The efficacy and adverse events of regorafenib in advanced gastrointestinal stromal tumors after imatinib and sunitinib failure: a systemic review and meta-analysis

DOI: https://doi.org/10.21203/rs.3.rs-2391619/v1

Abstract

Background

Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced gastrointestinal stromal tumors (GISTs) previously treated with imatinib and sunitinib.

Objective

The systematic review and meta-analysis aim to quantify the efficacy and adverse events of regorafenib for patients with advanced GISTs.

Methods

Based on predetermined selection criteria, we looked through the PubMed, Embase, and Cochrane databases from establishment until September 2022 to identify pertinent papers. Combined percentages were presented as risk ratios (95% confidence intervals) using Stata 17.0 and the Review Manager 5.3.

Results

Following the screening and quality evaluation, eleven studies were included, two randomized controlled trials and nine non-randomized prospective or retrospective review articles of intervention, involving 768 patients, 400 of whom were male. This meta-analysis showed that the pooled mPFS was 7.18 (95%CI, 5.87–8.50; Z = 10.68, p < 0.001) and the pooled mOS was 19.67 months (95%CI, 11.32–28.03; Z = 4.61, p < 0.001) in patients after receiving regorafenib treatment, which was administered following failure with imatinib and sunitinib therapies. The combined analysis of the studies revealed that the incidence of any grade toxicities associated with regorafenib treatment of GISTs was 97% (95%CI, 0.96–0.98; Z = 144.09, p < 0.001). Regarding specific AEs, the most common AE was hand-foot syndrome (77%, 95%CI, 0.66–0.88; Z = 14.00, p < 0.001), followed by fatigue (55%, 95%CI, 0.41–0.69; Z = 7.83, p < 0.001), hypertension (53%, 95%CI, 0.34–0.72; Z = 5.56, p < 0.001), anemia (53%, 95%CI, 0.03–1.03; Z = 2.06, p = 0.04), thrombocytopenia (53%, 95%CI, 0.02–1.04; Z = 2.02, p = 0.04), liver damage (52%, 95%CI, 0.30–0.74; Z = 4.64, p < 0.001), diarrhea (43%, 95%CI, 0.33–0.53; Z = 8.40, p < 0.001) and hypophosphatemia (42%, 95%CI, 0.30–0.54; Z = 6.98, p < 0.001), hoarseness (34%, 95%CI, 0.18–0.51; Z = 4.06, p < 0.001), oral mucositis (31%, 95%CI, 0.21–0.41; Z = 5.96, p < 0.001), hypothyroidism (30%, 95%CI, 0.12–0.48; Z = 3.22, p < 0.001), eta. In addition, the pooled analysis of the studies revealed that grade3-4 toxicities rate was 59% (95%CI, 0.52–0.66; Z = 16.38, p < 0.001), among which the incidence of hand-foot syndrome, hypertension and hypophosphatemia was 20% (95%CI, 0.16–0.24; Z = 13.22, p = 0.15), 16% (95%CI, 0.10–0.22; Z = 30.62, p < 0.001) and 13% (95%CI, 0.05–0.22; Z = 0.13, p = 0.72).

Conclusion

The efficacy and adverse events of regorafenib in advanced GISTs after imatinib and sunitinib failure in the present study was similar with demonstrated in other tumors in real-world practice settings. The incidence of several common AEs for regorafenib was lower in our analysis than previously reported, probably due to the fact that adverse events in the included studies involved a lower than the recommended daily dose of 160 mg.

Background

Gastrointestinal stromal tumors (GISTs) are the most typical mesenchymal tumors arising from the gastrointestinal tract. According to epidemiological research, the incidence of GISTs varies with geographic distribution and ranges from 7 to 15 new cases per million population per year [1]. A paradigm of precision medicine for contemporary cancer treatment, molecular diagnostics and targeted therapy of GISTs highlights the significance of matching various molecular subtypes of oncogenic driver genes with particular medicines. With the advancement of technology and the deepening of research, fundamental changes have taken place in the classification and diagnosis and treatment of GISTs molecular subtypes. About 99% of GISTs can identify driver gene mutations, and the existence of specific driver genes has different molecular biological characteristics, thus guiding the use of different targeted drugs [2, 3]. The three principal GISTs mutant subtypes are the receptor tyrosine kinases (KIT) mutations, platelet-derived growth factor receptor alpha (PDGFRA) mutations, and succinate dehydrogenase deficiency (SDH), these three mutant subtypes account for approximately 95% of all mutations of GISTs, A few additional GISTs are classified as wild-type GISTs due to they have activating mutations in the BRAF gene [4].

Imatinib considerably raises the survival rate of for metastatic and/or unresectable advanced GISTs when used as a first-line treatment. In the face of primary or secondary resistance of imatinib [5], sunitinib, another PDGFRA and KIT inhibitor, was utilized as a second-line treatment and shown clinically substantial benefit [6]. Regorafenib, a different multi-kinase inhibitor, was authorized as a third-line treatment option following the failure of both imatinib and sunitinib. Although the fact that numerous studies have demonstrated the transfer of regorafenib resistance to first- and second-line therapy advanced GISTs, but largely limited conclusions have been made about the drug's efficacy and adverse events. To broaden the study’s focus, we conducted the systematic review and meta-analysis of available evidence from observational studies to quantify the efficacy and adverse events of regorafenib in patients with advanced GISTs after imatinib and sunitinib failure.

Materials And Methods

Literature search strategy

All potentially relevant studies were searched on PubMed, Embase, and Cochrane databases from the establishment of the database to September 2022 with language restrictions English using the following keywords: “regorafenib”, “gastrointestinal stromal tumors” or “advanced gastrointestinal stromal tumors” or “metastatic and/or unresectable GIST” or “advanced GIST”. This article was based on prior research, none of the authors conducted any experiments involving humans or animals. Two investigators separately conducted the preliminary screening to identify studies that did not satisfy the criteria based on the titles and abstracts of the papers, and they also noted the reasons for exclusions. The pertinent data was extracted after thoroughly reviewing all potentially pertinent reports.

Inclusion And Exclusion Criteria

The following criteria must be met for inclusion in this meta-analysis: (1)

Subjects were over-18-year-old patients with advanced GISTs; (2) Regorafenib was administered as imatinib and sunitinib treatment after failure; (3) Clinical results include at least one of the following: clinical benefit (CB), partial response (PR), stable disease (SD), median progression-free survival (mPFS), median overall survival (mOS), treatment-related adverse events (AEs), and patients with clinical outcomes defined as CB, PR, or SD Proportion; (4) Literature in English. Exclusion criteria: (1) GISTs that are non-metastatic, unresectable, or not being treated with regorafenib; (2) Duplicate publications; (3) Reviews, reports, or meeting abstracts; (4) In vitro experiments; (5) Non-English publications. Two researchers looked over and evaluated the proposed research from the abstract and title perspectives. The entire texts were read when the abstracts weren't enough to judge if the trial was eligible. When disagreements arose, a third investigator was consulted to help address the issue.

Data Extraction And Outcome Assessments

First author, country, year of publication, trial phase, sample size, sex, age, previous treatment and outcome indicators, among other data, were included into pre-designed tables. Two investigators separately extracted the data, and differences were settled through conversation or by consulting a third investigator to guarantee consistency of evaluation.

Risk Of Bias And Certainty Of Evidence Assessment

Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias Assessment Tool [7]. The risk of bias of in non-randomized studies were assessed according to the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool [8]. The seven domains of the ROBINS-I instrument allow for the assessment of bias, which is attributed to confounding, selection of participants, exposure assessment, misclassification during follow-up, missing data, outcome assessment, and selective reporting. Each domain's risk was graded by two reviewers as low, moderate, serious, critical, or lacking information. A senior investigator settled disagreements.

Statistical analysis

Stata Statistical Software version 17.0 and Review Manager 5.3 were used to examine the extracted data for the meta-analysis. P values were two-sided, and significance was determined by an alpha level of 0.05. A DerSimonian-Laird random effects model was used to assess the odds ratios (ORs) and 95% confidence intervals (CI) for effectiveness and adverse events of regorafenib [9]. The I2 statistic was used to calculate the degree of heterogeneity between studies (0–25% low heterogeneity, 25–50% moderate heterogeneity, 50–75% considerable heterogeneity, and 75–100% high heterogeneity).

Results

Characteristics of studies based on the selection criteria, eleven studies with 768 patients were considered, 400 of whom (52.08%) were male and whose ages varied from 56 to 68 years [1020]. Advanced GISTs patients would at least have undergone systemic antineoplastic therapy with imatinib and sunitinib. Two RCTs and nine prospective and retrospective studies with sample sizes ranging from 18 to 236 were found in this systematic review. The whole selection procedure was shown in Fig. 1. Regorafenib 160 mg/day was administered in four-week cycles with three weeks on and one week off, as the standard of care in all investigations. Demetri et al evaluated the regorafenib compared to the placebo for patients with advanced GISTs [11]. Another RCT performed by Kang et al evaluated the avapritinib versus regorafenib [19]. These studies were published between 2012 and 2022. More thorough research data are shown in Table 1.

Table 1

Basic characteristics of included literatures M male, F Female, CB clinical benefit, PR partial response, SD stable disease, mPFS median progression-free survival, mOS median overall survival, AEs adverse events, NA Not available

First author

(year)

Country

Trial phase

Sample

size

Sex

(M/F)

Age (years)

Median (rang)

Regorafenib

does

(mg/day)

Previous

treatment

Outcoms

George S, et al (2012)

Multicenter

phase II

33

19/14

56(25–76)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, PR, SD, mPFS, AEs

Demetri GD, et al (2012)

Multicenter

phase III

133

85/48

60(51–67)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, SD, mPFS, AEs

Kollàr A, et al (2014)

UK

retrospective study

20

13/7

68(45–87)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, PR, SD, mPFS, OS, AEs

Ben-Ami E, et al (2016)

Multicenter

phase II

33

19/14

56(25–76)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, PR, SD, mPFS,OS, AEs

Son MK, et al (2016)

Korea

prospective study

57

34/23

56(50–62)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, SD, mPFS, OS, AEs

Yeh CN et al (2017)

Taiwanese

phase II

18

14/4

59(36–71)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, PR, SD, mPFS, AEs

Kim JJ, et al (2019)

Korea

phase II

25

21/4

60(42–74)

100mg daily

for 28 days

imatinib sunitinib

CB, PR, SD, mPFS, AEs

Hu CH, et al (2020)

Taiwanese

prospective study

28

20/8

61(36–71)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

CB, PR, SD, mPFS, mOS AEs

Nannini M, et al (2021)

Multicenter

retrospective study

49

NA

58(19–78)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

mPFS, OS

103

NA

personalized schedules

 

Kang YK, et al (2022)

Multicenter

phase III

236

156/80

62(31–86)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

PR, SD, mPFS, AEs

Teranishi R, et al (2022)

Japanese

retrospective study

33

19/14

62(26–81)

160mg,3-weeks-on, 1-week-off

imatinib sunitinib

PR, SD, mPFS, mOS, AEs

Risk Of Bias Assessment

The Cochrane Collaboration's tool classified the total bias risk of each study as "low" when more than four items classified as "low risk" were considered applicable, "moderate" when two to three items were considered applicable, and "high" when fewer than two "low risk" items or more than one "high risk" item were considered applicable. Two included RCTs were well designed and had a low bias risk by the Cochrane Collaboration’s tool (Fig. 2A). Except for Son's and Yeh's studies [14, 15], which had a high bias risk and a moderate bias risk, the other non-randomized studies contained trials that were carefully planned and had a low bias risk according to the ROBINS-I tool (Fig. 2B).

Sensitivity Analyses

Galbraith plot was performed the heterogeneity sources, we can observe that all points fall inside the interior of the confidence interval regression line in Galbraith plot (Fig. 3B-Fig. 9B). With the exception of SD and mPFS, where three studies [12, 14, 15] with conflicting directions of association were included, we conducted sensitive analysis by removing one study at a time and discovered that no study had significant effects on any of the major outcomes (Fig. 3C-Fig. 9C).

Efficacy Outcomes

The summary of pooled ORs for the efficacy of regorafenib in advanced GISTs after imatinib and sunitinib failure was reported in Fig. 3- Fig. 9. Among the studies, significant heterogeneity was observed for the CB rate (I2 = 85.81%, P = 0.00; Z = 9.59, p < 0.001) (Fig. 3A) and SD rate (I2 = 91.54%, P = 0.00; Z = 9.48, p < 0.001) (Fig. 5A); thus, the random-effects model was used for pooling data. Since there no significant heterogeneity (I2 = 20.47%, P = 0.27; Z = 6.54, p < 0.001) (Fig. 4A) was observed for the PR rate; hence, the fixed-effects model was used. The pooled results showed that approximately 67% (95%CI 53–80, Fig. 3A), 9% (95%CI 6–12, Fig. 4A), and 60% (95%CI 48–73, Fig. 5A) of patients with GISTs attained CB, PR, and SD rate respectively after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments. Further study revealed that Kollàr’s study had effects on the major outcomes (Fig. 5C). When this study was deleted, the SD rate results showed that approximately 57% (95%CI 48–65, Fig. 8A). The mPFS was determined for all eleven studies, and significant heterogeneity (I2 = 97.9%, P = 0.00; Z = 5.27, p < 0.001) was observed among the studies. This meta-analysis revealed that the pooled mPFS was 8.59 months (95%CI 5.40-11.78, Fig. 6A) in patients after regorafenib treatment. Further study showed that Son’s and Yeh’s studies had an impact on the key results (Fig. 6C). When studies were deleted, the pooled mPFS results was 7.18 (95%CI 5.87–8.50, Z = 10.68, p < 0.001; Fig. 9A). The pooled mOS was determined for 4 studies, and significant heterogeneity (I2 = 98.9%, P = 0.00; Z = 4.61, p < 0.001) was observed among the studies also. This meta-analysis revealed that the pooled mOS was 19.67 months (95%CI 11.32–28.03; Fig. 7A) in patients after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments.

Risk Of Aes

The pooled analysis of the studies revealed that the incidence of any grade toxicities related to the treatment of GISTs by regorafenib was 97% (OR = 0.97; 95%CI, 0.96–0.98; I2 = 0.00%, Z = 144.09, p < 0.001). Regarding specific AEs, hand-foot syndrome was the most common AE (77%, OR = 0.77; 95%CI, 0.66–0.88; I2 = 90.43%, Z = 14.00, p < 0.001), followed by fatigue (55%, OR = 0.55; 95%CI, 0.41–0.69; I2 = 90.90%, Z = 7.83, p < 0.001), hypertension (53%, OR = 0.53; 95%CI, 0.34–0.72; I2 = 96.35%, Z = 5.56, p < 0.001), anemia (53%, OR = 0.53; 95%CI, 0.03–1.03; I2 = 99.27%, Z = 2.06, p = 0.04), thrombocytopenia (53%,OR = 0.53; 95%CI, 0.02–1.04; I2 = 98.29%, Z = 2.02, p = 0.04), liver damage (52%, OR = 0.52; 95%CI, 0.30–0.74; I2 = 77.01%, Z = 4.64, p < 0.001), diarrhea (43%, OR = 0.43; 95%CI, 0.33–0.53; I2 = 83.34%, Z = 8.40, p < 0.001) and hypophosphatemia (42%, OR = 0.42; 95%CI, 0.30–0.54; I2 = 0.00%, Z = 6.98, p < 0.001), hoarseness (34%, OR = 0.34; 95%CI, 0.18–0.51; I2 = 95.84%, Z = 4.06, p < 0.001), oral mucositis (31%, OR = 0.31; 95%CI, 0.21–0.41; I2 = 85.01%, Z = 5.96, p < 0.001), hypothyroidism (30%, OR = 0.30; 95%CI, 0.12–0.48; I2 = 54.73%, Z = 3.22, p < 0.001), eta. The rate of specific AEs was listed in Table 2. In addition, the pooled analysis of the studies revealed that specific grade3-4 toxicities were 59% (OR = 0.59; 95%CI, 0.52–0.66; I2 = 62.91%, Z = 16.38, p < 0.001), among which the incidence of hand-foot syndrome, hypertension and hypophosphatemia was 20% (OR = 0.20; 95%CI, 0.16–0.24; I2 = 31.93%, Z = 13.22, p = 0.15), 16%(OR = 0.16; 95%CI, 0.10–0.22; I2 = 70.61%, Z = 30.62, p < 0.001) and 13%(OR = 0.13; 95%CI, 0.05–0.22; I2 = 0.00%, Z = 0.13, p = 0.72). It was common AEs of GISTs grade3-4 toxicities treated by regorafenib after the failure of imatinib and sunitinib. The rate of specific grade3-4 toxicities was listed in Table 3.

Table 2

Risk of specific adverse events AEs adverse events, OR odds ratio, CI confidence intervals

Any grade

No of study

Rate of AEs (%)

Pooled OR 95% CI

I 2 (%)

Z

p

Hand-foot syndrome

10

0.77

0.66–0.88

90.43

14.00

< 0.001

Fatigue

9

0.55

0.41–0.69

90.90

7.83

< 0.001

Hypertension

10

0.53

0.34–0.72

96.35

5.56

< 0.001

Anemia

4

0.53

0.03–1.03

99.27

2.06

0.04

Thrombocytopenia

3

0.53

0.02–1.04

98.29

2.02

0.04

Liver damage

3

0.52

0.30–0.74

77.01

4.64

< 0.001

Diarrhea

10

0.43

0.33–0.53

83.34

8.40

< 0.001

Hypophosphatemia

2

0.42

0.30–0.54

0.00

6.98

< 0.001

Hoarseness

8

0.34

0.18–0.51

95.84

4.06

< 0.001

Oral mucositis

9

0.31

0.21–0.41

85.01

5.96

< 0.001

Hypothyroidism

2

0.30

0.12–0.48

54.73

3.22

< 0.001

Myalgia

7

0.29

0.17–0.41

85.41

4.61

< 0.001

Headache

4

0.29

0.10–0.47

85.58

3.09

< 0.001

Anorexia

9

0.26

0.20–0.31

53.74

8.57

< 0.001

Abdominal pain

2

0.26

0.15–0.37

0.00

4.49

< 0.001

Alopecia

7

0.24

0.14–0.34

81.4

4.53

< 0.001

Nausea

6

0.22

0.14–0.29

70.75

5.80

< 0.001

Rash, maculopapular

5

0.20

0.15–0.24

11.75

8.13

< 0.001

Constipation

5

0.19

0.14–0.23

46.51

7.98

< 0.001

Voice alteration

2

0.19

0.00-0.41

74.71

1.75

0.08

Arthralgia

2

0.18

0.06–0.30

34.68

2.88

< 0.001

Hyperbilirubinemia

2

0.17

0.12–0.22

0.00

7.28

< 0.001

Decreased weight

3

0.15

0.08–0.21

53.97

4.29

< 0.001

Sensory neuropathy

2

0.15

0.07–0.22

0.00

3.74

< 0.001

Vomiting

4

0.12

0.06–0.18

52.51

3.92

< 0.001

Palpitation

2

0.08

0.00-0.16

0.00

2.05

0.04

Hepatobiliary toxicity

2

0.05

0.02–0.08

0.00

3.63

< 0.001

Table 3

Risk of specific grade3-4 toxicities

Grade3-4

No of study

Rate of AEs (%)

Pooled OR 95% CI

I 2 (%)

Z

p

Hand-foot syndrome

10

0.20

0.16–0.24

31.93

13.22

0.15

Hypertension

10

0.16

0.10–0.22

70.61

30.62

< 0.001

Hypophosphatemia

2

0.13

0.05–0.22

0.00

0.13

0.72

Hepatobiliary toxicity

4

0.09

0.03–0.15

11.67

3.40

0.33

Diarrhea

5

0.06

0.04–0.09

0.00

3.49

0.48

Anemia

3

0.05

0.00-0.11

36.23

3.14

0.21

Fatigue

7

0.04

0.02–0.05

0.00

2.76

0.84

Rash, maculopapular

5

0.04

0.01–0.07

12.58

4.58

0.33

Abdominal pain

2

0.03

0.00-0.08

0.00

0.04

0.84

Anorexia

2

0.02

0.00-0.05

0.00

0.14

0.71

Oral mucositis

3

0.01

0.00-0.02

0.00

0.96

0.62

Myalgia

3

0.01

0.00-0.02

0.00

0.76

0.68

Nausea

3

0.01

0.00-0.01

0.00

0.85

0.65

Vomiting

3

0.01

0.00-0.03

0.00

0.37

0.83

AEs adverse events, OR odds ratio, CI confidence intervals

Discussion

Regorafenib, a multikinase inhibitor, inhibits a number of protein kinases involved in the control of tumor angiogenesis (vascular endothelial growth factor receptor (VEGFR)-1, -2, and − 3), oncogenesis (RAF1, BRAF, RET, KIT and BRAFV600E), the tumor microenvironment (PDGFR), and fibroblast growth factor receptor (FGFR) [2124]. As a result, patients with advanced GISTs, hepatocellular carcinoma and metastatic colorectal cancer now have more therapy choices. Regorafenib's efficacy and safety in everyday practice need be addressed, nevertheless, as patients may be slightly different from those in clinical studies [25].

In the present study, we conducted a systematic review and meta-analysis of trials to quantitatively quantify the efficacy and adverse events of regorafenib in advanced GISTs after imatinib and sunitinib failure. Our pooled data demonstrated the beneficial impact of regorafenib on survival rates of patients with advanced GISTs after imatinib and sunitinib failure. Although effectiveness data revealed substantial between-study heterogeneity, the pooled analysis of the P values was considered significant. We further conducted subgroup analysis and found that heterogeneity was reduced but persisted (data not provided in this paper). Based on the number of included studies being less than ten, no meta-regression analysis was conducted to evaluate the extent and source of heterogeneity between studies. All the AEs outcomes specific investigated in almost. Hand-foot syndrome, fatigue, hypertension, anemia, thrombocytopenia, liver damage, diarrhea, hypophosphatemia, hoarseness, oral mucositis, hypothyroidism, etc. were common AEs. The incidence of these AEs was generally greater than 30%, and the majority of them were grade1-2. According to the table, we can see that the most serious was the hand-foot syndrome, which can reach 77% for grade1-2 toxicities, and 20% for grade3-4 toxicities. Grade 1–2 hypertension can reach 53%, whereas toxicity in the grade 3–4 range can reach 16%. Other symptoms include myalgia, headache, anorexia, abdominal pain, alopecia, nausea, rash, maculopapular, etc., which were all less common and the symptoms were not serious.

Hand-foot syndrome was a frequent AE to regorafenib therapy. Its exact pathogenesis was still unclear, and it may be related to the following factors: microvascular damage [26, 27], gene polymorphism [28, 29], an inflammatory response at the junction of the epidermis and dermis [30, 31], the high concentration of sweat glands in the hands and feet [32, 33], and a variation in the distribution of tissue enzyme activity [34, 35]. According to some research, hand-foot syndrome may be associated with improved OS, with more skin responses occurring and longer survival [3638]. Regorafenib's hand-foot syndrome, in other words, was connected to the prognosis, the potential for a better curative impact increases with the severity of the skin response. The drug's effectiveness was related to the skin response, this could be connected to how regorafenib affects the blood flow to tumor blood vessels. Another common AE was hypertension. As long as they impacted intravascular growth factors, all targeted medications will affect blood pressure, while the strength of the effect varies. Decreased nitric oxide production, upregulated endothelin-1, activation of the renin-angiotensin-aldosterone pathway, and capillary rarefaction was thought to be the mechanism underlying this symptom [3941]. In addition, hypertension can also develop as a result of advanced patients increased psychological and emotional stress. Depending on the degree of hypertension and impaired liver function, the dose can be changed easily.

There were some limitations of this study. The most significant limitations of our current investigation were the small sample size of all trials and the fact that there were only three RCTs evaluating the efficacy of regorafenib. Second, due to there was only one RCT comparing regorafenib and placebo and insufficient clinically controlled studies, regorafenib and placebo were not compared. It is hoped that more research will be conducted in the future comparing regorafenib with other drugs to demonstrate the superiority of regorafenib in the treatment of advanced GISTs. Third, significant heterogeneity was observed across studies. This was primarily due to the serious bias caused by research confounding factors (such as ethnicity, duration of follow-up or participant age, study designs, analytical methods and study quality), which were included in our meta-analysis. Evidence from observational studies needs to be interpreted with caution, as these types of studies are prone to selection bias, recall bias, and inflated associations. Finally, we found that the low-quality evidence of study findings was largely attributed to the nature of the observational study designs and potential confounding biases, without adjustment for sufficient confounders. We prospect quality of evidence will improve with future updates and more high-quality studies.

Conclusion

The efficacy and adverse events of regorafenib in advanced GISTs after imatinib and sunitinib failure in the present study was similar with demonstrated in other tumors in real-world practice settings. The rate of some common AEs for regorafenib was lower in our analysis than previously reported, most likely owing to the fact that adverse events in the included studies involved a lower than the recommended daily dose of 160 mg. In addition, among grade3-4 toxicities which the incidence of hand-foot syndrome, hypertension and hypophosphatemia. We should close monitor patients to detect and manage the grade3-4 toxicities.

Declarations

Acknowledgements 

We appreciate all our authors whose names appear in this manuscript.

Author contributions 

The composition of the manuscript, its critical editing, and its final review were all contributions from all of the authors. The study's inception, design, and critical revision of the manuscript were assisted by XZ and AZ. JZ, HX and XG helped with the data processing. The study selection, data extraction, and quality evaluation were carried out by LD, XZ, and EY. The final manuscript was reviewed and approved by all writers.

Funding 

Not applicable.

Availability of data and materials

Any researcher seeking to utilize the materials detailed in the manuscript for non-commercial reasons will be allowed to do so without charge, including any pertinent raw data. If you have any questions about the data, kindly get in touch with Dr. Yin, the corresponding author.

Ethics approval and consent to participate 

Not applicable. 

Consent for publication 

Not applicable. 

Competing interest

The authors declare that they have no competing interests.

Author details

1Department of Pharmacy, Kunming Yan’an Hospital, Yan’an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China.2 Department of Scientific Research, Kunming Yan’an Hospital, Yan’an Affiliated Hospital of Kunming Medical University, Kunming 650051, Yunnan, China.3 Department of Basic Medicine, Zhaotong Health Vocational college, Zhaotong 657000, Yunnan, China.

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