Oncologist. The. Sarcomas. Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

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1 The Oncologist Sarcomas Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors TAE WON KIM, a MIN-HEE RYU, a HEUNGNAM LEE, b SUN JIN SYM, b JAE-LYUN LEE, a HEUNG MOON CHANG, a YOUNG SUK PARK, c KYUNG HEE LEE, d WON KI KANG, c DONG BOK SHIN, e YUNG-JUE BANG, f JUNG SHIN LEE, a YOON-KOO KANG a a Section of Oncology, Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; b Section of Oncology, Department of Medicine, Asan Medical Center, Seoul, Korea; c Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul, Korea; d Department of Hemato-Oncology, College of Medicine, Yeungnam University, Daegu, Korea; e Department of Internal Medicine, Gachon University of Medicine and Science Gil Hospital, Incheon, Korea; f Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Key Words. Imatinib Gastrointestinal stromal tumor KIT mutation PDGFRA mutation Korean Disclosures: Tae Won Kim: None; Min-Hee Ryu: None; Heungnam Lee: None; Sun Jin Sym: None; Jae-Lyun Lee: None; Heung Moon Chang: None; Young Suk Park: None; Kyung Hee Lee: None; Won Ki Kang: None; Dong Bok Shin: None; Yung-Jue Bang: None; Jung Shin Lee: None; Yoon-Koo Kang: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers. ABSTRACT Purpose. This study analyzed the relationship between treatment outcome and kinase mutational status in Korean patients with advanced gastrointestinal stromal tumors (GISTs). Experimental Design. Clinical data were collected from 113 consecutive patients with metastatic or unresectable GISTs treated with imatinib from June 2001 through June 2005 at five institutions in Korea. KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were examined. Results. The median patient age was 57 years (range, years). The overall response rate was 67.2%. KIT mutations were found in exon 11 (n 92, 81.4%) and exon 9 (n 10, 8.8%). One patient had a PDGFRA exon 18 mutation. The overall mutation rate was 91.2%. Response rates were 68.4%, 50.0%, and 80.0% in patients with KIT exon 11 mutations, KIT exon 9 mutations, and no kinase mutations, respectively. With a median follow-up of 49.0 months, the median progression-free survival (PFS) time was 42.0 months and median overall survival (OS) time was not reached. PFS and OS times did not differ significantly according to KIT genotype. Conclusion. This study was unable to find an association between KIT mutational status and clinical outcome of imatinib in Korean patients with advanced GISTs. There was a trend toward better outcomes for patients with wild-type KIT or exon 11 Correspondence: Yoon-Koo Kang, M.D., Section of Oncology, Department of Medicine, Asan Medical Center, Poongnap-dong, Songpa-ku, Seoul, Korea Telephone: ; Fax: ; ykkang@amc.seoul.kr Received July 25, 2008; accepted for publication March 16, 2009; first published online in The Oncologist Express on May 2, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 Kim, Ryu, Lee et al. 541 mutations compared with exon 9 mutations, although this was not statistically significant. Compared with previous studies in western populations, these results suggest that ethnic differences may influence the relationship between KIT genotype and clinical outcome to imatinib. The Oncologist 2009;14: INTRODUCTION Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI system. In most cases, GISTs are characterized by gain-of-function mutations in the KIT proto-oncogene, most commonly involving exon 11, less frequently involving exon 9, and rarely involving exons 13 or 17 [1 3]. In GISTs without KIT mutations, gain-of-function mutations may occur in the platelet-derived growth factor receptor (PDGFRA) gene, thereby providing an alternative oncogenic mechanism [4]. PDGFRA mutations have been identified in up to 7.2% of all GISTs and about 30% of KIT wild-type GISTs [4 6]. Imatinib mesylate is an oral tyrosine kinase inhibitor that has dramatically changed GIST therapy. This drug inhibits the KIT and PDGFR tyrosine kinases as well as other members of the type III group of tyrosine kinases [7]. In phase II and phase III clinical trials, imatinib produced clinical benefit in up to 85% of patients with advanced GISTs, with 4% 5% of patients achieving complete responses, 45% 67% achieving partial responses, and 18% 32% having stable disease after follow-up for 9 24 months [8 11]. Moreover, long-term follow-up of the pivotal phase II B2222 study showed that imatinib extended the median overall survival (OS) time to 57 months, which is nearly six times longer than survival in the preimatinib era [12]. Several studies have investigated the clinical and molecular factors that influence outcome in GIST patients treated with imatinib [13, 14]. Heinrich and colleagues reported that KIT and PDGFRA genotype predicted imatinib responses in metastatic GISTs, finding response rates of 84% and 48% in patients with KIT exon 11 and exon 9 mutations, respectively, but 0% in patients with wild-type KIT and PDGFRA [14]. Similarly, Debiec-Rychter and coworkers found tumor response rates of 69% in patients with KIT exon 11 mutations, 34% in those with KIT exon 9 mutations, and 25% in those with wild-type tumors [13]. In addition, patients with KIT exon 11 mutations had significantly better progression-free survival (PFS) and OS times than those with KIT exon 9 mutations or wild-type tumors [13, 14]. This study was designed to confirm and expand our knowledge about the influence of kinase mutational status on responses and outcomes to imatinib in patients with advanced GISTs. We evaluated kinase mutational status, clinical responses to imatinib, and their relationship in a cohort of consecutive Korean patients with metastatic or unresectable GISTs. MATERIALS AND METHODS Patients and Treatment The protocol for this study was approved by the institutional review board of each participating institution. Clinical data were collected from 126 patients with unresectable or metastatic GISTs who were treated with imatinib from June 2001 to June 2005 at five institutions in Korea. Paraffin-embedded tumor specimens were not available in 13 patients. Therefore, 113 patients were included in this analysis. All patients had histologic confirmation of GIST, with positive KIT expression as shown by CD117 immunohistochemical staining (A4502; DAKO, Glostrup, Denmark), and at least one measurable lesion [15]. Patients received treatment with imatinib at the standard dose of 400 mg/day, which was continued until disease progression, unacceptable toxicity, or patient refusal. Patients were re-evaluated every 8 weeks by computed tomography (CT), with tumor response determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) [15]. However, consistent with Southwest Oncology Group criteria, an increase in the sum of the longest diameters of the target lesions was not regarded as disease progression if it was accompanied by definite cystic changes suggestive of necrosis [16]. In addition, the development of new, small cystic lesions in the liver at an early stage of imatinib treatment was not regarded as disease progression [17]. Polymerase Chain Reaction and Sequencing of KIT and PDGFRA Amplification and direct DNA sequencing of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were performed according to previously described procedures [2, 14]. Patient samples negative for KIT or PDGFRA mutations were subsequently amplified with primers specific for KIT exons 8, 14, and 15 followed by direct DNA sequencing [18, 19]. Each sample was sequenced at least twice. Statistical Analyses Statistical analyses were performed using the 2 test or Fisher s exact test in cross tables and the Student s t-test

3 542 KIT Mutational Status and Efficacy of Imatinib Table 1. Clinical and pathologic characteristics of patients Characteristic Patients n 113 Age, median (range) 57 (31 82) Gender, n (%) Male 75 (66.4) Female 38 (33.6) Metastatic, n (%) 76 (67.3) Recurrent, n (%) 37 (32.7) ECOG performance status score, n (%) 0 24 (21.2) 1 82 (72.6) 2 6 (5.3) 3 1 (0.9) Primary tumor localization, n (%) Stomach 49 (43.4) Small bowel 53 (46.9) Colorectum 10 (8.9) Omentum 1 (0.9) Site of active disease, n (%) Liver 72 (63.7) Lung 3 (2.7) Peritoneum 50 (44.2) Bone 2 (2.7) Previous treatment, n (%) Operation 91 (80.5) Chemotherapy 15 (13.3) Embolization 3 (2.7) Abbreviations: ECOG, Eastern Cooperative Oncology Group. for comparison of means to assess the relationship between kinase mutational status and imatinib response. Cofactors investigated in the analysis included age, gender, performance status, primary site of disease, previous treatment, tumor size, baseline laboratory parameters, and tumor genotypes. All statistical tests were two-sided. PFS was measured from the first day of imatinib treatment to disease progression or death resulting from any cause, and OS was measured from the first day of treatment to death resulting from any cause. Survival curves were constructed according to the Kaplan Meier method, and the log-rank test was used to compare differences between the curves. Multivariate analysis was performed using Cox proportional hazards regression modeling. p.05 was considered statistically significant. Table 2. Prevalence of kinase mutations in GIST (n 113) Mutation Patients, n (%) KIT Exon (81.4) Exon 9 10 (8.8) Exon 13 0 Exon 17 0 PDGFRA Exon 12 0 Exon 18 1 (0.9) No mutation 10 (8.8) Abbreviation: GIST, gastrointestinal stromal tumor; PDGFRA, platelet-derived growth factor receptor. RESULTS Patient Characteristics The cohort of 113 patients had a median age of 57 years (range, 31 82) and included 75 males (66.4%) and 38 females (33.6%) (Table 1). The majority of patients had metastatic disease (67.3%) rather than recurrent disease (32.7%), and most (93.8%) had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. The most common primary tumor sites were the small bowel (46.9%) and stomach (43.4%), whereas the liver (63.7%) and peritoneum (44.2%) were the most common sites of metastasis. Responses to Imatinib Treatment with imatinib produced complete responses in six patients (5.3%), partial responses in 70 patients (61.9%), and stable disease in 31 patients (27.4%). The overall response rate was 67.2% (95% confidence interval [CI], 58.5% 75.9%), whereas clinical benefit was achieved in 94.5% of patients. The remaining six patients (5.3%) had disease progression on treatment with imatinib. Kinase Mutational Analysis Ninety-two patients (81.4%) had GISTs with KIT exon 11 mutations, and 10 patients (8.8%) had mutations in exon 9 of KIT (Table 2). No tumors had KIT exon 13 or 17 mutations. Of the KIT exon 11 mutations, 74 tumors had deletions of one or more amino acids, nine tumors had point mutations, five tumors had insertions, and four tumors had mixed types of mutations. All 10 tumors with KIT exon 9 mutations had duplication of amino acid residues Ala 502 Tyr 503. On further evaluation, none of the 11 tumors without KIT exon 9 or 11 mutations had mutations in KIT exon

4 Kim, Ryu, Lee et al. 543 Figure 1. Response rate according to KIT mutation status. 8, 14, or 15. However, one of these tumor specimens did have a deletion/substitution mutation in PDGFRA exon 18 (IMHDS T). Therefore, the overall mutation rate of KIT or PDGFRA was 91.2% (95% CI, 85.7% 96.7%). Kinase Mutations and Responses to Imatinib As shown in Figure 1, the response rates to imatinib were 68.4% (63 of 92) in patients with KIT exon 11 mutations, 50.0% (5 of 10) in those with KIT exon 9 mutations, and 80.0% (8 of 10) in those without kinase mutations (p.457). The lone patient with the PDGFRA exon 18 mutation had stable disease in response to imatinib. Overall, the response rate did not differ according to primary tumor site (p.111), ECOG performance status score (p.214), or any other baseline clinical characteristic, such as gender, tumor size, or clinical laboratory findings. Figure 2. Progression-free survival (A) and overall survival (B) according to KIT mutational status. Kinase Mutations and Clinical Outcome to Imatinib With a median follow-up of 47.1 months (range, months), the median PFS duration was 42.0 months (95% CI, months) and the median OS time was not yet reached. Neither the PFS (exon 11 versus exon 9 versus wild-type: median, 44.1, 24.4, and 34.0 months, respectively; p.418) nor OS (p.755) time differed significantly according to KIT mutational status (Fig. 2). Similarly, the PFS and OS times did not differ according to the type of KIT mutation (deletion versus other mutation) or codon of KIT exon 11 mutation. Sunitinib was administered to 11 patients after progression on imatinib. When survival was censored at the time of sunitinib administration, the OS data were again unrelated to KIT mutational status or type. On univariate analysis, poor performance status was significantly associated with a shorter PFS time (p.015) and OS time (p.005), whereas male gender showed a trend for adversely affecting both PFS and OS (p.052 and p.063, respectively) (Table 3). The presence of liver metastases adversely impacted PFS (p.016), whereas larger tumor size (p.003) and larger body surface area (p.037) adversely affected OS. No other baseline demographic or clinical characteristic was significantly associated with PFS or OS in the univariate analysis. On multivariate analysis, performance status was the strongest prognostic factor for PFS and OS (Table 4). The hazard ratio (95% CI) for patients with an ECOG performance status score of 2 or 3 compared with 0 or 1 was 4.77 ( ) for PFS (p.001) and 6.05 ( ) for OS (p.003). Male gender also independently predicted shorter PFS and OS times, whereas tumor size 5 cm predicted a shorter OS time. DISCUSSION The results of this study show that the type of KIT mutation is not associated with overall response, PFS, or OS in Korean patients with metastatic or unresectable GISTs treated

5 544 KIT Mutational Status and Efficacy of Imatinib Table 3. Univariate analyses of prognostic factors for progression-free survival and overall survival Progression-free survival Overall survival Factor Median HR 95% CI p-value Median HR 95% CI p-value Age (years) NR NR Gender Male NR Female NR Type of KIT mutation Exon NR 1 Exon NR Wild-type NR Tumor size (mm) NR Performance status score ECOG NR 1 ECOG Primary tumor site Stomach NR 1 Other NR Body surface area (m 2 ) NR NR Baseline hemoglobin level (mg/dl) NR NR Baseline granulocyte level (10 9 /l) , NR 1 3, NR Baseline platelet level (10 9 /l) NR NR Baseline albumin level (mg/dl) NR NR Baseline creatinine level (mg/dl) NR NR Liver metastases No NR 1 Yes NR Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NR, not reached. with imatinib. These results differ from previous studies, which showed different clinical outcomes when patients from western populations treated with imatinib were stratified by KIT genotype [13, 14]. Interestingly, those studies

6 Kim, Ryu, Lee et al. 545 Table 4. Multivariate analyses of prognostic factors for progression-free survival and overall survival Progression-free survival Overall survival Factor HR 95% CI p-value HR 95% CI p-value Gender Male 1 1 Female Type of KIT mutation Exon Exon Wild-type Tumor size (mm) Performance status ECOG ECOG Body surface area (m 2 ) Liver metastases No Yes Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio. showed that mutations in codons located in the distal part of KIT exon 11 were associated with poorer responses to imatinib [13]. However, we did not find any differences in clinical outcome according to which codon of KIT exon 11 had undergone mutation. Consistent with our findings, a small study in Taiwanese patients found that clinical outcome to imatinib did not differ according to kinase mutational status [20]. The mutation rate for KIT in 54 Taiwanese GIST patients was 90.7%, and included 40 patients with KIT exon 11 mutations and nine patients with KIT exon 9 mutations. Although response rates to imatinib tended to be higher in patients with KIT exon 11 mutations (57.5%) or no kinase mutations (60.0%) than in those with KIT exon 9 mutations (22.2%), the OS times of these three subsets did not differ. Taken together, the results of the present study and the previous study in Taiwanese patients suggest that there may be an ethnic difference between western and Asian populations in whether the type of KIT mutation is associated with clinical outcomes to imatinib. The present study should be interpreted with caution because of the small sample size. It is possible that the response rates seen in patients with KIT exon 9 mutations and in those without kinase mutations could be significantly different if additional cases were added to these cohorts (currently only 10 patients in each group). However, the demographic features, clinical characteristics, and clinical responses to imatinib in this study cohort were similar to those identified in other series of patients with advanced GISTs. The KIT mutation rate (91%) observed in this Korean cohort was relatively high. We additionally sequenced KIT exons 8, 14, and 15 in cases where KIT exon9or11 mutations were not detected. At this point, the apparent ethnic difference in the relationship between KIT genotype and clinical outcome to imatinib cannot be clearly explained. The Korean patients in the present study had a lower body weight (median, 58 kg) than western patients in other clinical studies (median, 71 kg) [21]. Debiec-Rychter and colleagues have shown that responses after crossover from 400 to 800 mg/day at disease progression occurred most often in patients with wild-type GISTs (83%) and in those with GISTs harboring a KIT exon 9 mutation (57%), and infrequently in patients with a KIT exon 11 mutation (7%) [13]. Moreover, high-dose imatinib (800 mg/day) produced a significantly longer PFS time than the standard 400-mg/day dose in patients with KIT exon 9 mutations but not in those with KIT exon 11 mutations [13, 22]. A fixed-dose schedule of imatinib (400 mg/day) was used in the current study. The 10 patients with KIT exon 9 mu-

7 546 KIT Mutational Status and Efficacy of Imatinib tations may have had better-than-expected outcomes resulting from the relatively low body weight of the Korean subjects. In other words, they would have been exposed to a higher dose on a mg/mg basis than western patients treated with the same 400- mg/day dose. European Organization for Research and Treatment of Cancer data show that high body weight correlates with lower exposure to imatinib and with higher drug clearance [23]. In patients with chronic myeloid leukemia, trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib [24]. In the current study, body surface area was significantly associated with OS in the univariate analysis, but did not maintain significance in the multivariate analysis. Kinase mutation negative patients in this Korean population had a much higher response rate than seen in two recent western studies, in which very few patients with wild-type KIT responded to imatinib [13, 14]. The higher relative dose of imatinib given to the Korean patients (using a fixed-dose strategy) could in part explain responses in these mutation-negative patients. The responses seen in Taiwanese patients are more similar to the results of the present study than to those of prior studies in western populations [13, 14, 20]. To confirm this hypothesis, a comparison of pharmacokinetic parameters between Asian and western GIST patients is needed. There was a trend toward better outcomes for patients with wild-type KIT or exon 11 mutation compared with exon 9 mutation, although this was not statistically significant. In addition to tumor genotype, other molecular markers such as vascular endothelial growth factor [25] or Bcl-2 [26] expression have been suggested to correlate with survival in GIST patients treated with imatinib. The role of these biomarkers in Korean patients compared with those from western populations also needs to be explored further. In the present study, poor performance status and male gender adversely affected both PFS and OS. These findings are consistent with previous reports [13, 27]. However, we did not find high baseline absolute neutrophil counts to be associated with outcome, unlike previous studies that showed this parameter to be associated with tumor response [23] and poor PFS and OS times [27]. The response rate (68.4%) in the present study was similar to that previously reported [8, 28]. The response rate was 54% in the initial report of the B2222 study, but it increased to 66.7% with long-term follow-up. In the present study, a cystic increase in tumor size with cystic change after imatinib was not regarded as progression. Choi et al. [29] have shown that a decreased density of responding tumors on CT is correlated with the development of tumor necrosis of cystic or myxoid degeneration. They proposed new CT response criteria; a 10% decrease in unidimensional tumor size or a 15% decrease in tumor density on contrast-enhanced CT correlated well with good response by position emission tomography and was more predictive of time to tumor progression than response by the RECIST [29, 30]. It is well known that the RECIST significantly underestimate tumor response in patients with GIST treated with imatinib. The median PFS duration in the present study (42 months) was much longer that those of western populations (18 23 months), which might also be related to underdosing in western populations and the use of different response evaluation criteria. PDGFRA mutations were observed in 0.9% of all GISTs and 9% of KIT wild-type GISTs. These figures are lower than data from previous studies [4 6]. However, this study included only CD117 GISTs, whereas other studies, including the one by Corless and colleagues [4], also evaluated CD117 tumors. Therefore, further investigation is required to clarify the frequency of PDGFRA mutations in Korean patients with GISTs. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. Although clinical benefit was observed in all major mutant types, the primary response rate was significantly higher for KIT exon 9 mutants [31]. This information has implications for optimization of the treatment of patients with GISTs. In conclusion, this study did not demonstrate that KIT genotype was associated with clinical outcome in Korean patients with advanced GISTs. Further investigation is needed to confirm our findings in a large number of patients. ACKNOWLEDGMENT This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare and Family Affairs, R.O.K. (A030001, A062254). AUTHOR CONTRIBUTIONS Conception/design: Tae Won Kim, Yoon-Koo Kang Financial support: Yoon-Koo Kang Administrative support: Tae Won Kim, Heungnam Lee, Jung Shin Lee, Yoon-Koo Kang Provision of study materials: Tae Won Kim, Min-Hee Ryu, Sun Jin Sym, Jae-Lyun Lee, Heung Moon Chang, Young Suk Park, Kyung Hee Lee, Won Ki Kang, Dong Bok Shin, Yung-Jue Bang, Jung Shin Lee, Yoon-Koo Kang Collection/assembly of data: Tae Won Kim, Min-Hee Ryu, Sun Jin Sym, Jae-Lyun Lee, Heung Moon Chang, Yoon-Koo Kang Data analysis: Tae Won Kim, Min-Hee Ryu, Sun Jin Sym, Heungnam Lee, Jae-Lyun Lee, Heung Moon Chang Manuscript writing: Tae Won Kim, Yoon-Koo Kang Final approval of manuscript: Tae Won Kim, Min-Hee Ryu, Sun Jin Sym, Heungnam Lee, Jae-Lyun Lee, Heung Moon Chang, Young Suk Park, Kyung Hee Lee, Won Ki Kang, Dong Bok Shin, Yung-Jue Bang, Jung Shin Lee, Yoon-Koo Kang Professional editorial support was provided by ProHealth. We appreciate Javerial Shahab, M.P.H., at ProHealth, for assistance in English editing and comments on the draft manuscript. The authors take full responsibility for the contents of the paper, and make it clear that there is neither compensation nor financial interests at stake for the study.

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