Japanese Journal of Clinical Oncology Advance Access published online on December 3, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn134
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© The Author (2008). Published by Oxford University Press. All rights reserved
Dose Escalation of Imatinib After Failure of Standard Dose in Korean Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumor
Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
For reprints and all correspondence: Yoon-Koo Kang, Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-2dong, Songpa-gu, Seoul 138-736, Republic of Korea. E-mail: ykkang{at}amc.seoul.kr
Received August 7, 2008; accepted October 26, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Objective: We evaluated the results of imatinib dose escalation in patients with advanced gastrointestinal stromal tumors (GISTs) after disease progression on standard-dose imatinib.
Methods: Clinical data from patients with metastatic or unresectable GISTs whose dose of imatinib was increased after disease progression on imatinib 400 mg/day were retrospectively reviewed.
Results: The 24 patients studied had a median age of 52 years. Imatinib dosing was escalated to 600 mg/day in 12 patients, then to 800 mg/day in four patients. The other 12 patients had dose escalation directly to 800 mg/day. Two patients (8.3%) achieved a partial response, and seven (29.2%) had stable disease. Six-month progression-free and overall survival rates were 33.3 and 70.7%, respectively. Dose escalation to 600 or 800 mg/day was generally well tolerated.
Conclusion: Imatinib dose escalation is feasible and well tolerated in patients with advanced GIST who progress on standard-dose therapy, producing clinical benefit in 
37% of patients.
Key Words: imatinib • gastrointestinal stromal tumor • resistance
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Gastrointestinal stromal tumors (GISTs)—the most common mesenchymal tumor of the gastrointestinal system—are thought to originate from the interstitial cells of Cajal (1). Activating mutations of KIT and PDGFRA have been described in
85 and 5% of human GISTs, respectively. These mutated genes encode receptor proteins with constitutively activated tyrosine kinase activity and are thought to have a pivotal role in the pathogenesis of GIST (2–5). The introduction of imatinib, a selective KIT and platelet-derived growth factor receptor alpha (PDGFR
) tyrosine kinase inhibitor (6), has greatly improved outcomes of patients with advanced GIST. As a result, imatinib is now recognized as standard first-line treatment of unresectable or metastatic GIST (7). In clinical studies, imatinib administered orally at the standard dose of 400 mg/day produced objective response rates ranging from 48 to 63% in patients with advanced GIST, and stable disease in an additional 27–37% (8–12). Long-term follow-up of the pivotal B2222 study showed that imatinib extended median survival to 57 months compared with historical values of 15 months in the pre-imatinib era (13). Previously, we also observed that standard-dose imatinib produces a high disease control rate of 81% and prolongs survival in Korean patients with advanced GIST (14).
Despite the ability of imatinib to control disease for prolonged periods, 50% of patients develop secondary resistance to standard-dose imatinib after a median of 2 years of treatment (12). In addition, 5% of patients show primary resistance to imatinib (9). Local treatment modalities, such as tumor excision or radiofrequency ablation, can be used for focal disease progression, but for generalized progression, a systemic intervention is needed to overcome imatinib resistance (9,11,12,15,16). Before the introduction of sunitinib, imatinib dose escalation was the only systemic treatment strategy for overcoming drug resistance to standard-dose imatinib. In two international Phase 3 studies, patients initially randomized to receive imatinib 400 mg/day were allowed to cross over to 800 mg/day upon disease progression (11,15). In the European Organization for Research and Treatment of Cancer (EORTC) 62005 study, 133 of 247 patients with progressive disease on standard-dose imatinib crossed over to imatinib 800 mg/day (12,15). Dose escalation produced partial responses in 2.3% of patients and stable disease in an additional 27%. Similar results were observed in the US S0033 study, in which 84 of 164 patients with progressive disease on the 400-mg/day dose crossed over to 800 mg/day (11). In this study, imatinib dose escalation produced partial responses and stable disease in 7 and 29% of patients, respectively. Median progression-free survival (PFS) in EORTC 62005 and S0033 was 81 days and 4 months, respectively.
We have also adopted imatinib dose escalation as the first-line salvage treatment for patients with advanced GIST that progresses on standard-dose imatinib. So far, clinical studies on dose escalation of imatinib have not been conducted in Korean patients with GIST. Here, we report the efficacy and safety of imatinib dose escalation after failure with standard-dose imatinib in Korean patients with advanced GIST. Because therapeutic outcomes of both standard-dose and high-dose imatinib are known to depend on the type of KIT or PDGFRA mutations (10,17,18), we also analyzed the mutational status of tumors in these patients.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients and Treatment
Clinical data from 116 patients with metastatic or unresectable GISTs who started standard-dose imatinib therapy at Asan Medical Center, Seoul, Korea, during the period between June 2001 and June 2006 were reviewed. Patients meeting the following criteria were identified: age
15 years, a histologically documented diagnosis of metastatic or unresectable GIST, KIT-positive tumors by DAKO antibody staining at a 1:400 dilution (Dako, Glostrup, Denmark), at least one evaluable disease site according to Response Evaluation Criteria for Solid Tumors (RECIST) (19), and dose escalation of imatinib to 600 or 800 mg/day in response to disease progression during treatment with imatinib 400 mg/day. A total of 24 patients met these inclusion criteria and were included in the analysis of the efficacy and toxicity of imatinib dose escalation. The data cutoff date for this analysis was 11 April 2007.
Toxicity and Response Evaluation
Patient evaluation included medical history, physical examination, hematology (including differential blood counts), serum chemistry (including hepatic and renal function tests), chest X-ray and computed tomography of the abdomen and pelvis. Positron emission tomography or a bone scan was performed if needed. Hematologic and non-hematologic toxicities were evaluated according to National Cancer Institute Common Toxicity Criteria version 3.0. The response evaluation was performed according to RECIST every 2–3 months. However, definite cystic changes of the tumor were not regarded as evidence of disease progression, even in cases when the tumor increased in size.
Mutation Analyses of KIT and PDGFRA
If available, formalin-fixed, paraffin-embedded tumor specimens were collected for mutational analyses of the KIT and PDGFRA genes. Genomic DNA was extracted from each tumor sample using a DEXPAT kit (TaKaRa, Kyoto, Japan). Only samples containing >80% of tumor cells were used for DNA extraction. Initially, polymerase chain reaction amplification and mutational analyses of KIT exon 11 were performed according to described methods (20). Patient samples negative for KIT exon 11 mutations were subsequently amplified with primers specific for KIT exons 9, 13 and 17, followed by direct sequencing. When KIT mutations were not identified, additional mutational analyses were conducted for exons 12 and 18 of the PDGFRA gene (21). Each sample was sequenced at least twice.
Survival and Statistical Analysis
A chi-square and Fisher’s exact tests were used to evaluate the relationship between categorical variables. The 95% confidence interval (CI) of the overall response and disease control rates was determined by the calculation formula of CI for proportion. PFS was measured from the first day of imatinib treatment at an escalated dose (i.e. 600 or 800 mg/day) until disease progression or death from any cause. Overall survival (OS) was measured from the first day of treatment at the escalated dose until death from any cause. Survival curves were constructed according to the Kaplan–Meier method, and the log-rank test was used to compare differences between curves. The Statistical Package for the Social Sciences, version 12.0 (SPSS, Chicago, IL, USA) was used for all statistical analyses, with a two-sided P < 0.05 considered statistically significant.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The median age of the 24 patients included in this analysis was 52 years (range, 31–73 years) (Table 1). Most patients were male (75%) and had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (91.7%). The most common primary tumor sites were small bowel (62.5%) and stomach (20.8%). At the time of imatinib dose escalation, the most common metastatic sites were liver (83.3%), peritoneum (62.5%) and retroperitoneum (20.8%). Initial treatment with standard-dose imatinib produced partial responses in nine patients (37.5%) and stable disease in eight patients (33.3%). The other seven patients (29.2%) had progressive disease in response to initial imatinib therapy. The median time to disease progression on standard-dose imatinib was 12.6 months (range, 0.9–50.9 months), with eight patients progressing within 6 months of starting standard-dose imatinib.
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Twenty patients had paraffin-embedded tissues obtained before imatinib treatment, which were available for mutational analyses. Of these, 11 patients (55%) had mutations in KIT exon 11, and four patients (20%) had mutations in KIT exon 9. The remaining five patients (25%) had primary tumors without mutations in the KIT or PDGFRA genes. Of the 11 KIT exon 11 mutations, nine were deletions, one was a deletion plus missense mutation and one was an insertion mutation. All of the KIT exon 9 mutations were duplications of codons 502–503.
The dose of imatinib was escalated after disease progression in patients receiving the standard 400-mg/day dose. The dose was increased to 600 mg/day in 12 patients (50%) and to 800 mg/day in the other 12 patients (50%). Following imatinib dose escalation, two patients (8.3%; 95% CI, 0–20.3) achieved partial responses, and seven (29.2%) had stable disease. Taken together, the disease control rate was 37.5% (95% CI, 16.6–58.4). The time to response in the two patients with partial responses was 2.6 and 3.7 months. The remaining 15 patients (62.5%) showed disease progression after dose escalation.
Among the 12 patients whose imatinib dose was escalated to 600 mg/day, one patient died of a cause unrelated to the malignancy or to imatinib treatment, and the remaining 11 eventually had disease progression after a median of 1.7 months (range, 0.7–24.9 months). Four patients received further imatinib dose escalation to 800 mg/day. Of these, the two patients who had stable disease on 600 mg/day experienced disease control with 800 mg/day, and the two patients who had disease progression on 600 mg/day also had disease progression within a short time at the higher dose.
KIT mutational status was the only baseline characteristic that was associated with disease control following imatinib dose escalation. Patients with KIT exon 9 mutations (100%) had a significantly higher disease control rate after dose escalation than patients with KIT exon 11 mutations (27.3%) or wild-type KIT (20%) (P = 0.023; Table 2). In contrast, patient age, sex and performance status; primary and metastatic sites of disease; prior response and time to progression on standard-dose imatinib; and initial escalated dose of imatinib (600 versus 800 mg/day) were not significantly associated with the disease control rate.
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With a median follow-up of 8.0 months (range, 1.4–22.3 months), the 6-month and 1-year PFS rates following imatinib dose escalation were 33.3 and 17.8%, respectively, and the 6-month and 1-year OS rates were 70.7 and 48.5%, respectively (Fig. 1). Patients with a partial response or stable disease on dose escalation had significantly longer PFS than those with progressive disease. Median PFS of patients with partial response or stable disease was 9.97 months, and median PFS of patients with progressive disease was 1.25 months. Although not statistically significant, OS also tended to be longer in patients with partial response or stable disease. Median OS of patients with partial response or stable disease was 22.27 months, and median OS of patients with progressive disease was 6.711 months. Consistent with the higher rate of disease control, patients with KIT exon 9 mutations tended to have longer PFS after imatinib dose escalation than those with KIT exon 11 mutation or wild-type KIT. Median PFS of patients with exon 9 mutation, exon 11 mutation, or wild-type were 9.97, 2.138 or 1.184 months. No other correlations were observed between baseline characteristics and either PFS or OS.
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Hematologic and non-hematologic toxicities are summarized in Tables 3 and 4, respectively. Dose escalation of imatinib was generally well tolerated, with most adverse events rated Grade 1 or 2 in severity. Most patients (87.5%) experienced anemia, although only six patients (25%) had Grade 3/4 anemia. Other Grade 3 hematologic toxicity consisted of one case each of leukopenia, granulocytopenia and thrombocytopenia. No patient experienced febrile neutropenia. Fatigue and edema (91.7% each) were the most common non-hematologic toxicities, but Grade 3 events were confined to fatigue (8.3%), hyperbilirubinemia (8.3%), nausea (4.2%) and vomiting (4.2%).
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In five patients (41.7%) whose imatinib dose was initially escalated to 600 mg/day, the dose of imatinib was reduced to 300–400 mg/day, and in four patients (33.3%) whose dose was initially increased to 800 mg/day, the dose was reduced to 400–600 mg/day. The reasons for dose reduction included fatigue (n = 4), severe anemia (n = 2) and nausea and vomiting (n = 3). However, further dose reduction or discontinuation of imatinib was not required in any patient owing to adverse events. No statistically significant differences in disease control rate, PFS and OS were seen between patients with and without dose reduction due to adverse events.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The results of this analysis show that, of patients with advanced GISTs that progress on standard-dose imatinib, approximately one-third achieve clinical benefit after the imatinib dose is increased to 600 or 800 mg/day. In turn, patients with clinical benefit—either partial response or stable disease—on the higher dose have longer PFS than those with only progressive disease following dose escalation. These findings are consistent with those observed previously in the pivotal Phase 2 B2222 trial and in two large international Phase 3 studies (9,11,12).
The introduction of imatinib has dramatically improved the prognosis of patients with advanced GISTs. Nevertheless, the survival curve does not plateau, suggesting that all patients eventually develop progressive disease. In the B2222 study, long-term treatment with imatinib extended median survival to 57 months, which is nearly four times longer than historic values from the pre-imatinib era (13). Similarly, in the Phase 3 EORTC 62005 study, with a median follow-up of 33 months, the median PFS and OS were 24 and 43 months, respectively (12). These data indicate that, even though imatinib extends survival, up to 50% of patients with advanced GISTs may develop resistance to imatinib within 2 years.
Several mechanisms may cause imatinib resistance, including: (1) new KIT or PDGFRA mutations that reduce the tyrosine kinase binding affinity of imatinib; (2) overexpression of the KIT protein, leading to increased tyrosine kinase activity in the presence of imatinib; (3) activation of alternative signaling pathways, making tumor growth independent of either KIT or PDGFR signaling; (4) altered pharmacokinetics, leading to increased imatinib clearance and lower plasma drug levels; and (5) expression of P-glycoprotein, leading to reduced uptake of imatinib by tumor cells (22–24). Dose escalation of imatinib is a viable strategy for overcoming drug resistance, particularly when it is caused by certain secondary KIT or PDGFRA mutations, overexpression of KIT, pharmacokinetic alterations, and expression of P-glycoprotein. In each of these situations, the higher dose restores imatinib drug concentrations to effective levels for inhibiting the KIT or PDGFR tyrosine kinase. In the EORTC 62005 study, for example, patients with GISTs expressing KIT exon 9 mutations had significantly better disease control rates and PFS when treated initially with imatinib 800 mg/day rather than 400 mg/day (10). Moreover, following disease progression on standard-dose imatinib, patients with KIT exon 9 mutation were more likely to respond to imatinib dose escalation than were those with other mutations or wild-type tumors. Consistent with these findings and despite the small sample size in our series, our patients with KIT exon 9 mutations also showed higher disease control rates and a trend towards longer PFS after dose escalation compared with patients with KIT exon 11 mutations or wild-type KIT.
In this retrospective analysis, the dose of imatinib was escalated to 600 or 800 mg/day at the discretion of the treating physician. Treatment outcomes did not differ between the two dose levels. So far, clinical studies have not compared the 600 and 800-mg/day dose levels either as initial treatment of advanced GIST or as dose escalation following progression at the standard 400-mg/day dose. The results following crossover to 600 mg/day in the B2222 study seem to be similar to those following crossover to 800 mg/day in the two Phase 3 studies (9,11,12). Because Korean patients tend to have a lower body weight and smaller body surface area compared with Western patients, in this population, initial dose escalation to 600 mg/day may be suitable for increasing drug exposure to overcome imatinib resistance resulting from KIT exon 9 mutation or pharmacokinetic alterations. Pharmacokinetic studies in Korean patients are needed to confirm this expectation.
In addition to dose escalation of imatinib, several new chemotherapeutic agents are available or under development for overcoming imatinib resistance (25). These include the tyrosine kinase inhibitors sunitinib and nilotinib, the molecular target of rapamycin (mTOR) inhibitor everolimus and the multiple kinase inhibitor sorafenib. Of these, sunitinib is currently the only drug approved in the USA and Europe for treating patients with GIST whose disease has progressed or who are intolerant to imatinib therapy (26). However, it remains to be determined whether imatinib dose escalation, switching to sunitinib or an experimental agent is the best strategy for treating patients who become resistant to standard-dose imatinib. To address this issue, a Phase 3 study comparing imatinib dose escalation with sunitinib is now under way in patients with advanced GISTs that progress on standard-dose imatinib. The results of this ongoing study should provide a better understanding of which approach to first-line salvage treatment is best in which types of patients. On the basis of available evidence, imatinib dose escalation is a generally accepted salvage strategy, particularly for patients with KIT exon 9 mutations. Dose escalation may be preferred to sunitinib, because imatinib is associated with less toxicity than sunitinib, and moreover, sunitinib can still be used in second-line salvage treatment if disease progresses following imatinib dose escalation (27).
In our series, imatinib dose escalation to 600 and 800 mg/day was generally well tolerated. The most common toxicities were anemia, fatigue, edema and a variety of gastrointestinal adverse events and were generally confined to Grade 1 or 2 in severity. However, compared with the high-dose arms of the B2222 and EORTC 62005 studies (9,12), our patients tended to have higher rates of anemia, thrombocytopenia and fatigue: any grade anemia, 88 versus 12–98%; Grade 3/4 anemia, 25 versus 3–17%; any grade thrombocytopenia, 29 versus 13%; Grade 3/4 thrombocytopenia, 4 versus 1%; and any grade fatigue, 92 versus 39–79%. In general, adverse events with salvage imatinib dose escalation are less severe than those with initial high-dose imatinib, presumably because imatinib clearance increases with prolonged treatment (22). However, the incidence and severity of anemia and fatigue observed in this study are consistent with the observations of Zalcberg et al. (15), who found higher rates of severe anemia and fatigue after dose escalation than on initial treatment. In addition, edema and gastrointestinal discomfort were also commonly observed with high-dose imatinib in our patients. Accordingly, the rate of dose reduction in our series (37.5%) was higher than that in the cohort evaluated by Zalcberg et al. (17%).
The present study is limited by its retrospective design and small sample size. However, the study cohort of 24 patients was identified from a total pool of 116 patients, which is not really small when one considers the low prevalence of GIST in the Korean population. Accordingly, the study cohort is likely representative of Korean patients with advanced GIST. In conclusion, imatinib dose escalation is well tolerated and produces clinical benefit in about one-third of Korean patients with GISTs that progress on standard-dose imatinib.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Yoon-Koo Kang is a consultant for Novartis, and has honorarium from Novartis.
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Footnotes |
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I.P. and M.-H.R. contributed equally to this work as co-first authors. 
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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