The Efficacy and Safety of Apatinib and Anlotinib in Advanced Non-Small Cell Lung Cancer

Figures & data

Figure 1 Flowchart of study selection and design.

Table 1 Baseline Characteristics of Patients

Characteristics	Apatinib	Anlotinib	Statistical Quantity	P-value
N	79	66
Mean age (95% CI), yr	64.58 (62.46–66.70)	64.47 (62.41–66.53)	t=0.075	0.83
Gender, n (%)
Female	57 (72.2)	45 (68.2)	X^2=0.27	0.60
Male	22 (27.8)	21 (31.8)
Smoking history, n (%)
Yes	26 (32.9)	7 (10.6)	X^2=10.18	0.001
No	53 (67.1)	59 (89.4)
ECOG/PS, n (%)
0–1	64 (81.0)	54 (81.8)	X^2=0.02	0.90
2	15 (19.0)	12 (18.2)
Bone metastases, n (%)
Yes	19 (24.1)	22 (33.3)	X^2=1.53	0.22
No	60 (75.9)	44 (66.7)
Brain metastases, n (%)
Yes	16 (20.3)	16 (24.2)	X^2=0.33	0.56
No	63 (79.7)	50 (75.8)
Treatment line, n (%)
First-line	22 (27.8)	7 (10.6)	X^2=13.48	0.001
Second-line	32 (40.5)	19 (28.8)
≥Third-line	25 (31.6)	40 (60.6)
Treatment method, n (%)
VEGFR-TKIs monotherapy	38 (48.1)	22 (33.3)	X^2=20.20	0.000
VEGFR-TKIs + Chemotherapy	32 (40.5)	15 (22.7)
VEGFR-TKIs + ICIs	7 (8.9)	25 (37.9)
VEGFR-TKIs + Chemotherapy + ICIs	2 (2.5)	4 (6.1)
Tumor histology, n (%)
Adenocarcinoma	46 (58.2)	45 (68.2)	X^2=3.25	0.20
Squamous carcinoma	23 (29.1)	18 (27.3)
Others	10 (12.7)	3 (4.5)
EGFR mutation status, n (%)
EGFR (+)	18 (22.8)	17 (25.8)	X^2=0.17	0.68
EGFR (-)	61 (77.2)	49 (74.2)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, Performance Status; VEGFR-TKIs, vascular endothelial growth factor receptor-tyrosine kinase inhibitors; ICIs, Immune checkpoint inhibitors; EGFR, epidermal growth factor receptor.

Table 2 Best Overall Tumor Response for the Apatinib and Anlotinib Groups

Observed indicators	Apatinib (n=79)	Anlotinib (n=66)	P-value
Best overall response, n (%)
Complete response (CR)	0	0
Partial response (PR)	8 (10.13)	2 (3.03)
Stable disease (SD)	33 (41.77)	46 (69.70)
Progressive disease (PD)	23 (29.11)	15 (22.73)
Not evaluable	15 (18.99)	3 (4.55)
Objective response rate (ORR), %	10.13	3.03	0.12
Disease control rate (DCR), %	51.90	72.73	0.21

Abbreviations: ORR, defined as the proportion of patients achieving CR or PR; DCR, defined as the proportion of patients achieving CR, PR, or SD.

Figure 2 Kaplan-Meier estimates compared in the apatinib and anlotinib groups. (a), Kaplan-Meier estimates of PFS compared in the apatinib and anlotinib groups; (b), Kaplan-Meier estimates of OS compared in the apatinib and anlotinib groups.

Table 3 Multivariable Regression Model for PFS

Factors	Univariate		Multivariable
	HR (95% CI)	P-value	HR (95% CI)	P-value
Group (Apatinib vs Anlotinib)	0.59 (0.41–0.84)	0.004	0.43 (0.27–0.70)	0.001
Gender (male vs female)	0.98 (0.67–1.44)	0.93
Age (<65 yr vs ≥65 yr)	0.97 (0.68–1.38)	0.85
Smoking history	0.75 (0.48–1.17)	0.21	0.90 (0.54–1.50)	0.68
ECOG/PS	0.87 (0.55–1.38)	0.54
Bone metastases (yes vs no)	0.38 (0.25–0.57)	0.000	0.33 (0.21–0.52)	0.000
Brain metastases (yes vs no)	0.97 (0.64–1.48)	0.90
Squamous carcinoma vs Adenocarcinoma	0.71 (0.47–1.07)	0.10	0.87 (0.56–1.36)	0.54
Others vs Adenocarcinoma	1.08 (0.59–1.99)	0.80	0.91 (0.48–1.72)	0.78
Genotype (EGFR+ vs EGFR-)	0.84 (0.55–1.28)	0.41
Treatment line	0.98 (0.78–1.23)	0.83	1.14 (0.88–1.47)	0.32
VEGFR-TKIs + Chemotherapy vs VEGFR-TKIs monotherapy	0.95 (0.63–1.43)	0.80	0.97 (0.63–1.50)	0.89
VEGFR-TKIs + ICIs vs VEGFR-TKIs monotherapy	0.82 (0.51–1.30)	0.39	1.17 (0.69–1.97)	0.57
VEGFR-TKIs + Chemotherapy + ICIs vs VEGFR-TKIs monotherapy	5.38 (2.06–14.05)	0.001	4.77 (1.75–12.99)	0.002

Table 4 Multivariable Regression Model for OS

Factors	Univariate		Multivariable
	HR (95% CI)	P-value	HR (95% CI)	P-value
Group (Apatinib vs Anlotinib)	0.68 (0.46–1.00)	0.05	0.59 (0.36–0.96)	0.03
Gender (male vs female)	1.25 (0.83–1.87)	0.29
Age (<65 yr vs ≥65 yr)	1.35 (0.91–2.00)	0.14	1.45 (0.94–2.25)	0.09
Smoking history	0.88 (0.56–1.40)	0.60	1.11 (0.66–1.88)	0.68
ECOG/PS	1.10 (0.67–1.82)	0.71
Bone metastases (yes vs no)	0.46 (0.30–0.70)	0.000	0.40 (0.26–0.63)	0.000
Brain metastases (yes vs no)	0.80 (0.51–1.24)	0.32
Squamous carcinoma vs Adenocarcinoma	0.80 (0.51–1.26)	0.35	0.89 (0.54–1.48)	0.66
Others vs Adenocarcinoma	2.39 (1.25–4.59)	0.009	1.92 (0.97–3.83)	0.06
Genotype (EGFR+ vs EGFR-)	0.97 (0.61–1.54)	0.89
Treatment line	1.10 (0.86–1.40)	0.46	1.39 (1.03–1.89)	0.03
VEGFR-TKIs + Chemotherapy vs VEGFR-TKIs monotherapy	1.04 (0.67–1.60)	0.88	1.11 (0.69–1.78)	0.67
VEGFR-TKIs + ICIs vs VEGFR-TKIs monotherapy	0.69 (0.40–1.17)	0.17	0.72 (0.40–1.29)	0.26
VEGFR-TKIs + Chemotherapy + ICIs vs VEGFR-TKIs monotherapy	0.86 (0.31–2.39)	0.77	0.66 (0.23–1.92)	0.45

Figure 3 Kaplan-Meier estimates of PFS compared in different subgroups. (a), apatinib group with bone metastases vs apatinib group without bone metastases; (b), anlotinib group with bone metastases vs anlotinib group without bone metastases; (c), apatinib group with bone metastases vs anlotinib group with bone metastases; (d), apatinib group without bone metastases vs anlotinib group without bone metastases.

Figure 4 Kaplan-Meier estimates of OS compared in different subgroups. (a), apatinib group with bone metastases vs apatinib group without bone metastases; (b), anlotinib group with bone metastases vs anlotinib group without bone metastases; (c), apatinib group with bone metastases vs anlotinib group with bone metastases; (d), apatinib group without bone metastases vs anlotinib group without bone metastases.

Table 5 Adverse Events

Adverse Event	Apatinib (n = 79)		Anlotinib (n = 66)
	Any Grade (n, %)	Grade 3–4 (n, %)	Any Grade (n, %)	Grade 3–4 (n, %)
Any adverse event	65 (82.28)	25 (31.65)*	49 (74.24)	9 (13.64)
Proteinuria	15 (18.99)	0	5 (7.58)	1 (1.52)
Hypocalcemia	15 (18.99)*	1 (1.27)	3 (4.55)	0
Hypertriglyceridemia	14 (17.72)	0	8 (12.12)	0
Secondary hypertension	14 (17.72)*	8 (10.13)*	2 (3.03)	0
Hypoproteinemia	14 (17.72)**	0	0	0
Hypokalemia	12 (15.19)*	1 (1.27)	2 (3.03)	0
Myelosuppression	12 (15.19)	1 (1.27)	13 (19.70)	3 (4.55)
Anemia	11 (13.92)	2 (2.53)	3 (4.55)	1 (1.52)
Hepatic function abnormal	11 (13.92)	1 (1.27)	9 (13.64)	0
Blood creatinine increased	11 (13.92)	0	7 (10.61)	0
Asthenia	8 (10.13)*	1 (1.27)	1 (1.52)	0
Hyponatremia	8 (10.13)*	0	1 (1.52)	0
Blood bilirubin increased	8 (10.13)	0	2 (3.03)	0
Hyperuricemia	7 (8.86)	0	6 (9.09)	1 (1.52)
Hypophosphatemia	7 (8.86)	3 (3.80)	1 (1.52)	0
Hypercholesteremia	7 (8.86)	0	7 (10.61)	0
Gamma-glutamyltransferase increased	7 (8.86)*	0	0	0
Hand-foot syndrome	5 (6.33)	5 (6.33)	1 (1.52)	1 (1.52)
Hypomagnesemia	5 (6.33)*	0	0	0
Decreased appetite	3 (3.80)	1 (1.27)	1 (1.52)	0
Hematuria	3 (3.80)	0	0	0
Mouth ulceration	1 (1.27)	0	3 (4.55)	2 (3.03)
Diarrhea	1 (1.27)	0	0	0
Alimentary tract hemorrhage	1 (1.27)	1 (1.27)	1 (1.52)	0
Nausea	1 (1.27)	0	0	0
Hemorrhinia	1 (1.27)	0	0	0
Hypothyroidism	1 (1.27)**	0	17 (25.76)	0
Tachycardia	1 (1.27)	0	0	0
Lymphocytopenia	1 (1.27)	0	0	0
Hyperglycemia	0	0	2 (3.03)	0

Notes: *Compared with anlotinib group, P < 0.05; **Compared with anlotinib group, P < 0.01.

Table 6 Multivariable Regression Model for Grade 3–4 AEs

Factors	Univariate		Multivariable
	OR (95% CI)	P-value	OR (95% CI)	P-value
Group	2.93 (1.26–6.85)	0.01	3.33 (1.19–9.36)	0.02
Gender	0.85 (0.37–1.94)	0.69
Age (≤65 yr vs >65 yr)	1.53 (0.71–3.31)	0.28
Smoking history	2.34 (1.00–5.46)	0.05	2.12 (0.82–5.50)	0.12
ECOG/PS	1.09 (0.40–2.96)	0.87
Bone metastases (yes vs no)	1.84 (0.81–4.14)	0.14	2.19 (0.90–5.32)	0.08
Brain metastases (yes vs no)	0.54 (0.19–1.52)	0.24
Squamous carcinoma vs Adenocarcinoma	0.93 (0.39–2.21)	0.87
Others vs Adenocarcinoma	1.00 (0.25–3.97)	1.00
Genotype (EGFR+ vs EGFR-)	2.50 (1.09–5.77)	0.03	3.03 (1.19–7.69)	0.02
Treatment line	1.10 (0.67–1.81)	0.71	1.00 (0.57–1.75)	0.99
VEGFR-TKIs + Chemotherapy vs VEGFR-TKIs monotherapy	0.97 (0.40–2.34)	0.95	1.10 (0.43–2.85)	0.84
VEGFR-TKIs + ICIs vs VEGFR-TKIs monotherapy	1.80 (0.59–5.51)	0.30	0.80 (0.22–2.91)	0.73
VEGFR-TKIs + Chemotherapy + ICIs vs VEGFR-TKIs monotherapy	0.67 (0.11–4.01)	0.66	0.91 (0.13–6.51)	0.92

Table 7 Safety of the Apatinib Group and the Anlotinib Group Under Different EGFR Mutation Status

EGFR Mutation Status	Grade 3–4 AEs	Apatinib (n = 79)	Anlotinib (n = 66)	X^2	P-value
EGFR(+)	Yes	9	4	2.62	0.105
	No	9	13
EGFR(-)	Yes	16	5	4.52	0.034
	No	45	44
X^2		3.63	1.90
P-value		0.057	0.168