Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

BACKGROUND: Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. METHODS: This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ(2) test) in the same molecular subgroups. RESULTS: Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment. CONCLUSIONS: This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status. TRIAL REGISTRATION: NCT01459757.

Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib.

BACKGROUND: The objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. (ClinicalTrials.gov identifier NCT00094029). METHODS: Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule of 50 mg daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment). Tumor assessment frequency was according to local practice, and response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post hoc analyses evaluated different patterns of treatment management. RESULTS: At final data cutoff, 1124 patients comprised the intent-to-treat population, and 15% of these patients had a baseline Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 7.0 months. The median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0-9.4 months), the median OS was 16.6 months (95% CI, 14.9-18.0 months), and 36% of patients were alive at the time of analysis. Patients for whom the initial dosing schedule was modified exhibited longer median OS (23.5 months) than those who were treated strictly according to the initial dosing schedule (11.1 months). The most common treatment-related grade 3 and 4 adverse events were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related adverse events associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each. CONCLUSIONS: This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure.

Results of a phase II trial of S-1 as first-line treatment of metastatic pancreatic cancer (CESAR-study group).

PURPOSE: S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. METHODS: Chemotherapy-naïve patients received S-1 orally at 30 mg/m(2) twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon's two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. RESULTS: Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. CONCLUSIONS: Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.

Docetaxel and gemcitabine in the treatment of soft tissue sarcoma - a single-center experience.

INTRODUCTION: Advanced stage/metastatic soft tissue sarcoma (STS) has a poor prognosis especially after failure of the established first-line treatment. In patients with relapsed leiomyosarcoma, however, the combination of gemcitabine (G) and docetaxel (D) recently has emerged as a valuable salvage therapy. PATIENTS AND METHODS: A retrospective analysis of G (900 mg/m2, days 1+8) and D (100 mg/m2, day 8) was performed in 34 patients with STS, and response rate (RR), overall survival (OS), time to progression (TTP), and toxicities were evaluated. RESULTS: Analysis of these 34 patients revealed a RR of 15% with no complete remission (CR) and 5 partial remissions (PR). Of note, 4/5 PR were achieved in patients with leiomyosarcoma. In 13 patients (38%) disease stabilization (SD) could be achieved resulting in a clinical benefit rate (CBR), defined as CR+PR+SD, of 53%. Median OS was 12.5 and TTP was 2.4 months for the whole group and 2.8 months for patients with leiomyosarcoma. A progression- free rate at 3 months of 38% and 45%, respectively, was observed in these 2 groups. Major side effects were 47% hematological and 26% grade 3/4 nonhematological toxicity. CONCLUSION: With regard to the observed CBR further use of GD seems to be warranted even in pretreated patients with STS.

Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors.

UNLABELLED: This study was implemented to compare the value of PET, CT, and dual-modality PET/CT imaging for assessing gastrointestinal stromal tumor (GIST) response to imatinib therapy. METHODS: Twenty patients with histologically proven GIST underwent (18)F-FDG PET/CT imaging before and 1, 3, and 6 mo after the start of imatinib therapy. Separate PET and CT datasets, side-by-side PET and CT datasets, and fused PET/CT images were evaluated according to World Health Organization, Response Evaluation Criteria in Solid Tumors, and European Organisation for Research and Treatment of Cancer criteria for therapy response. Hounsfield units (HU) were assessed on CT images. A mean follow-up period of 381 +/- 134 d served as the standard of reference. RESULTS: The numbers of lesions detected in all patients were 135 with PET, 249 with CT, 279 on side-by-side evaluation, and 282 on fused PET/CT images. Tumor response was correctly characterized in 95% of patients after 1 mo and 100% after 3 and 6 mo with PET/CT. PET and CT images viewed side by side were correct in 90% of patients at 1 mo and 100% at 3 and 6 mo. PET accurately diagnosed tumor response in 85% of patients at 1 mo and 100% at 3 and 6 mo. CT was found to be accurate in 44% of patients at 1 mo, 60% at 3 mo, and 57% at 6 mo. HU were found to decrease by at least 25% in 12 of 14 responders after 1 mo. CONCLUSION: Tumor response to imatinib should be assessed with a combination of morphologic and functional imaging. Image fusion with combined PET/CT can provide additional information in individual cases when compared with side-by-side PET and CT.