Sunitinib In Chinese Patients Research Articles

1759P Long-term updated outcomes of a phase II study of ripretinib vs. sunitinib in chinese patients with advanced gastrointestinal stromal tumor

1759P Long-term updated outcomes of a phase II study of ripretinib vs. sunitinib in chinese patients with advanced gastrointestinal stromal tumor

Pazopanib versus sunitinib in Chinese patients with locally advanced or metastatic renal cell carcinoma: pooled subgroup analysis from the randomized, COMPARZ studies

BackgroundWe performed a pooled analysis of the COMPARZ study assessing efficacy and safety of pazopanib versus sunitinib in treatment-naïve Chinese patients with locally advanced and/or metastatic renal cell carcinoma (a/mRCC).MethodsIn the COMPARZ study, patients were randomized (1:1) to receive pazopanib 800 mg once daily (QD) continuously or sunitinib 50 mg QD in 6-week cycles (4 weeks on, 2 weeks off). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. PFS and ORR were assessed by independent review committee (IRC) and local investigators.ResultsOf the 209 Chinese patients (pazopanib, [n = 109] and sunitinib, [n = 100]), 155 (74%) were males and median age was 57 years (range, 18–79). Median PFS was 13.9 months for pazopanib versus 14.3 months for sunitinib per investigator assessment and 8.3 months in both arms per IRC assessment; PFS hazard ratio was 1.17 (investigator) and 0.99 (IRC). Median OS was not reached in pazopanib arm and was 29.5 months in sunitinib arm. ORR was significantly higher in pazopanib arm versus sunitinib arm (investigator: 41% versus 23% [P = 0.0052]; IRC: 35% versus 20% [P = 0.0203]). Pazopanib was generally well tolerated in Chinese patients with a/mRCC. Most frequent AEs in the pazopanib arm were diarrhea and hair color changes whereas the most frequent AEs in the sunitinib arm were decreased platelets, decreased neutrophil count, and thrombocytopenia.ConclusionThe results of the pooled analysis were consistent with the overall population in the COMPARZ study, and confirmed similar PFS and OS of pazopanib and sunitinib in the Chinese patients.Trial registrationclinical trials.gov, NCT00720941 (August 14, 2008) and NCT01147822 (May 19, 2010).

Individualized dosing schedule of sunitinib switched through plasma concentration monitoring in patients with metastatic renal cell carcinoma.

694 Background: The aim of this study was to investigate the survival benefit and safety of switched dosing schedules for sunitinib in Chinese patients with metastatic renal cell carcinoma through plasma concentration monitoring. Methods: One hundred and twelve patients with mRCC were enrolled who were treated with Sunitinib. Patients were classified into 3 groups: switched dosing schedule through plasma concentration monitoring (4/2-2/1 schedule, 4/2-2/1-individualized and 2/1-individualized schedule), switched dosing schedule empirically due to severe adverse events (AEs)(4/2-2/1 schedule) and dosing schedule without switching (initial 4/2 or 2/1 schedule).The blood samples of patients in monitoring group were collected at different medication points consecutively within one or two course of treatment. In monitoring group, dosing schedule was switched according to plasma concentration curve. For patients whose dosing schedule was switched empirically, the switching was from 4/2 to 2/1 schedule because of intolerance to initial 4/2 schedule. The survival benefit and safety were compared among these 3 groups. Results: From plasma concentration curves, dosing schedules were switched in 17 patients. The dosing schedule was switched from 4/2 to 2/1 in 37 patients empirically, while 58 patients were administrated with a 4/2 or 2/1 schedule without switching. Among the monitoring, empirical and initial group, the median PFS was 30.0,20.0 and 9.0 months,respectively(P = 0.001), and the median OS was not-reach, 37.0, and 18.0 months, respectively (p = 0.004). Moreover, patients with a switched schedule through monitoring had better tolerance after switching. The incidence of grade 3/4 AEs fell from 88.2% to 41.2% (p = 0.001).In empirical group, the incidence of grade 3/4 AEs fell from 73.0% to 37.8% (p = 0.001). Conclusions: Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with switched schedules by monitoring could achieve a better survival benefit.

Phase IV Study of Sunitinib in Chinese Patients with Imatinib-Resistant or Imatinib-Intolerant Gastrointestinal Stromal Tumors

Abstract Introduction Sunitinib is approved in China for treatment of gastrointestinal stromal tumors (GIST), after disease progression on, or intolerance to, imatinib. However, available data from prospective clinical trials on its efficacy and safety in Chinese patients is limited. Our objective is to determine the efficacy and safety of sunitinib in Chinese patients with imatinib-resistant/intolerant GIST. Methods An open-label, single-arm, multicenter, phase IV study was performed in Chinese patients with imatinib-resistant/intolerant GIST. Sunitinib was administered orally in 6-week cycles of 4 weeks on-treatment (50 mg once daily) and 2 weeks off-treatment. The primary endpoint was progression-free survival (PFS). Tumors were assessed every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Responses were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Results A total of 60 patients were enrolled, of whom 59 were treated with sunitinib. All patients were Asian, and mean age was 55.1 years. Median PFS was 46.4 weeks (95% CI 33.6–53.1). An objective response (complete or partial) was observed in 11/58 (19%) patients. Median overall survival was 111.3 weeks (95% CI 75.4–167.1), median time to tumor progression was 47.3 weeks (95% CI 34.1–59.3), and median time to tumor response was 22.6 weeks (95% CI 10.4–57.3). The most common adverse events included leukopenia, fatigue, hand-foot syndrome, and neutropenia. No new safety concerns were identified. Conclusions This study confirms that sunitinib is active and well tolerated in Chinese patients with imatinib-resistant/intolerant GIST. ClinicalTrials.gov identifier NCT00793871. Funding Pfizer Inc, USA.

Sunitinib is effective and tolerable in Chinese patients with advanced pancreatic neuroendocrine tumors: a multicenter retrospective study in China

To determine the efficacy and safety of sunitinib in Chinese patients with unresectable or metastatic pancreatic neuroendocrine tumors (pNETs) and the clinical significance of steady-state sunitinib serum concentrations. We conducted a multicenter retrospective study including six centers from across China. A total of 60 patients with unresectable or metastatic pNETs who were treated with sunitinib were evaluated retrospectively. The median overall survival (OS) was 47.5months and the median time to progression (TTP) was 15.3months. The objective response rate was 5.0%, and the stable disease (SD) rate was 81.7%. About 35.2% of patients required a dosage decrease from 37.5 to 25mg/day due to adverse events, which in most cases were alleviated or disappeared with the dosage reduction. In 14 patients who experienced sunitinib-related hypertension, 2 achieved a partial response (PR) and 11 had SD. The median OS and TTP of these 14 patients experienced hypertension were both not reached. The median Css of sunitinib was similar between patients treated with sunitinib 37.5 and 25mg/day (P=0.955), but higher in patients who had PR than in those who achieved SD or progressive disease, although no statistically significant difference was found (P=0.173). Sunitinib had similar treatment efficacy to western patients with pNET in China. A 25mg/day dosage was better tolerated than 37.5mg/day in Chinese patients, and there were no significant differences in sunitinib Css between the two dosage groups. Patients with higher sunitinib Css seem to have better efficacy. Sunitinib-related hypertension may be a predictor of a better treatment effect.

Efficiency of Sunitinib in Chinese Patients with Advanced Progressive Pancreatic Neuroendocrine Tumor.

Objective To explore the efficiency of sunitinib in Chinese pancreatic neuroendocrine tumors (pNET) patients. Methods Advanced pNET patients who had accepted sunitinib treatment in the oncology department of PUMC Hospital from January 2009 to June 2015 after disease progression were enrolled in this study. Data collection included clinicopathological characteristics,medical therapies and outcomes. Results Eighteen pNET patients were collected. The overall response rate (ORR) was 27.7% and the disease control rate (DCR) was 83.3%. Nine patients received sunitinib as the first-line therapy and 9 as the second/post-second line. The median progression-free survival (mPFs)(12 month vs. 12 month;HR:0.92,95%CI:0.31-2.75,P=0.88),ORR (22.2% vs.33.3%;Χ(2)=0.055,P=0.98),and DCR (88.9% vs.77.8%;Χ(2)=0.4,P=0.98)showed no significant difference between first-line therapy and post-second line therapy. The mPFS of Ki-67≥10% and Ki-67<10% group patients was not significantly different (8 months vs. 13 months;HR:1.13,95% CI:0.34-3.77,P=0.845). The commonly reported adverse events included bone marrow suppression,diarrhea,roteinuria,hypertension,and rash. Conclusions First-line or second/post-second line sunitinib treatment has certain antitumor activity in Chinese patients with advanced pNET. The efficiency and commonly reported adverse events of Sunitinib are consistent with the known Western data.

Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors

The aim of this study was to investigate the associations between secondary mutations of c-KIT/PDGFRα and acquired imatinib resistance or efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors (GISTs). Mutations of c-KIT (exons 9, 11, 13, 14, 17, and 18) and PDGFRα (exons 12 and 18) in tumor samples of 50 patients were analyzed by direct sequencing. A total of 50 samples before imatinib and 52 samples after imatinib were collected. Among 52 samples after imatinib, 38 samples were imatinib resistant and 14 samples were imatinib sensitive. All patients before imatinib treatment had primary mutations of c-KIT exon 11 (n = 45) or exon 9 (n = 5), and no PDGFRα mutations were found in these patients. After imatinib treatment, 25 of 38 (65.8 %) resistant tumors had secondary mutations in c-KIT exon 13 (n = 10), exon 14 (n = 1), exon 17 (n = 12) and exon 18 (n = 2), while no secondary mutations of c-KIT were found in 14 sensitive tumors (P < 0.001), indicating the close association of c-KIT secondary mutations with imatinib-acquired resistance. In our study, 19 patients received sunitinib treatment after the failure of imatinib, and it seemed that the median progression-free survival (7 vs. 19 months, P = 0.244) in patients with secondary mutations (n = 13) was lower than that in patients without secondary mutations (n = 6). Secondary mutations of c-KIT were significantly associated with acquired resistance to imatinib in Chinese GIST patients, and whether secondary mutations of c-KIT could influence the efficacy of sunitinib needed to be further investigated.

Simultaneous determination of sunitinib and its two metabolites in plasma of Chinese patients with metastatic renal cell carcinoma by liquid chromatography–tandem mass spectrometry

A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of sunitinib and its two metabolites in plasma of Chinese patients with metastatic renal cell carcinoma (mRCC). After simple one-step protein precipitation with methanol-acetonitrile (1:1, v/v), all three analytes were separated on an Agilent Zorbax SB-C(18) column using a gradient mobile phase consisting of water (0.1% formic acid)-acetonitrile (0.1% formic acid) at a flow rate of 0.50 mL/min. The detection was performed in multiple reaction monitoring mode, using the transitions of m/z 399.0 → 326.2, m/z 371.0 → 283.1, m/z 343.0 → 283.1 and m/z 386.3 → 122.2 for sunitinib, M1, M2 and buspirone, respectively. The method was linear over the range of 0.10-100 ng/mL for all three analytes using only 50 μL of plasma and the lower limit of quantifications for the three analytes were all 0.10 ng/mL. The intra-day and inter-day precisions were all less than 15% and the accuracies were within the range of ±15%; recoveries were between 85.0 and 115%. The validated method was successfully applied to an explorative pharmacokinetic study of sunitinib in Chinese patients with mRCC following multi-dose oral administration.

Efficacy and Safety of Sunitinib in Chinese Patients with Imatinib-Resistant or -Intolerant Gastrointestinal Stromal Tumors

To assess the efficacy and safety of sunitinib in Chinese patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors (GISTs), and evaluate the impact of genotype on sunitinib efficacy. In a single-arm retrospective study, 55 patients with recurrent or metastatic GISTs who were resistant or intolerant to prior imatinib treatment received sunitinib for at least one treatment cycle. The median progression-free survival was 35 weeks (95% CI: 24.6-45.4) in patients who received sunitinib 37.5 mg/day as a continuous daily dose versus 30 weeks (95% CI: 12.8-47.2) in those who received sunitinib 50 mg/day as a 4-weeks-on, 2-weeks-off (4/2) schedule (p = 0.707). The median overall survival of all patients was 86 weeks (95% CI: 75.0-97.0). Patients with KIT exon 9 mutations had a significantly longer progression-free survival compared with those with KIT exon 11 mutations and patients with wild-type GISTs (p = 0.022). Sunitinib therapy was well tolerated, with most adverse events rated as grade 1 or 2 in severity. The sunitinib 37.5 mg/day continuous daily dose schedule was better tolerated by Chinese GIST patients than the 50 mg/day 4/2 schedule. Sunitinib was effective and well tolerated in Chinese patients with imatinib-resistant or -intolerant GISTs. Patients with KIT exon 9 mutations showed the best efficacy. A 37.5 mg/day continuous daily dose sunitinib dosing schedule appears to be the optimal choice for Chinese patients due to a decreased incidence of adverse events.

A pilot study of sunitinib in Chinese patients with heavily pretreated metastatic breast cancer.

e11506 Background: Sunitinib malate, an oral multitargeted tyrosine kinase inhibitor has shown antitumor activity in metastatic breast cancer. This study was conducted to evaluate the efficacy and safety of single-agent sunitinib in chinese breast cancer patients with multiple-resistant to antitumor drugs. Methods: Metastatic breast cancer patients with multiple-resistant to antitumor drugs received the treatment with single-agent sunitinib at dose 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment), and toxicity-related dose reduction was permitted. The primary end point was objective response rate, and the second end point was the safety. Results: 29 patients were enrolled, the median age was 45 (27-68) ys, the median previous chemotherapy lines was 7 (3-17), 15 patients were ER/PR negative, 14 patients were ER/PR positive, 8 patients were HER-2 positive. 10 patients received a starting dose of sunitinib orally 50mg/d in 6-week cycles schedule, all patients had the dose reduction because of severe hematologic toxicity. So the following 19 patients received a starting dose of sunitinib orally 37.5mg/d schedule. The most frequent nonhematologic toxicity were yellow skin (100%), fatigue (82.8%), and hypertention (34.5%). Grade 3/4 hematologic toxicity included neutropenia (82.8%), thrombocyte decrease (79.3%). Of the 25 patients with measurable disease at baseline, 4 patients achieved a partial response (16%), 10 additional patients (40%) maintained stable disease for more than 10 weeks. Median time to progression and overall survival were 10 and 32 weeks, respectively. Notably, all the responses occurred in patients with a tumor ulcer. The median follow-up time was 26 (6-52) weeks, 4 patients were lost,17 patients were dead, and 8 patients were alive with metastatic disease. Conclusions: These data indicate that sunitinib has the sure activity in the chinene patients with pretreated metastatic breast cancer, especially in tumor ulcer. The recommended sutent monotherapy regimen was administered orally at 37.5mg/d in chinese breast cancer patients, and the major treatment-related adverse effects was hematologic toxicity.