Sunitinib in Advanced Gastrointestinal Stromal Tumors: A Systematic Review of Real-World and Randomized Controlled Trials

  

    
  
      
Study
    
  
      
Number of Cases
    
Median PFS (months)
    
Median OS

      (Months)
    
Complete Response/

      Sample size
    
Partial Response/ Sample size
    
Incidence of Grade 
      

        

          


            = 3 ADRs
        
      
  
  

    
Demetri,2009 (17)
    
97
    
7.8
    
19 
    
0/97
    
Jul-97
    
82/570
  
  

    
Heinrich, M,2008 (18)
    
Exon 9 mutation
    
19
    
19.4
    
26.9
    
0/19
    
19-Jul
    
  
  
  

    
Shiaro,2010 (16)
    
Exon 11 mutation
    
44
    
5.1
    
12.3
    
0/44
    
Feb-44
    
NR
  
  

    
George,2009 (9)
    
Wildtype-genotype
    
9
    
19
    
30.5
    
NR
    
NR 
    
      
  
  

    
Lilshen,2017 (22)
    
36
    
6.6
    
Not reached 
    
0/36
    
13/36
    
62/381
  
  

    
LiJ,2012 (21)
    
60
    
7.93
    
24.97
    
0/60
    
Aug-60
    
62/381
  
  

    
Yoon,2012 (24)
    
59
    
10.8
    
26
    
0/59
    
Nov-59
    
40/58
  
  

    
Chen, YY,2011 (23)
    
55
    
8.16
    
Not reached 
    
0/55
    
Jun-55
    
7/128
  
  

    
Matsumoto,2011 (20)
    
88
    
NR
    
17.6
    
0/88
    
Sep-88
    
200/743
  
  

    
Komatsu,2015 (19)
    
23
    
8.4
    
14.1
    
23-Feb
    
23-Apr
    
14/145
  
  

    
Sahu,2015 (27)
    
18
    
NR
    
NA
    
0/18
    
18-Jan
    
16/140
  
  

    
Rutkowski,2018 (26)
    
470
    
5.22
    
5.6
    
2/470
    
75/470
    
329/447
  
  

    
Reichardt,2015 (28)
    
15
    
15.5
    
18.7
    
0/15
    
15-Apr
    
12-Dec
  
  

    
Reichardt,2016 (29)
  
  

    
Prior, J,2009 (15)
    
232
    
10.3
    
22.9
    
NR
    
NR
    
53/433
  
  

    
Zhang,2021 (35)
    
1124
    
8.3
    
16.6
    
NR
    
NR
    
197/516
  
  

    
Demetri,2009 (17)
    
23
    
6.2
    
14
    
NR
    
NR
    
NR
  
  

    
Heinrich, M,2008 (18)
    
45
    
8
    
33
    
Jul-45
    
Apr-45
    
36/45
  
  

    
PFS: Progression-Free    Survival, OS: Overall Survival, ORR: Objective Response Rate, Adrs: Adverse    Drug Reactions, NR: Not Reported. 
  

Table 5 off 1: Laboratory values at hospital admission.

The efficacy of CDD was evaluated in a phase II open-label nonrandomized clinical trial conducted by Demetri et al. as well (2009) [9], revealing an ORR of 13.3%, a median PFS of 7.9 months, and a median OS of 25 months. Table 5

These two regimens were compared in a subgroup analysis by Reichardt (2015) [28,29], with the median PFS for the IDR groups at 5.2 months versus 12.7 months for the CDD. Correspondingly, median OS values were 11.1 months versus 23.5 months, respectively.

Also, sunitinib was compared with dose-escalated imatinib after progression on first line imatinib in studies by Yang (2018) and Huang (2023). Huang (2023) showed a median PFS of 12 months for the sunitinib group compared to 5 months for the imatinib group. Sunitinib significantly reduced the hazard of tumor progression with an HR of 0.348 (95% CI: 0.251-0.482, p-value==<0.001) [34]. However, there was less difference in the median OS, which was 25 months for the sunitinib group versus 21.5 months for the doseescalated imatinib group. On the other hand, Yang (2018) reported equal median PFS of 4 months for both regimens and a median OS of 19 months for the imatinib escalation group compared to 9 months for the sunitinib group [33].

Recently, the IDR and CDD were compared in a double-armed observational study by Saski (2023) [25] where 41 patients were retrospectively analyzed, with 21 patients assigned to the IDR and 20 patients to the CCD regimen. The ORR was 19% in the IDR arm and 30% in the CDD group. Median PFS durations were 1.4 months for IDR and 4 months for CCD. Despite differences in ORR and median PFS, the discrepancy in median OS was slight, with values of 13.4 months and 13.7 months, respectively (Table 5).

Patients with exon 9 mutations exhibited a superior response to Sunitinib, as demonstrated by Heinrich in 2008 [18]. This cohort showed an ORR of 37%, with a median PFS of 19.4 months and a median OS of 26.9 months, compared to 5.1 months and 12.3 months, respectively, in patients with exon 11 mutations. These results are consistent with a subgroup analysis conducted by Reichardt in 2015 [28,29], which revealed a median PFS of 12.3 months and a median OS of 26.3 months among patients with KIT exon 9 mutations and a median PFS of 7 months and a median OS of 16.3 months in patients with exon 11 mutations.

Rutkowski (2018) [26] aimed to analyze treatment outcomes in older patients. The median PFS for patients aged <70 and those aged >70 (10.3 vs. 9.7 months, respectively), and the median OS was (22.9 vs. 21.5 months, respectively).

In single-armed observational studies conducted in Asian countries, varied results were demonstrated. ORR ranged from 10.2% to 36.1%, with median PFS ranging from 5.22 to 10.8 months, and median OS ranging from 5.6 to 26 months (Table 5).

Safety

When the IDR was contrasted with placebo (Demetri, 2012) [8] the predominant hematological ADRs of grade 3 and above were thrombocytopenia (4%), neutropenia (12%), lymphocytopenia (12%), anemia (11%), and leukopenia (3%). The most common severe (grade 3 or 4) non-hematological adverse events associated with treatment included fatigue (10%), hypertension (8%), and hand-foot syndrome, asthenia, and diarrhea (5% each) [8,9].

A comparison of hematological ADRs revealed a higher incidence with CDD compared to IDR specifically, thrombocytopenia occurred in 4% of patients on CDD versus 3% on intermittent dosing, lymphocytopenia in 12% versus 25%, neutropenia in 12% versus 13%, leukopenia in 3% versus 12%, and anemia in 5% versus 7%, respectively.

Additionally, two observational studies; (Saski, 2023) [28] and (Li, J, 2012) [21] investigated the incidence of ADRs in patients receiving IDR and CDD reported different results. IDR group had a higher incidence of thrombocytopenia compared to CDD (24.5% vs. 12.8%). Rates of neutropenia were similar between the groups (26.3% vs. 25.6%). Anemia was reported in 10.5% of patients with IDR versus 7.7% with CDD. Hand-foot syndrome incidences were comparable (5.2% vs. 5.12%), while diarrhea was more prevalent in the IDR group (3.5% vs. 0%).

In single-arm observational studies, ADRs of grade 3 or higher were commonly reported regardless of the dosage administered. Hematological adverse effects were notably common, with thrombocytopenia being the most prevalent, followed by neutropenia and anemia. Leukopenia was also observed. Additionally, handfoot syndrome, hypertension, fatigue, and diarrhea were reported. Changes in complete blood count parameters and abnormal liver function tests were noted in some patients. Hypothyroidism and increased lipase levels or pancreatitis were also reported in a smaller proportion of cases.

Table 5 illustrates the efficacy/effectiveness and safety data from RCTs and comparative observational studies and Table 5 presents the efficacy/effectiveness and safety data of single armed studies.

Discussion

Our systematic review results showed that since Sunitinib's FDA approval for the treatment of GISTs in June 2006 [30], only one RCT, led by Demetri, has been conducted [7,8]. However, our review found increased interest in generating real word evidence using observational study designs.

In the sole multinational RCT, Sunitinib (50mg/day for four weeks with a two-week break) was compared with a placebo. The Sunitinib group had a higher confirmed ORR (7% vs 0%). Demetri et al. showed Sunitinib prolonged PFS to 5.32 months versus 1.5 months with placebo. Additionally, Sunitinib nearly doubled the median OS (16.9 months vs 9.6 months) and halved the risk of death compared to placebo [7,8].

A CDD administration of Sunitinib at a dosage of 37.5 mg/ day was explored as an alternative to the standard IDR in a phase II clinical trial [9]. Results revealed an ORR of 13.3%, along with a median PFS of 7.9 months and a median OS of 25 months. Despite these promising findings, further investigation of this regimen was not pursued beyond this phase II clinical trial, thereby relegating it to off-label use [9].

Direct comparison between these two regimens in an observational study conducted by Saski [23] revealed higher ORR in the IDR arm compared to the CDD (30% vs 19%), and a notable difference in median PFS with the IDR arm showing a PFS of 1.4 months compared to 4 months in the CDD. However, the median OS was quite similar between the two arms, with 13.4 months in the 50mg/day arm and 13.7 months in the 37.5mg/day arm [23]. CDD appears to offer no efficacy or safety advantage [23].

Building upon the findings of the clinical trials, our systematic review delved into single-armed observational studies, further illuminating sunitinib's performance across a diverse array of patient populations. Our research uncovered eleven single-armed observational studies, with seven focusing on Asian populations, including Japanese, [16,19,20] Korean, [23] Taiwanese, [23] and Chinese [21,22] populations. Other studies were conducted in India, [27] Poland, [26] and across multiple countries [15,17,18,28,29]. These studies unveiled median PFS durations ranging from 5.1 to 19.4 months, median OS durations spanning from 5.6 to 27 months, and ORR ranging between 6% and 36%.

Overall, efficacy measures in these studies were of high diversity, non-randomized studies showed higher median PFS and median OS, probably due to confounding factors, such as ethnicity, while certain studies involving Asian populations suggested better efficacy outcomes compared to Western populations, Asians and specifically Japanese patients appear to be more sensitive to sunitinib, resulting in higher incidence of grade 3-5 ADRs [16,19,20]. In general, Sunitinib presents a manageable toxicity profile, which can often be addressed by dosage adjustments, supportive measures, or temporary pauses in treatment [7,8]. Lowering the dose below the standard 50-mg 4/2 dosing schedule notably reduces the incidence of AEs, with discontinuation being contemplated for more severe cases [7,8].

Another confounding factor might be considered is tumor genotype. The results also demonstrated that patients with primary KIT exon 9 mutations or a wild-type genotype achieved an ORR, median PFS and median OS are considerably higher compared to those with exon 11 mutations [18].

Considering escalated imatinib dose as a comparator for sunitinib remains controversial. While direct head-to-head RCTs comparing these interventions are lacking, comparative observational studies and systematic reviews suggest that patients with wild-type KIT and exon 9 mutations are more likely to respond to escalated doses of imatinib compared to those with exon 11 mutations [30,31,32].

Results of this systematic review align with what is followed in guidelines [6], as regarding Imatinib dosing, patients with Imatinibsensitive tumors typically commence treatment at a daily dosage of 400mg. In cases where secondary resistance to Imatinib occurs, dose escalation to a daily dosage of 800mg may be considered. However, for patients encountering primary or early resistance, switching to an alternative therapeutic agent becomes necessary [6]. Those with exon 9 mutations typically initiate therapy at the maximum daily dose of 800mg, with a transition to an alternative treatment regimen required upon disease progression [6,30].

This aligns with the understanding that Sunitinib is typically viewed as a second-line agent following both standard and high doses of Imatinib [6]. However, there's a growing recognition in clinical practice of the potential for mutational status to guide the customization of a patient's initial Imatinib dose [30]. HTA agencies relied on the RCT for economic evaluation, which served as the basis for recommendations from the National Institute for Health and Care Excellence (NICE) and the Canadian Agency for Drugs and Technologies in Health (CADTH). According to this trial, about 22% of patients completed the treatment after disease progression [7,8]. It was possible that patients receiving sunitinib post-progression experienced additional benefits, and some may have had tumor flares on sudden withdrawal of sunitinib [36]. For the economic evaluation, NICE included treatment costs beyond disease progression, and the treatment met the criteria for being a life-extending, end-of-life treatment, making it cost-effective [36]. CADTH's report resulted in a higher incremental cost-effectiveness ratio (ICER), primarily due to the greater acquisition cost of sunitinib and the calculation of effects only until disease progression [37].

To our knowledge, this systematic review is the first to incorporate data from both RCTs and real-world data (RWD). By addressing this gap in the literature, we aim to assess the suitability of the target population for this intervention and evaluate its efficacy and safety for resource allocation decisions. Integrating data from both RCTs and RWD ensures a more comprehensive understanding of the benefits and risks of the intervention, aiming to provide a more thorough HTA report.

However, the limitations and challenges of this systematic review include the exclusion of non-English studies, which may result in missing relevant data, and the reliance on published studies only, potentially overestimating sunitinib's effectiveness and safety. Interpreting the findings within the broader clinical context requires careful consideration of potential biases and challenges present in the included studies.

Additionally, the small number of RCTs assessing the efficacy of Sunitinib and the reliance on non-randomized, observational data poses limitations to our systematic review. These studies are susceptible to heterogeneity and various biases, such as confounding, and are often characterized by small sample sizes. Ideally, enhancing the existing evidence base with new RCTs and comparative observational trials would be advantageous. However, the feasibility of conducting such trials may be hindered by the nature of the disease and its low incidence rates.

Conclusion

In conclusion, the findings from the double-blind RCT emphasize sunitinib's effectiveness, evidenced by a notable improvement in time to tumor progression, which was four times longer with sunitinib compared to placebo. Additionally, the median PFS and OS demonstrated notable results. The treatment exhibited good tolerability with an acceptable safety profile, indicating the potential suitability of sunitinib for our population. This was supported by realworld evidence from observational studies across diverse populations. However, addressing existing uncertainties and providing a more definitive basis for decision-making requires conducting more randomized trials, which is crucial for better consideration in resource allocation decisions. At our institution, there is currently no available choice for patients with GIST who have developed progression on imatinib or were unable to tolerate it.

Acknowledgements

The authors thank the Center of Drug Policy and Technology Assessment (CDPTA) at King Hussein Cancer Center for their support in conducting this review. We also extend our gratitude to our colleagues for their valuable input and assistance throughout the research process.

Authors' Contributions

Tala Asha designed the study, developed the search strategy, and conducted the literature search, screening, and data extraction. Khader Al-Habash screened the studies, performed data extraction, and contributed to the analysis. Dr. Abeer A. Al-Rabaiah resolved disagreements, ensured the review's integrity, and supervised the process. All authors contributed to drafting and revising the manuscript. All authors have read and approved the final manuscript.

Use of Artificial Intelligence Tools

ChatGPT was used to assist in reviewing the grammer and the clarity of sentences and all content was reviewed and edited after its use.

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