The Efficacy and Safety of Anlotinib in Extensive-Stage Small Cell Lung Cancer: A Multicenter Real-World Study

Figures & data

Table 1 Baseline Clinical Characteristics of Patients

Characteristics, n(%)	Overall (n=202)	Monotherapy (n = 78)	Combination (n = 124)	P-value
Age (years)				0.001
Median (range)	61 (28–87)	65 (28–87)	59 (30–83)
<65	118 (58.4)	34 (43.6)	84 (67.7)
≥65	84 (41.6)	44 (56.4)	40 (32.3)
Sex				0.323
Male	164 (81.2)	66 (84.6)	98 (79.0)
Female	38 (18.8)	12 (15.4)	26 (21.0)
Smoking status				0.369
Ever	137 (67.8)	50 (64.1)	87 (70.2)
Never	65 (32.2)	28 (35.9)	37 (29.8)
ECOG PS				0.001
0–1	117 (57.9)	34 (43.6)	83 (66.9)
≥2	85 (42.1)	44 (56.4)	41 (33.1)
aCCI				0.023
≤8	121 (59.9)	39 (50.0)	82 (66.1)
>8	81 (40.1)	39 (50.0)	42 (33.9)
TNM stage				0.468
III	25 (12.4)	8 (10.3)	17 (13.7)
IV	177 (87.6)	70 (89.7)	107 (86.3)
T stage				0.318
T1-2	76 (37.6)	26 (33.3)	50 (40.3)
T3-4	126 (62.4)	52 (66.7)	74 (59.7)
N stage				0.771
N0-2	47 (23.3)	19 (24.4)	28 (22.6)
N3	155 (76.7)	59 (75.6)	96 (77.4)
Number of metastatic sites				0.481
<3	143 (70.8)	53 (67.9)	90 (72.6)
≥3	59 (29.2)	25 (32.1)	34 (27.4)
Brain metastases				0.299
Yes	49 (24.3)	22 (28.2)	27 (21.8)
No	153 (75.7)	56 (71.8)	97 (78.2)
Hepatic metastases				0.721
Yes	52 (25.7)	19 (24.4)	33 (26.6)
No	150 (74.3)	59 (75.6)	91 (73.4)
Osseous metastases				0.699
Yes	59 (29.2)	24 (30.8)	35 (28.2)
No	143 (70.8)	54 (69.2)	89 (71.8)
Pleural metastases/pleural effusion				0.320
Yes	87 (43.1)	37 (47.4)	50 (40.3)
No	115 (56.9)	41 (52.6)	74 (59.7)
Lung metastases				0.945
Yes	59 (29.2)	23 (29.5)	36 (29.0)
No	143 (70.8)	55 (70.5)	88 (71.0)
Baseline NSE				0.041
≤20ng/mL	58 (28.7)	16 (20.5)	42 (33.9)
>20ng/mL	144 (71.3)	62 (79.5)	82 (66.1)
Anlotinib initial dose				0.294
10mg	30 (14.9)	9 (11.5)	21 (16.9)
12mg	172 (85.1)	69 (88.5)	103 (83.1)
Number of treatment lines				0.010
1	93 (46.0)	27 (34.6)	66 (53.2)
≥2	109 (54.0)	51 (65.4)	58 (46.8)
Plus radiotherapy				0.010
Yes	57 (28.2)	14 (17.9)	43 (34.7)
No	145 (71.8)	64 (82.1)	81 (65.3)
Post-medication hypertension				0.743
Yes	80 (39.6)	32 (41.0)	48 (38.7)
No	122 (60.4)	46 (59.0)	76 (61.3)
Post-medication hand-foot syndrome				0.625
Yes	61 (30.2)	22 (28.2)	39 (31.5)
No	141 (69.8)	56 (71.8)	85 (68.5)

Note: Bold value represents P-value <0.05.

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; aCCI, age-adjusted Charlson comorbidity index; NSE, neuron specific enolase.

Table 2 Multivariate Cox Regression Analysis of Factors Associated with PFS in All Patients

Factors	HR	95% CI	P-value
Age (≥65 vs <65)	1.11	0.76–1.62	0.579
Sex (Male vs Female)	1.65	1.05–2.59	0.030
ECOG PS (≥2 vs 0–1)	2.99	1.94–4.61	<0.001
aCCI (>8 vs ≤8)	1.13	0.77–1.66	0.534
T stage (T3-4 vs T1-2)	1.51	1.06–2.17	0.024
N stage (N3 vs N0-2)	1.47	0.97–2.22	0.070
Number of metastatic sites (<3 vs ≥3)	0.95	0.62–1.47	0.824
Hepatic metastases (Yes vs No)	1.06	0.67–1.68	0.794
Osseous metastases (Yes vs No)	0.92	0.61–1.39	0.694
Baseline NSE (>20ng/mL vs ≤20ng/mL)	1.41	0.93–2.12	0.103
Number of treatment lines (≥2 vs 1)	1.43	1.00–2.05	0.049
Plus chemotherapy/immunotherapy (Yes vs No)	0.49	0.34–0.70	<0.001
Plus radiotherapy (Yes vs No)	0.62	0.40–0.95	0.027
Post-medication hypertension (Yes vs No)	0.36	0.24–0.52	<0.001

Note: Bold value represents P-value <0.05.

Abbreviations: PFS, progression-free survival; HR, Hazard ratio; CI, Confidence inter; ECOG PS, Eastern Cooperative Oncology Group Performance Status; aCCI, age-adjusted Charlson comorbidity index; NSE, neuron specific enolase.

Table 3 Multivariate Cox Regression Analysis of Factors Associated with OS in All Patients

Factors	HR	95% CI	P-value
Age (≥65 vs <65)	1.48	0.95–2.30	0.081
Sex (Male vs Female)	0.67	0.37–1.21	0.186
Smoking status (Ever vs Never)	2.09	1.24–3.52	0.006
ECOG PS (≥2 vs 0–1)	4.32	2.65–7.04	<0.001
aCCI (>8 vs ≤8)	0.96	0.63–1.47	0.840
N stage (N3 vs N0-2)	1.41	0.87–2.29	0.160
Number of metastatic sites (<3 vs ≥3)	0.86	0.54–1.35	0.506
Hepatic metastases (Yes vs No)	1.44	0.92–2.23	0.109
Baseline NSE (>20ng/mL vs ≤20ng/mL)	1.48	0.93–2.35	0.101
Number of treatment lines (≥2 vs 1)	1.15	0.77–1.70	0.500
Plus chemotherapy/immunotherapy (Yes vs No)	0.48	0.32–0.72	<0.001
Plus radiotherapy (Yes vs No)	0.57	0.35–0.91	0.019
Post-medication hypertension (Yes vs No)	0.26	0.17–0.41	<0.001
Post-medication hand-foot syndrome (Yes vs No)	1.19	0.80–1.79	0.393

Note: Bold value represents P-value <0.05.

Abbreviations: OS, overall survival; HR, hazard ratio; CI, confidence inter; ECOG PS, Eastern Cooperative Oncology Group Performance Status; aCCI, age-adjusted Charlson comorbidity index; NSE, neuron specific enolase.

Figure 1 Efficacy of anlotinib in all patients. (A) The PFS of all patients; (B) the OS of all patients; (C) the waterfall plot of tumor best response compared with baseline measurable lesions. *The target lesions shrink but new metastases appear.

Abbreviations: PFS, progression-free survival; OS, overall survival; PR, partial response; SD, stable disease; PD, progressive disease.

Figure 2 The PFS in monotherapy and combination groups.

Abbreviation: PFS, progression-free survival.

Figure 3 Subgroup analysis of PFS.

Abbreviations: PFS, progression-free survival; ECOG PS, Eastern Cooperative Oncology Group Performance Status; aCCI, age-adjusted Charlson comorbidity index; NSE, neuron-specific enolase.

Figure 4 The OS in monotherapy and combination groups.

Abbreviation: OS, overall survival.

Figure 5 Subgroup analysis of OS.

Abbreviations: OS, overall survival; ECOG PS, Eastern Cooperative Oncology Group Performance Status; aCCI, age-adjusted Charlson comorbidity index; NSE, neuron-specific enolase.

Table 4 Comparison of Efficacy Between Monotherapy and Combination

	Monotherapy (n = 78)	Combination (n = 124)	P-value
PR, n(%)	10 (12.8)	51 (41.1)	-
SD, n(%)	52 (66.7)	63 (50.8)	-
PD, n(%)	16 (20.5)	10 (8.1)	-
ORR, %	12.8	41.1	<0.001
DCR, %	79.5	91.9	0.010
mPFS (months)	3.6	6.0	<0.001
mOS (months)	4.8	9.2	<0.001
6-month PFS, %	20.8	46.1	0.001
6-month OS, %	39.4	69.5	<0.001
1-year OS, %	14.9	24.1	0.163

Note: Bold value represents P-value<0.05.

Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival.

Figure 6 Kaplan–Meier curves of different number of treatment lines. (A) PFS of first-line treatment; (B) OS of first-line treatment; (C) PFS of second-line and above treatment; (D) OS of second-line and above treatment.

Abbreviations: PFS, progression-free survival; OS, overall survival.

Table 5 Summary of Adverse Reactions

Toxicity	Overall (n = 202)		Monotherapy (n = 78)		Combination (n = 124)
	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Hypertension	80 (39.6)	3 (1.5)	32 (41.0)	1 (1.3)	48 (38.7)	2 (1.6)
Hand-foot syndrome	61 (30.2)	1 (0.5)	22 (28.2)	0 (0.0)	39 (31.5)	1 (0.8)
Fatigue	60 (29.7)	0 (0.0)	23 (29.5)	0 (0.0)	37 (29.8)	0 (0.0)
Gastrointestinal reaction	58 (28.7)	2 (1.0)	22 (28.2)	1 (1.3)	36 (29.0)	1 (0.8)
Hyperlipemia	39 (19.3)	0 (0.0)	16 (20.5)	0 (0.0)	23 (18.5)	0 (0.0)
Hemorrhage	30 (14.9)	4 (2.0)	11 (14.1)	2 (2.6)	19 (15.3)	2 (1.6)
Lymphopenia	24 (11.9)	0 (0.0)	7 (9.0)	0 (0.0)	17 (13.7)	0 (0.0)
Transaminase elevation	23 (11.4)	1 (0.5)	5 (6.4)	1 (1.3)	18 (14.5)	0 (0.0)
Hyponatremia	22 (10.9)	0 (0.0)	9 (11.5)	0 (0.0)	13 (10.5)	0 (0.0)
Hyperbilirubinemia	20 (9.9)	3 (1.5)	7 (9.0)	1 (1.3)	13 (10.5)	2 (1.6)
Hypophosphatemia	19 (9.4)	1 (0.5)	9 (11.5)	1 (1.3)	10 (8.1)	0 (0.0)
Thrombocytopenia	16 (7.9)	4 (2.0)	7 (9.0)	1 (1.3)	9 (7.3)	3 (2.4)
Mucositis oral	14 (6.9)	1 (0.5)	7 (9.0)	1 (1.3)	7 (5.6)	0 (0.0)
Rash	13 (6.4)	0 (0.0)	6 (7.7)	0 (0.0)	7 (5.6)	0 (0.0)
Thyroid dysfunction	13 (6.4)	0 (0.0)	5 (6.4)	0 (0.0)	8 (6.5)	0 (0.0)
Hypokalemia	10 (5.0)	0 (0.0)	2 (2.6)	0 (0.0)	8 (6.5)	0 (0.0)
Proteinuria	9 (4.5)	0 (0.0)	3 (3.8)	0 (0.0)	6 (4.8)	0 (0.0)
Hoarseness	4 (2.0)	0 (0.0)	2 (2.6)	0 (0.0)	2 (1.6)	0 (0.0)
Arthralgia	3 (1.5)	0 (0.0)	1 (1.3)	0 (0.0)	2 (1.6)	0 (0.0)