain the probability of HPD by adding up the points identified on the points scale for each variable, which included the presence of liver metastasis, more than two metastatic sites, APTT and Treg cells. Each patient has a different score due to different indicator points and is then divided into different risk groups. (B) Calibration curve of our nomogram. (C) The AUC of our nomogram was 0.845 (95% CI: 0.719–0.950, P<0.001). (D) The results of decision curve analysis. Decision curve analysis for the nomogram and other previously reported variables. The gray line represents the assumption that all patients have HPD. The thin black line represents the assumption that no patients have HPD.

Figure 6 Discrimination of the nomogram was performed by using a concordance index (C-index) and ROC curve in the validation cohort. (A) Calibration curve of the nomogram in the validation cohort. (B) The AUC of our nomogram was 0.960 (95% CI: 0.874–0.987, P<0.001) in the validation cohort.