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


CONCLUSIONS
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.
Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
Lile
L
Wu
Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
Zhongqiang
Z
Zhang
Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
Hongliang
H
Yao
Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
Kuijie
K
Liu
Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
Yu
Y
Wen
Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
Li
L
Xiong
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000077210:Sunitinib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C559147:regorafenib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000077210:Sunitinib
gastrointestinal stromal tumor; imatinib; nilotinib; regorafenib; tyrosine kinase inhibitor