Metformin Use and the Outcome of Metastatic Renal Cell Carcinoma Treated with Sunitinib or Pazopanib

Figures & data

Table 1 Patient Characteristics

	Metformin Use		Chi-Square p-value
	No (n=307)	Yes (n=36)
Gender			1.000
Male	228 (74.3)	27 (75.0)
Female	79 (25.7)	9 (25.0)
Age at diagnosis (years)
Median (range)	65 (37–83)	64 (52–83)
ECOG PS			0.432
0	92 (30.0)	8 (22.2)
1	215 (70.0)	28 (77.8)
BMI			0.055
Low (≤25)	52 (16.9)	2 (5.6)
High (>25)	152 (49.5)	26 (72.2)
Unknown	103 (33.6)	8 (22.2)
Type 2 diabetes mellitus			-
Yes	16 (5.2)	36 (100.0)
No	291 (94.8)	0
Histology			1.000
Clear cell carcinoma	287 (93.5)	34 (94.4)
Non-clear cell carcinoma	17 (5.5)	2 (5.6)
Unknown	3 (1.0)	0 (0.0)
Primary tumor grade			0.011
G1-2	165 (53.7)	25 (69.4)
G3-4	121 (39.4)	5 (13.9)
Unknown	21 (6.8)	6 (16.7)
Synchronous metastatic disease			0.106
Yes	138 (45.0)	10 (27.8)
No	165 (53.7)	24 (66.7)
Unknown	4 (1.3)	2 (5.6)
Distant metastatic sites			0.901
Lung	202 (65.8)	22 (61.1)
Liver	41 (13.4)	3 (8.3)
Bone	73 (23.8)	9 (25)
Lymph nodes (non-regional)	125 (40.7)	15 (41.7)
Skin	5 (1.6)	0 (0.0)
Brain	12 (3.9)	1 (2.8)
Peritoneum	15 (4.9)	3 (8.3)
Other	80 (26.1)	12 (33.3)
MSKCC risk group			0.423
Favorable-risk group	119 (38.8)	17 (47.2)
Intermediate-risk group	188 (61.2)	19 (52.8)
Previous nephrectomy			0.542
Yes	256 (83.4)	28 (77.8)
No	51 (16.6)	8 (22.2)
Previous cytokine therapy			0.692
Yes	8 (2.6)	0 (0.0)
No	299 (97.3)	36 (100.0)
First-line targeted therapy			1.000
Sunitinib	239 (77.9)	28 (77.8)
Pazopanib	68 (22.1)	8 (22.2)
Second-line therapy			0.964
Everolimus	77 (25.1)	9 (25.0)
Axitinib	39 (12.7)	5 (13.9)
Sorafenib	38 (12.4)	3 (8.3)
Nivolumab	36 (11.7)	4 (11.1)
None	117 (38.1)	15 (41.6)
Metformin daily dose			-
Low (≤850 mg)	-	19 (52.8)
High (>850 mg)	-	17 (47.2)

Note: Bold indicates p<0.05.

Abbreviations: n, number of included patients; ECOG PS, Eastern Cooperative Oncology Group performance status; MSKCC, Memorial Sloan–Kettering Cancer Center (MSKCC) risk; BMI, body mass index; G1, well differentiated; G2, moderately differentiated; G3/G4, poorly differentiated/undifferentiated.

Table 2 Progression-Free and Overall Survival According to the Use of Metformin

	Metformin Use		p-value
	No	Yes
Median PFS (CI 95%)	9.31 Months (8.03–12.00)	31.13 Months (20.62–35.10)	<0.0001
3-months PFS (CI 95%)	0.879 (0.843–0.916)	0.972 (0.920–1.000)
6-months PFS (CI 95%)	0.613 (0.561–0.670)	0.916 (0.831–1.000)
12-months PFS (CI 95%)	0.443 (0.390–0.502)	0.833 (0.720–0.964)
18-months PFS (CI 95%)	0.274 (0.228–0.329)	0.750 (0.621–0.906)
Median OS (CI 95%)	22.40 Months (19.40–26.80)	51.60 Months (44.70-NA)	0.0002
12-months OS (CI 95%)	0.710 (0.661–0.763)	0.915 (0.828–1.000)
24-months OS (CI 95%)	0.473 (0.420–0.534)	0.858 (0.750–0.981)
36-months OS (CI 95%)	0.350 (0.299–0.409)	0.769 (0.641–0.923)

Note: Bold indicates p<0.05.

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

Figure 1 Kaplan–Meier estimates of progression-free survival (PFS) and overall survival (OS) according to the use of metformin and other OADs.

Figure 2 Kaplan–Meier estimates of progression-free survival (PFS) and overall survival (OS) according to the dose of metformin.

Table 3 Multivariate Cox-Proportional Hazards Model for Progression-Free and Overall Survival

Characteristic	Category	Progression-Free Survival (PFS)		Overall Survival (OS)
		HR (95% CI)	p-value	HR (95% CI)	p-value
Gender
	Female	1		1
	Male	0.793 (0.574–1.096)	0.160	0.830 (0.579–1.189)	0.309
Age
	<65 years	1		1
	≥65 years	0.877 (0.657–1.170)	0.371	0.891 (0.649–1.224)	0.477
ECOG PS
	1	1		1
	0	0.665 (0.487–0.909)	0.010	0.665 (0.479–0.924)	0.015
BMI
	Low (≤25)	1		1
	High (>25)	1.090 (0.768–1.547)	0.630	1.349 (0.914–1.990)	0.132
Histology
	Clear cell carcinoma	1		1
	Other	2.286 (1.184–4.414)	0.014	1.970 (0.974–3.984)	0.059
Grade
	G1-G2	1		1
	G3-G4	1.417 (1.043–1.926)	0.026	1.889 (1.351–2.640)	<0.001
Synchronous metastases
	No	1		1
	Yes	0.943 (0.660–1.348)	0.748	0.935 (0.635–1.376)	0.732
MSKCC risk group
	Favorable-risk group	1		1
	Intermediate-risk group	0.987 (0.724–1.345)	0.932	1.310 (0.944–1.820)	0.106
Previous nephrectomy
	No	1		1
	Yes	0.699 (0.439–1.115)	0.133	0.557 (0.336–0.921)	0.023
First-line targeted therapy
	Sunitinib	1		1
	Pazopanib	1.028 (0.700–1.509)	0.889	1.094 (0.719–1.666)	0.674
Metformin use
	No	1		1
	Yes	0.550 (0.343–0.883)	0.013	0.450 (0.256–0.794)	0.006

Note: Bold indicates p<0.05.

Abbreviations: n, number of included patients; ECOG PS, Eastern Cooperative Oncology Group performance status; MSKCC, Memorial Sloan–Kettering Cancer Center (MSKCC) risk; BMI, body mass index; G1, well differentiated; G2, moderately differentiated; G4, poorly differentiated/undifferentiated.