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Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials.

Wu L, Zhang Z, Yao H, Liu K, Wen Y, Xiong L - Drug Des Devel Ther (2014)

Bottom Line: In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19-0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63-1.08; P=0.17).Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib.Second-generation TKIs (sunitinib, nilotinib, and regorafenib) are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib or to imatinib and sunitinib.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.

ABSTRACT

Background: Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI), is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST). Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST.

Methods: Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK). Weighted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies.

Results: Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib) and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24-0.59; P<0.0001). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71-1.03; P=0.09). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19-0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63-1.08; P=0.17). Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib.

Conclusion: Second-generation TKIs (sunitinib, nilotinib, and regorafenib) are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib or to imatinib and sunitinib. Regorafenib is promising as a third-line treatment option for patients with advanced GIST.

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Related in: MedlinePlus

Forest plot of hazard ratios comparing overall survival in tyrosine kinase inhibitor treatment versus control group. Hazard ratios for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% confidence interval.Abbreviations: SE, standard error; CI, confidence interval; df, degrees of freedom.
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f3-dddt-8-2061: Forest plot of hazard ratios comparing overall survival in tyrosine kinase inhibitor treatment versus control group. Hazard ratios for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% confidence interval.Abbreviations: SE, standard error; CI, confidence interval; df, degrees of freedom.

Mentions: Heterogeneity was found across the three studies for progression-free survival (I2=81%, P=0.005), which may have resulted from differences in interventions and prestudy treatments used in the different studies. Therefore, a random model was used for meta-analysis of progression-free survival. No heterogeneity was shown for overall survival (I2=0%, P=0.92) and a fixed model was applied for analysis of overall survival. Among patients who were resistant or intolerant to imatinib, 541 received TKIs (sunitinib, nilotinib, or regorafenib) and 267 patients received placebo or best supportive care as controls. Progression-free survival was significantly improved in the TKI-treated group when compared with the control group (HR 0.38; 95% CI 0.24–0.59; P<0.0001, Figure 2). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71–1.03; P=0.09, Figure 3). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, a total of 298 received TKIs (nilotinib or regorafenib) and 149 received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.40; 95% CI 0.19–0.84; P=0.02, Figure 2). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.83; 95% CI 0.63–1.08; P=0.17, Figure 3). Discordance of the progression-free survival result was reported in the study of nilotinib.18 While blinded central radiology review showed no significant difference between the treatment group and the control group, local investigator assessment revealed that progression-free survival was significantly longer in the treatment group. Data from the local investigator assessment was used for the meta-analysis because a high discordance rate was documented for the central reviewers.


Clinical efficacy of second-generation tyrosine kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors: a meta-analysis of recent clinical trials.

Wu L, Zhang Z, Yao H, Liu K, Wen Y, Xiong L - Drug Des Devel Ther (2014)

Forest plot of hazard ratios comparing overall survival in tyrosine kinase inhibitor treatment versus control group. Hazard ratios for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% confidence interval.Abbreviations: SE, standard error; CI, confidence interval; df, degrees of freedom.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219427&req=5

f3-dddt-8-2061: Forest plot of hazard ratios comparing overall survival in tyrosine kinase inhibitor treatment versus control group. Hazard ratios for each trial are represented by the squares, and the horizontal line crossing the square represents the 95% confidence interval.Abbreviations: SE, standard error; CI, confidence interval; df, degrees of freedom.
Mentions: Heterogeneity was found across the three studies for progression-free survival (I2=81%, P=0.005), which may have resulted from differences in interventions and prestudy treatments used in the different studies. Therefore, a random model was used for meta-analysis of progression-free survival. No heterogeneity was shown for overall survival (I2=0%, P=0.92) and a fixed model was applied for analysis of overall survival. Among patients who were resistant or intolerant to imatinib, 541 received TKIs (sunitinib, nilotinib, or regorafenib) and 267 patients received placebo or best supportive care as controls. Progression-free survival was significantly improved in the TKI-treated group when compared with the control group (HR 0.38; 95% CI 0.24–0.59; P<0.0001, Figure 2). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71–1.03; P=0.09, Figure 3). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, a total of 298 received TKIs (nilotinib or regorafenib) and 149 received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.40; 95% CI 0.19–0.84; P=0.02, Figure 2). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.83; 95% CI 0.63–1.08; P=0.17, Figure 3). Discordance of the progression-free survival result was reported in the study of nilotinib.18 While blinded central radiology review showed no significant difference between the treatment group and the control group, local investigator assessment revealed that progression-free survival was significantly longer in the treatment group. Data from the local investigator assessment was used for the meta-analysis because a high discordance rate was documented for the central reviewers.

Bottom Line: In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19-0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63-1.08; P=0.17).Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib.Second-generation TKIs (sunitinib, nilotinib, and regorafenib) are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib or to imatinib and sunitinib.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.

ABSTRACT

Background: Primary and secondary resistance to imatinib, a selective receptor tyrosine kinase inhibitor (TKI), is a serious clinical problem in the control of advanced gastrointestinal stromal tumors (GIST). Here we report on a meta-analysis we performed to evaluate the efficacy of second-generation TKIs in the treatment of patients with imatinib-resistant GIST.

Methods: Randomized controlled trials evaluating the clinical efficacy of second-generation TKIs were identified by searching PubMed and EMBASE from 2000 to February 2014. Outcomes subjected to analysis were progression-free survival and overall survival. Statistical analyses were performed using Review Manager version 5.1.0 (Cochrane Collaboration, Oxford, UK). Weighted hazard ratios (HR) with 95% confidence intervals (CIs) were calculated for the outcomes. Fixed-effects or random-effects models were used, depending on the degree of heterogeneity across the selected studies.

Results: Three randomized controlled trials were selected for meta-analysis. Among imatinib-resistant or imatinib-intolerant patients, 541 received second-generation TKIs (sunitinib, nilotinib, or regorafenib) and 267 controls received placebo or best supportive care. Progression-free survival was significantly improved in the TKI-treated group (HR 0.38; 95% CI 0.24-0.59; P<0.0001). No statistically significant difference was detected in overall survival between the treatment group and the control group (HR 0.85; 95% CI 0.71-1.03; P=0.09). In the subgroup of patients who were resistant or intolerant to both imatinib and sunitinib, TKI therapy (nilotinib or regorafenib) improved progression-free survival (HR 0.40; 95% CI 0.19-0.84; P=0.02) but not overall survival (HR 0.83; 95% CI 0.63-1.08; P=0.17). Regorafenib was shown to be effective in terms of progression-free survival across different subpopulations of patients who were resistant to both imatinib and sunitinib.

Conclusion: Second-generation TKIs (sunitinib, nilotinib, and regorafenib) are effective in improving progression-free survival but not overall survival in patients with GIST who are resistant or intolerant to imatinib or to imatinib and sunitinib. Regorafenib is promising as a third-line treatment option for patients with advanced GIST.

Show MeSH
Related in: MedlinePlus