Dosing Patterns,Toxicity, and Outcomes in Patients Treated With First-Line Sunitinib for Advanced Renal Cell Carcinoma in Community-Based Practices

BackgroundThis retrospective study by McKesson Specialty Health (MSH)/US Oncology Network (USON) evaluates dosing patterns of first-line sunitinib for patients with advanced renal cell carcinoma (aRCC) and its association with toxicities and clinical outcomes in community practices.Patients and MethodsPatients with aRCC who started first-line sunitinib between June 1, 2007, and May 31, 2011, were identified from 17 MSH/USON practices. Clinical data were extracted from iKnowMed electronic medical records linked to the MSH/USON pharmacy database.ResultsIn total, 134 patients were included; mean age was 63.9 years, 85% of the patients had an Eastern Cooperative Oncology Group performance score of 0 or 1, 82% had clear-cell renal cell carcinoma, and 65% had undergone nephrectomy. The median treatment duration was 4 cycles (range, 1-19). Overall, 113 patients discontinued sunitinib, mainly because of disease progression (45.1%) or toxicities (16.8%). Of all discontinuations, 77% occurred within the first 5 cycles. A total of 45 patients were dose-reduced, mostly because of toxicities (93%); 67% of all dose reductions occurred in the first 3 cycles. The objective response rate was 16.4%, median overall survival (OS) was 15.5 months, and progression-free survival (PFS) was 7.5 months. Multivariate analysis showed that OS and PFS were associated with sunitinib treatment duration.ConclusionsPatients with aRCC from community practices undergo sunitinib dose reductions more frequently because of toxicities and discontinue therapy sooner than in clinical trials. Clinical outcomes were inferior to those reported in clinical trials, potentially because of shorter duration of therapy. Sunitinib therapy optimization remains an important challenge in community practices.     

Sorafenib and Sunitinib

This article reviews the mechanism of action, pharmacokinetics, and pharmacodynamics of sorafenib and sunitinib.     

RECIST 1.1与Choi标准在舒尼替尼治疗胃肠胰神经内分泌肿瘤早期疗效评估的比较

目的比较实体瘤疗效评价标准(response evaluation criteria in solid tumors version 1.1,RECIST 1.1)和Choi标准评估舒尼替尼对晚期胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)的早期疗效。方法18例使用舒尼替尼治疗的晚期GEP-NENs患者。所有患者治疗前后均行CT检查。测量治疗前及治疗后2~3个月肿瘤大小及密度变化并根据两种评价标准分别评估肿瘤的早期应答。记录肿瘤进展时间(TTP)并用Kaplan Meier法比较各组间的TTP。结果 18例患者中,使用RECIST 1.1标准评价早期疗效时,4例(22%)为部分缓解(PR),9例(50%)为疾病稳定(SD),和5例(28%)出现疾病进展(PD),PR、SD和PD组的中位TTP分别为16.6、10.8和2.3个月。根据Choi标准,8例(44%)为PR,4例(22%)为SD,6例(33%)为PD,PR、SD和PD组的中位TTP分别为未达到10.8和2.3个月。根据RECIST 1.1标准,PR和PD组、SD和PD组的TTP有显著差异(分别为P=0.007和P0.001),但PR和SD组的TTP差异不具有统计学意义(P=0.131)。根据Choi标准,PR组的TTP较SD组和PD组长,且差异具有统计学意义(P=0.026和P0.001),SD组的TTP显著长于PD组(P=0.006)。结论评估舒尼替尼对GEP-NENs的早期疗效时,使用Choi标准能够较RECIST 1.1标准识别出更多的缓解病例,且Choi标准的分组TTP具有统计学差异,较RECIST 1.1标准得到更为客观的评效结果。     

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: A phase II randomised trial

BackgroundNew strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting.MethodsPatients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5 mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; β .10, the target accrual was 26 patients per arm.Results28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7–186). Main grade 3–4 toxicity was thrombocytopenia, neutropenia and hand–foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0–10.6%) and 22.2% (95% CI: 6.2–38.2%; P < 0.01); 2y overall survival was 7.1% (95% CI: 0–16.8%) and 22.9% (95% CI: 5.8–40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02).ConclusionThis is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.     

Active Smoking May Negatively Affect Response Rate,Progression‐Free Survival,and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

Background.

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).

Methods.

An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.

Results.

Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).

Conclusion.

Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.     

The Alternative 2/1 Schedule of Sunitinib is Superior to the Traditional 4/2 Schedule in Patients With Metastatic Renal Cell Carcinoma: A Meta-analysis

Alternate sunitinib schedules attracted the interest of oncologists recently owing to their superior safety profile. This meta-analysis compared the tolerability and efficacy of a new alternative dosing schedule (2 weeks on/1 week off) of sunitinib with the traditional 4/2 schedule in patients with metastatic renal cell carcinoma (mRCC). Studies were retrieved from Medline, Cochrane Central, Scopus, Embase, and Web of Science databases. Data were extracted and pooled as hazard ratio (HR: survival data) or odds ratio (OR: dichotomous data) using Comprehensive Meta-analysis software. Based on data of 1173 patients, the progression-free survival (HR, 0.52; 95% confidence interval [CI], 0.39-0.95; P < .0001), overall survival (HR, 0.6; 95% CI, 0.43-0.85; P < .0001), and stable disease rates (OR, 0.38; 95% CI, 0.19-0.76; P = .006) were significantly improved on the alternative 2/1 schedule, compared with the traditional 4/2 schedule. However, the complete response (OR, 1.32; 95% CI, 0.34-5.22; P = .69) and partial response (OR, 1.34; 95% CI, 0.44-4.14; P = .61) rates were comparable between the 2 regimens. The tolerability of the alternative 2/1 schedule was superior to the traditional one as investigated adverse events like fatigue (OR, 2.91; 95% CI, 1.89-4.46; P < .0001), hypertension (OR, 2.08; 95% CI, 1.56-2.75; P < .0001), and diarrhea (OR, 2.18; 95% CI, 1.19-3.98; P = .012) were significantly less common. In conclusion, the alternative 2/1 sunitinib schedule provides improved tolerability and survival in patients with mRCC. Large randomized trials with long follow-up periods are required to validate and confirm these findings.     

COMPARZ Post Hoc Analysis: Characterizing Pazopanib Responders With Advanced Renal Cell Carcinoma

BackgroundThe phase III COMPARZ study showed noninferior efficacy of pazopanib versus sunitinib in advanced renal cell carcinoma. In this COMPARZ post hoc analysis we characterized pazopanib responders, patient subgroups with better outcomes, and the effect of dose modification on efficacy and safety.Patients and MethodsPatients were randomized to pazopanib 800 mg/d (n = 557) or sunitinib 50 mg/d, 4 weeks on/2 weeks off (n = 553). Secondary end points included time to complete response (CR)/partial response (PR); the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days.ResultsMedian time to response was numerically shorter for patients treated with pazopanib versus sunitinib (11.9 vs. 17.4 weeks). Similar percentages of pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). For patients without versus with adverse event (AE)-related dose reductions, median PFS, median overall survival, and ORR were 7.3 versus 12.5 months, 21.7 versus 36.8 months, and 22% versus 42% (all P < .0001) for pazopanib, and 5.5 versus 13.8 months, 18.1 versus 38.0 months, and 16% versus 34% (all P < .0001) for sunitinib; results were similar for dose interruptions.ConclusionDose modifications when required because of AEs were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients.     

舒尼替尼治疗神经内分泌瘤的研究进展

舒尼替尼是一种多靶点的小分子酪氨酸激酶抑制剂,对多种介导肿瘤发生发展的激酶均有抑制作用,目前已用于肾细胞癌、胃肠道间质瘤等多种肿瘤的治疗。神经内分泌瘤是罕见的恶性肿瘤类型,占全部恶性肿瘤的比例不足1%,理论上可发生于整个神经内分泌系统,但多发生于胃、肠、胰腺。该药已被批准用于胰腺神经内分泌瘤的治疗,且收到较好的近远期效果。本文就舒尼替尼治疗神经内分泌瘤的疗效、不良反应和疗效影响因素等方面进行综述,现报道如下。