Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma

Original Study

Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma Lana Hamieh,1 Rana R. McKay,1 Xun Lin,2 Raphael B. Moreira,1 Ronit Simantov,2 Toni K. Choueiri1 Abstract In light of the emerging evidence of the antineoplastic potential of metformin, we investigated its effect on survival outcomes in metastatic renal cell carcinoma using a large clinical trial database. Although metformin did not affect survival in the overall cohort, it conferred a survival advantage in diabetic metastatic renal cell carcinoma patients treated with sunitinib. Introduction: Observational studies have suggested that metformin use is associated with favorable outcomes in several cancers. For renal cell carcinoma (RCC), data have been limited. Therefore, we investigated the effect of metformin on survival in metastatic RCC (mRCC) using a large clinical trial database. Patients and Methods: We conducted a retrospective analysis of patients with mRCC in phase II and III clinical trials. The overall survival (OS) in metformin users was compared with that of users of other antidiabetic agents and those not using antidiabetic agents. Progression-free survival, objective response rate, and adverse events were secondary endpoints. Subgroup analyses were conducted after stratifying by class of therapy, type of vascular endothelial growth factor tyrosine kinase inhibitors, and International Metastatic RCC Database Consortium (IMDC) risk groups. Results: We identified 4736 patients with mRCC, including 486 with diabetes, of whom 218 (4.6%) were taking metformin. Metformin use did not affect OS when compared with users of other antidiabetic agents or those without diabetes. Furthermore, metformin use did not confer an OS advantage when stratified by class of therapy and IMDC risk group. However, in diabetic patients receiving sunitinib (n ¼ 128), metformin use was associated with an improvement in OS compared with users of other antidiabetic agents (29.3 vs. 20.9 months, respectively; hazard ratio, 0.051; 95% confidence interval, 0.0090.292; P ¼ .0008). Conclusion: In the present study, we found a survival benefit for metformin use in mRCC patients treated with sunitinib. Clinical and preclinical studies are warranted to validate our results and guide the use of metformin in the clinic. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Diabetes, Kidney cancer, Prognosis, Sunitinib, Targeted therapy

Introduction Type 2 diabetes mellitus (DM) affects 28.9 million people in the United States, comprising 12.3% of the adult population.1 DM is common among cancer patients, with prevalence rates ranging from 8% to 18%.2 The high prevalence of DM in cancer is associated with the increasingly aging population, the obesity epidemic in the United States, and the increased cancer risk with DM.3-6 L.H. and R.R.M. are co-first authors with equal contributions. 1

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA Pfizer Oncology, Pfizer Inc, New York, NY

2

Submitted: Mar 21, 2016; Revised: Jun 17, 2016; Accepted: Jun 19, 2016 Address for correspondence: Toni K. Choueiri, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 E-mail contact: [email protected]

1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.06.017

Epidemiologic studies have shown that DM is associated with an increased risk of renal cell carcinoma (RCC) incidence, recurrence, and mortality.3,7-9 Metformin, a biguanide hypoglycemic agent, has been prescribed extensively for > 30 years to treat patients with type 2 DM.10,11 In addition to its wide use as an antidiabetic drug, recent evidence has demonstrated its role as a potential antineoplastic agent. Some observational studies have shown that metformin reduces cancer risk and recurrence and increases survival in several malignancies, including breast, colorectal, lung, prostate, and endometrial cancers.12,13 However, the results have been controversial, given the inconsistencies among the existing studies. In RCC, studies of the effect of metformin on survival outcomes have been limited to small retrospective series, most of which have failed to show a clinical benefit.14,15 Experimental studies have highlighted the antineoplastic activity of metformin in several cancers, including RCC.

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Metformin and Survival in mRCC Metformin inhibited the proliferation of RCC cell lines and tumor xenografts in preclinical models. The inhibitory effect of metformin is hypothesized to occur through activation of the AMP-activating protein kinase (AMPK) pathway and lowering of the insulin levels.16-18 We investigated the effect of metformin on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in a large clinical trial database of patients with metastatic renal cell carcinoma (mRCC).

and sorafenib), and IMDC risk group (favorable, intermediate, and poor risk). Treatment-associated toxicities were defined and evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0. Frequent serious (grade  3) AEs occurring in > 3% of patients were summarized. The statistical analyses were predefined at the inception of the project, although the study itself was a post hoc analysis of prospectively collected data. The analyses were conducted using SAS.

Results Patients and Methods

Patient Characteristics and Treatment Exposure

Study Design

We identified 4736 patients treated with first-line or second-line therapy for mRCC from January 2003 to June 2013. The median age at diagnosis was 61.5 years, with most patients (66.5%) < 65 years (Table 1). The patients were mostly men (71.0%), were of white ethnicity (77.4%), and had a good performance status (52.7%). Clear cell RCC was the dominant histologic type (89.4%), and the lung was the most common site of metastasis (76.6%). Most of the patients had undergone previous nephrectomy (70.2%) and a few had received previous therapy (33.2%). The IMDC risk was favorable, intermediate, and poor in 13.6%, 42.4%, and 24.1% of the patients, respectively. Of the 4736 patients analyzed, 644 (13.6%) were categorized as “diabetic,” and 486 patients (10.3% of the total cohort and 73.2% of the diabetic patients) received antidiabetic treatment. The patients with type 2 DM were grouped as metformin users (n ¼ 218) and users of other antidiabetic therapies (n ¼ 268). The other antidiabetic therapies included insulin, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide agonists (Supplemental Table 1 in the online version). Most of the antidiabetic therapy users had hypertension (75.2% and 73.5% of the metformin and other antidiabetic users, respectively), in contrast to the nonusers of antidiabetic therapy, of whom only 41.5% of patients had hypertension. The baseline patient and disease characteristics were similar across the 3 cohorts, except for the baseline medical conditions, including DM and hypertension, and concomitant use of statins and angiotensin system inhibitors, for which we adjusted in our analyses. The patients were treated with sunitinib (n ¼ 1059, 22.4%), axitinib (n ¼ 896, 18.9%), bevacizumab-containing regimens (n ¼ 784, 16.6%), sorafenib (n ¼ 772, 16.3%), temsirolimus-containing regimens (n ¼ 665, 14.0%), and IFN-alfa (n ¼ 560, 11.8%) (Supplementary Table 2 in the online version). A total of 3511 patients (74.1%) received VEGF-targeted therapy, with sunitinib the most prevalent treatment (n ¼ 1059, 22.4%). Of the patients receiving antidiabetic therapy, most (67.7%) received first-line therapy.

We conducted a retrospective survival analysis of patients with mRCC treated in phase II clinical trials (ClinicalTrials.gov identifiers, NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, and NCT00835978) and phase III clinical trials (ClinicalTrials.gov identifiers, NCT00083889, NCT00065468, NCT000678392, NCT00474786, NCT00631371, and NCT00920816) sponsored by Pfizer. Eligible patients had a diagnosis of mRCC of any histologic subtype. Baseline demographic, clinical, and laboratory data were collected for all the patients from the case report forms. The medication data collected included the following: treatment type, reason for treatment, start date, end date, and whether the use was ongoing. It was individually reviewed by our pharmacist (K.M.) to confirm accurate designation of metformin use. The patients were grouped into 3 cohorts, depending on the baseline use of antidiabetic treatment as follows: metformin users, users of other antidiabetic agents, and nonusers of antidiabetic therapy.

Treatment Outcomes OS was defined as the time from randomization for randomized studies and from the initiation of therapy for nonrandomized studies to death from any cause. PFS was defined as the time from randomization for randomized studies and from the initiation of therapy for nonrandomized studies to the date of progression or death from any cause, whichever came first. The response was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.0.

Statistical Analysis

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The primary objective of the present study was to evaluate OS for patients receiving metformin compared with patients treated with other antidiabetic therapies or no antidiabetic therapy. PFS, ORR, and adverse events (AEs) were secondary endpoints. OS and PFS were estimated using the Kaplan-Meier method and were assessed using multivariate Cox regression analysis, adjusting for age, gender, race, Eastern Cooperative Oncology Group performance status, histologic type, International Metastatic RCC Database Consortium (IMDC) risk criteria, baseline creatinine level, previous nephrectomy, previous therapy, sites of metastasis, baseline hypertension, baseline statin use, and baseline angiotensin system inhibitor use. All P values were 2 sided. Subgroup analyses were conducted by the class of mRCC therapy (vascular endothelial growth factor [VEGF]-targeted therapy, mammalian target of rapamycin [mTOR]-targeted therapy, and interferon-alfa therapy), type of VEGF-tyrosine kinase inhibitor (TKI; sunitinib, axitinib,

Clinical Genitourinary Cancer Month 2016

Effect of Metformin on Survival In the overall cohort, metformin use did not affect OS or PFS compared with patients who used other antidiabetic therapy (OS: hazard ratio [HR], 0.771; 95% confidence interval [CI], 0.5661.049; P ¼ .0980; PFS: HR, 0.905; 95% CI, 0.682-1.199; P ¼ .4858) or patients who did not use antidiabetic therapy (OS: HR, 1.053; 95% CI, 0.837-1.324; P ¼ .6606; PFS: HR, 0.979; 95% CI, 0.806-1.189; P ¼ .8274; Table 2, Figure 1).

Lana Hamieh et al Table 1 Patient Characteristics Antidiabetic Therapy Users Characteristic

Metformin (n [ 218)

Other Antidiabetic Therapy (n [ 268)

Antidiabetic Therapy Nonuser (n [ 4250)

Total Cohort (n [ 4736)

Age at therapy initiation (Years) <65

145 (67)

144 (54)

2969 (70)

3258 (69)

65

73 (33)

124 (46)

1281 (30)

1478 (31)

151 (69)

195 (73)

3017 (71)

3363 (71)

67 (31)

73 (27)

1233 (29)

1373 (29)

White

166 (76)

206 (77)

3292 (77)

3664 (77)

Other

52 (24)

62 (23)

958 (23)

1072 (23)

0

113 (52)

129 (48)

2253 (53)

2495 (53)

1

98 (45)

131 (489)

1929 (45)

2158 (46)

2

6 (3)

7 (3)

47 (1)

60 (1)

Unknown

1 (0.5)

1 (0.4)

21 (0.5)

23 (0.5)

199 (91)

241 (90)

3795 (89)

4235 (89)

14 (7)

21 (8)

302 (7)

337 (7)

5 (2)

6 (2)

153 (4)

164 (4)

Sex Male Female Race

ECOG PS

Pathologic type Clear cell carcinoma Nonclear cell carcinoma Unknown Baseline metastatic site Bone

56 (26)

65 (24)

1180 (28)

1301 (28)

Lung

178 (82)

204 (76)

3247 (76)

3629 (77)

Liver

61 (28)

68 (25)

1109 (26)

1238 (26)

>ULN

69 (32)

130 (49)

1428 (34)

1627 (34)

ULN

146 (67)

137 (51)

2716 (64)

2999 (63)

106 (2)

110 (3)

Baseline creatinine

Unknown

3 (1)

1 (0.4)

Previous nephrectomy Yes

133 (61)

201 (75)

2991 (70)

3325 (70)

No

73 (34)

55 (21)

1079 (26)

1207 (26)

Unknown

12 (5)

12 (4)

180 (4)

204 (4)

Any previous therapy

61 (28)

98 (37)

1414 (33)

1573 (33)

Cytokine therapy

21 (10)

45 (17)

605 (14)

671 (14)

Targeted therapy

27 (12)

28 (10)

518 (12)

573 (12)

Previous type of therapy

IMDC risk level Low Intermediate

25 (12)

32 (12)

589 (14)

646 (14)

100 (46)

117 (44)

1789 (42)

2006 (42)

Poor

51 (23)

71 (26)

1021 (24)

1143 (24)

Unknown

42 (19)

48 (18)

851 (20)

941 (20)

Medical condition Diabetes

210 (96)

253 (94)

181 (4)

644 (14)

Hypertension

164 (75)

197 (74)

1762 (42)

2123 (45)

Concomitant medication Statin ASI

61 (28)

66 (25)

384 (9)

511 (11)

132 (61)

152 (57)

1203 (28)

1487 (31)

Data presented as n (%). Abbreviations: ASI ¼ angiotensin system inhibitor; ECOG ¼ Eastern Oncology Cooperative Group; IMDC ¼ International Metastatic RCC Database Consortium; PS ¼ performance status; RCC ¼ renal cell carcinoma; ULN ¼ upper limit of normal.

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Metformin and Survival in mRCC Table 2 Effect of Metformin on OS and PFS in Overall Cohort OS Variable

Patients (n) Median (mo)

PFS

HR (95% CI)

P Value

Median (mo)

a

HR (95% CI)

P Value

a

Overall cohort (n ¼ 4736) Metformin users

218

18.04

Other antidiabetic therapy usersb

268

17.97

0.771 (0.566-1.049)

.0980

6.94

0.905 (0.682-1.199)

.4858

4069

19.67

1.053 (0.837-1.324)

.6606

7.04

0.979 (0.806-1.189)

.8274

Metformin users

162

22.04

Other antidiabetic therapy usersb

190

20.59

0.770 (0.525-1.130)

.1813

8.61

0.889 (0.621-1.274)

.5228

Metformin users

116

21.02

Other antidiabetic therapy usersb

157

21.39

0.803 (0.493-1.309)

.3787

8.54

0.852 (0.550-1.319)

.4725

53

29.34

75

20.89

0.051 (0.009-0.292)

.0008c

13.73

0.399 (0.111-1.428)

.1577

893

23.39

0.587 (0.273-1.264)

.1736

10.51

0.715 (0.410-1.247)

.2372

Metformin users

53

19.25

Other antidiabetic therapy usersb

75

NR

0.956 (0.529-1.726)

.8811

Metformin users

31

15.92

Other antidiabetic therapy usersb

41

29.31

2.672 (1.141-6.258)

.0236

Metformin users

29

12.66

Other antidiabetic therapy usersb

44

10.36

1.075 (0.353-3.271)

.8993

Metformin users

27

11.86

Other antidiabetic therapy usersb

34

14.94

0.449 (0.153-1.314)

.144

Metformin users

25

NR

Other antidiabetic therapy usersb

32

35.86

0.842 (0.254-2.789)

.778

Antidiabetic therapy nonusers

7.27

Antidiabetic therapy by therapy type (n ¼ 486) VEGF therapy (n ¼ 352) 8.28

VEGF-TKIs (n ¼ 273) 8.28

Sunitinib (n ¼ 128) Metformin users Other antidiabetic therapy usersb Antidiabetic therapy nonusers

10.97

Axitinib (n ¼ 128) 8.08 1.154 (0.552-2.414)

.7038

8.11

1.604 (0.525-4.903)

.4075

0.658 (0.170-2.551)

.5453

3.75

0.286 (0.078-1.051)

.0595

3.75

Sorafenib (n ¼ 72) 4.76 7.89

mTOR-targeted therapy (n ¼ 73) 3.78

IFN-alfa therapy (n ¼ 61) 3.65

IMDC risk level, antidiabetic therapy usersd (n ¼ 486) Low (n ¼ 57)

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12.66 1.275 (0.186-8.740)

When stratified by class of mRCC therapy, OS and PFS were not significantly different between the metformin users and users of other antidiabetic therapies for patients receiving VEGF-targeted therapy, mTOR-targeted therapy, or IFN-alfa therapy (Table 2). Because most patients in the overall cohort received sunitinib (n ¼ 1059, 22.4%; Table 1), we conducted a subgroup analysis to

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.8047

13.73

assess the effect of metformin on survival in sunitinib users. Among the patients treated with sunitinib, 53 (5%) received metformin, 75 (7%) received other antidiabetic therapies, and 893 (84%) did not receive antidiabetic treatment (Table 2). In patients treated with sunitinib, OS was significantly improved in metformin users compared with other antidiabetic therapy users (HR, 0.051; 95%

Lana Hamieh et al Table 2 Continued OS Variable

Patients (n) Median (mo)

PFS

HR (95% CI)

P Value

Median (mo)

0.867 (0.526-1.431)

.5777

8.11

0.728 (0.393-1.350)

.3134

3.13

a

HR (95% CI)

P Value

1.132 (0.772-1.775)

.5885

0.477 (0.253-0.898)

.0218

a

Intermediate (n ¼ 217) Metformin users

100

18.04

Other antidiabetic therapy usersb

117

20.26

Metformin users

51

11.51

Other antidiabetic therapy usersb

71

6.07

7.47

Poor (n ¼ 122) 3.78

Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio; IFN-alfa ¼ interferon-alfa; IMDC ¼ International Metastatic RCC Database Consortium; mTOR ¼ mammalian target of rapamycin; NR ¼ median OS not reached; OS ¼ overall survival; PFS ¼ progression-free survival; TKI ¼ tyrosine kinase inhibitor; VEGF ¼ vascular endothelial growth factor. a HR of metformin users to comparator group from multivariate analysis, adjusted for age, sex, race, Eastern Cooperative Oncology Group performance status, histologic type, IMDC risk criteria, baseline creatinine, previous nephrectomy, previous therapy, sites of metastasis, hypertension, statin use, and angiotensin system inhibitor use. b Other antidiabetic therapy included insulin, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide agonists, sulfonylurea/thiazolidinedione, and pentoxifylline. c Statistically significant. d The IMDC prognostic model uses the following risk factors: Karnofsky performance status < 80%, time from diagnosis to treatment of < 1 year, hemoglobin < lower limit of normal, and serum calcium neutrophils and platelets greater than the upper limit of normal to stratify patients with metastatic renal cell carcinoma into 3 risk categories: favorable risk (no risk factors), intermediate risk (1-2 risk factors), and poor risk (3-6 risk factors).

CI, 0.009-0.292; P ¼ .0008; Table 2, Figure 2). However, PFS was not improved (HR, 0.399; 95% CI, 0.111-1.428; P ¼ .1577). When the overall population was stratified by IMDC risk group, no significant difference was found in OS and PFS for the metformin users compared with the other antidiabetic therapy users.

Effect of Metformin on Response Rate The ORR for the overall cohort was 24.5%, with similar rates among the 3 patient cohorts. Metformin use did not affect the response outcomes in the overall cohort or when stratified by class of mRCC therapy, including sunitinib treatment.

Adverse Events The most common AE of interest, of any grade, experienced by patients in the overall cohort was diarrhea (44%), with similar rates among metformin users, other antidiabetic therapy users, and antidiabetic therapy nonusers (Table 3). The most frequent serious (grade  3) AEs in the overall cohort were fatigue, hypertension, anemia, hand-foot syndrome, diarrhea, dyspnea, neutropenia, proteinuria, and decreased appetite. The incidence of these AEs was comparable among the 3 cohorts. Given that diabetic patients have an increased risk of cardiovascular events, we specifically explored the incidence of acute coronary syndrome, myocardial infarction, cerebrovascular accident, transient ischemic attack, and visceral arterial ischemia in the 3 groups of patients. We also explored the incidence of diarrhea because it is a known toxicity of metformin. The incidence of these AEs of interest was similar among the 3 groups of patients (Table 3). Additionally, hypoglycemia was not observed in the patients receiving antidiabetic therapy.

Discussion Drug repurposing is an emerging field that capitalizes on the use of known drugs for new indications.19 This approach expedites drug discovery given that the pharmacokinetics and toxicity have

already been established, thus streamlining the time and cost associated with new drug development. With the recent evidence of its antineoplastic activity, repurposing metformin in cancer has been gaining interest during the past decade. Therefore, we assessed the effect of metformin on survival in mRCC in the largest series to date. Metformin use did not affect survival or response rate in the total cohort of 4736 mRCC patients nor in the subset analysis by class of therapy and IMDC risk group. However, metformin use was associated with improved OS in mRCC diabetic patients treated with sunitinib. Although metformin has demonstrated preclinical antitumor activity and possible efficacy in other cancer types, its activity in RCC appears to be limited to the context of specific cancer-directed therapies, as seen with sunitinib in our cohort. Previous reports have failed to show a significant improvement in survival with the use of metformin in diabetic RCC patients, particularly in the setting of metastatic disease.14,15,20 However, in a retrospective analysis of patients treated with sunitinib, Keizman et al21 found a survival advantage associated with the use of metformin in a subset of diabetic mRCC patients (n ¼ 108). Our results have validated these findings in a larger data set of diabetic patients with mRCC, raising the possibility of synergy between metformin and sunitinib. From our study, it does not seem that this effect could be generalized to other VEGF-TKIs, because metformin did not affect survival in the sorafenib and axitinib cohorts. The mechanism underlying our clinical observations has not been fully elucidated. Metformin has been shown to have an antiproliferative effect in RCC cell lines and tumor xenografts.16,17 Its antineoplastic activity is thought to stem from its AMPK-activating and insulin-lowering properties.16-18 AMPK is a major metabolic checkpoint linked to cancer that suppresses the downstream phosphoiniositide-3 kinase (PI3K)/Akt/mTOR pathway.22,23 AMPK also inhibits the insulin receptor substrate-1, which activates the PI3K/Akt/mTOR pathway.24,25 Therefore, by being a

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Metformin and Survival in mRCC Figure 1 Kaplan-Meier Estimates of Median Overall Survival (mOS) Comparing Metformin Users and Other Antidiabetic Therapy Users (A) and Nonusers of Antidiabetic Therapy (B) in the Overall Cohort

Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio.

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pharmacologic activator of AMPK and by lowering insulin levels, metformin inhibits the PI3K/Akt/mTOR pathway, which plays an essential role in RCC pathogenesis. The inhibition of several pathways implicated in the pathogenesis of RCC by metformin, VEGF-TKIs, and mTOR inhibitors suggests synergy between these different treatment modalities. Sorafenib was shown to activate AMPK through oxidative stress-induced cell death, thereby synergizing with metformin in nonesmall-cell lung cancer cells in vitro.26,27 In our study, metformin did not show a survival advantage for patients treated with mTOR inhibitors or VEGF-TKIs other than sunitinib, despite evidence of a synergistic antitumor effect.26,28 These preclinical studies used doses of metformin that exceeded the conventional prescribed doses, potentially explaining the lack of survival effect seen in our cohort. Further experimental studies of the combination of metformin with targeted

Clinical Genitourinary Cancer Month 2016

agents used in RCC are warranted to understand the mechanisms underlying the interaction of these agents. Numerous clinical trials are exploring the use of metformin in cancer treatment.29 Most of the studies have demonstrated modest activity at best with metformin in the metastatic setting. Specifically, a multicenter single-arm phase II trial evaluated the benefit of metformin alone in nondiabetic, chemotherapy-naive patients with castration-resistant prostate cancer.30 Although the efficacy was limited, the study results highlighted the importance of patient selection, drug dosing, and drug combinations in clinical trial designs. Hyperinsulinemia has been observed in several cancer types and has been shown to be associated with worse outcomes. Given the suppressive effects of metformin on insulin, the potential exists for additional activity of this agent in high insulin states, as seen in diabetic cancer patients.24 Additionally, Davis et al31 and Carew

Lana Hamieh et al Figure 2 Kaplan-Meier Estimates of Median Overall Survival (mOS) Comparing Metformin Users and Other Antidiabetic Therapy Users (A) and Nonusers of Antidiabetic Therapy (B) in the Sunitinib Cohort

Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio.

and Huang32 have demonstrated that cancers with mutations in genes of respiratory complex I of the mitochondrial electron transport chain, including RCC, have greater sensitivity to metformin.33 These factors are important to consider in selecting patients who might potentially derive the most benefit from metformin. Although we used data from the largest database to assess the survival effect of metformin in mRCC patients, our study had several limitations. The diabetic patients represented only 13.6% of our cohort. Although this was reflective of the rate of diabetes in the general population, the diabetic cohort was smaller in number than the overall cohort, reducing the power of the analyses. Additional stratification of diabetic patients by type of therapy and IMDC stage further reduced the number of patients and the power of the

analysis in each subset. It is possible that the isolated effect to sunitinib in our cohort could potentially result from the limited number of patients treated with other TKIs. Additionally, the database was not designed for the purpose of exploring the effect of metformin on survival. Therefore, data regarding the dose, schedule, duration, and adherence to metformin were not available, and the decision to initiate and modify metformin use was at the discretion of the treating physician. Additionally, information regarding the severity of DM was not available. Furthermore, data generated from this clinical trial population might not be fully generalizable to the real-world RCC population. Finally, not all agents approved for the treatment of mRCC were present and analyzed in this database.

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Metformin and Survival in mRCC Table 3 Adverse Events Variable

Metformin Users (n [ 218)

Other Antidiabetic Therapy Users (n [ 268)

Antidiabetic Therapy Nonusers (n [ 4250)

Total Cohort (n [ 4736)

102 (2)

123 (3)

AEs of interest (any grade) Cardiovascular events

12 (6)

9 (3)

Acute coronary syndrome

0 (0)

0 (0)

Myocardial infarction/ischemia

4 (2)

5 (2)

44 (1)

Cerebrovascular accident

3 (1)

3 (1)

35 (1)

41 (1)

Transient ischemic attack

5 (2)

1 (0.4)

19 (0.4)

25 (0.5)

3 (0.1)

3 (0.1) 53 (1)

Myositis

0 (0)

1 (0.4)

5 (0.1)

6 (0.1)

Diarrhea

108 (50)

116 (43)

1858 (44)

2082 (44)

24 (11)

41 (15)

399 (9)

464 (10)

9 (4)

30 (11)

381 (9)

420 (9)

18 (8)

27 (10)

318 (8)

363 (8)

Most frequent grade 3-5 AEs (observed in >3% of patients) Fatigue Hypertension Anemia Asthenia

11 (5)

17 (6)

243 (6)

271 (6)

Hand-foot syndrome

12 (6)

18 (7)

237 (6)

267 (6)

Diarrhea

12 (6)

13 (5)

231 (5)

256 (5)

Dyspnea

10 (5)

14 (5)

169 (4)

193 (4)

Neutropenia

5 (2)

7 (3)

174 (4)

186 (4)

Proteinuria

10 (5)

8 (3)

141 (3)

159 (3)

7 (3)

12 (5)

122 (3)

141 (3)

Decreased appetite Data presented as n (%).

Conclusion The results of the present large retrospective study demonstrated that metformin did not improve survival in a large cohort of clinical trial patients with mRCC. However, a subgroup analysis of 108 mRCC patients demonstrated a survival benefit of metformin in mRCC patients treated with sunitinib. Clinical studies are warranted to validate our results and guide the use of metformin in the clinical setting. Additionally, preclinical studies assessing the synergistic effects of metformin and sunitinib are important to provide insight into our results. Finally, the treatment landscape for mRCC is diverse and has been rapidly evolving. Studies exploring the utility of metformin with newer agents, including cabozantinib, and checkpoint inhibitors might inform the effect of this agent in the modern era.

Clinical Practice Points  Metformin, a biguanide hypoglycemic agent with a tolerable

toxicity profile, is widely prescribed for the treatment of type 2 DM.  With studies shedding light on its antineoplastic activity in

several cancers, its repurposing in the cancer setting is an area of great interest.  In RCC, data are scarce; however, our study is the largest study to date to assess the effect of metformin on survival outcomes in patients with mRCC.  Metformin conferred an OS advantage only in patients with mRCC treated with sunitinib, suggesting a synergistic effect

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of these agents. No effect was found on response rate or PFS.  Further experimental studies to evaluate the combination of VEGF-TKIs and metformin in cancer are needed.

Acknowledgments The authors thank the patients and investigators who participated in the clinical trials used for our analysis. We would also like to acknowledge Suzanne Mickey and Marina D. Kaymakcalan for their help with the project. No writing assistance was provided for this work.

Disclosure R.R.M. has received institutional research funding from Pfizer and Bayer. T.K.C. has received institutional research funding from Pfizer and has an advisory role at Pfizer, Novartis, GlaxoSmithKline, Genentech, Merck, Bayer, and Onyx. X.L. and R.S. are employees at Pfizer. The remaining authors declare that they have no competing interests.

Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clgc.2016.06.017.

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