Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a sin

To explore the efficacy and safety of pazopanib in a 'real-world' setting in unselected patients, as data regarding unselected patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line pazopanib are limited. We reviewed records of patients with metastatic ccRCC treated with first-line pazopanib from 1 November 2009 through to 1 November 2012. Cox models were fitted to evaluate the association of progression-free survival (PFS) and overall survival (OS) with patient co-variables. In all, 88 patients were identified; 74 were evaluable for response: two (3%) had a complete response, 27 (36%) a partial response, 36 (49%) had stable disease and nine (12%) had progressive disease. The median PFS was 13.7 months [95% confidence interval (CI) 8.7-18.3]. PFS was correlated with a Karnofsky Performance Status score of <80 [hazard ratio (HR) 3.26, P < 0.001] and serum lactate dehydrogenase of >1.5 × upper limit of normal (HR 3.25, P = 0.014). The median OS was 29.1 months (95% CI 20.2-not reached). The OS was correlated with brain metastasis (HR 2.55, P = 0.009), neutrophilia (HR 1.179, P = 0.018), and anaemia (HR 3.51, P < 0.001). There were no treatment-related deaths. In all, 53 patients received second-line therapy [vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in 22 patients, mammalian target of rapamycin inhibitors (mTORi) in 22 patients, and other therapy in nine patients]; the median PFS was 8.6 months (95% CI 3.3-25.7) with VEGFR-TKI and 5 months (95% CI 3.5-15.2) with mTORi (P = 0.41); the median OS was 19.9 months (95% CI 12.9-not reached) and 14.2 months (95% CI 8.1-not reached), from initiation of second-line VEGFR-TKI or mTORi, respectively (P = 0.37). In this retrospective study, first-line pazopanib confirmed its efficacy in metastatic ccRCC. Trends for longer PFS and OS were seen with VEGFR-TKI compared with mTORi after first-line pazopanib.

Matrana MR ，Bathala T ，Campbell MT ，Duran C ，Shetty A ，Teegavarapu P ，Kalra S ，Xiao L ，Atkinson B ，Corn P ，Jonasch E ，Tannir NM ... -  《-》

First-Line and Sequential Use of Pazopanib Followed by Mammalian Target of Rapamycin Inhibitor Therapy Among Patients With Advanced Renal Cell Carcinoma in a US Community Oncology Setting.

Clinical trials have demonstrated that pazopanib prolongs progression-free survival (PFS), with an acceptable safety profile, for patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mammalian target of rapamycin (mTOR) inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. The present study evaluated the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting. The present study was a retrospective analysis of eligible patients in US Oncology's iKnowMed electronic health records database who had been treated for aRCC from November 1, 2009 to August 31, 2012. The patients received first-line therapy with pazopanib (cohort 1), followed by second-line therapy with either everolimus or temsirolimus (cohort 2). The key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use. The median OS in cohort 1 (n = 177) was 22 months, and the median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). The median persistence was 151 days with pazopanib. The median OS in cohort 2 (n = 35) was 16 months; the median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). The median persistence was 93 days with everolimus and 49 days with temsirolimus. The outcomes for the patients treated with first-line pazopanib in the community setting were consistent with those reported by previous prospective and retrospective studies. Although the second-line cohort was small, the results of mTOR inhibitors after pazopanib were also consistent with those of previous observations.

Vogelzang NJ ，Hackshaw MD ，Hutson TE ，Bhowmik D ，Yap M ，Rembert D ，Jonasch E ... -  《-》

Vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) rechallenge for patients with metastatic renal cell carcinoma after treatment failure using both VEGFR-TKI and mTOR inhibitor.

Park I ，Lee JL ，Ahn JH ，Lee DH ，Lee KH ，You D ，Jeong IG ，Song C ，Hong B ，Hong JH ，Ahn H ... -  《-》

Retrospective comparison of triple-sequence therapies in metastatic renal cell carcinoma.

The optimal sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been defined. To describe the efficacy and toxicity of the most common sequences of targeted therapy, namely, receptor tyrosine kinase inhibitor (rTKI) and mammalian target of rapamycin inhibitor (mTORi), in different sequences after failure of vascular endothelial growth factor signaling inhibition (VEGFi) in first-line therapy. Retrospective study of 103 patients receiving VEGFi-rTKI-mTORi (n=62) or VEGFi-mTORi-rTKI (n=41) at two German academic centers. Sequence of systemic targeted treatment. Response was assessed using Response Evaluation Criteria in Solid Tumors 1.0 and toxicity was measured using the Common Terminology Criteria for Adverse Events 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of survival were analyzed using Cox regression. Sequence groups did not significantly differ by patient characteristics and response rate following first VEGFi failure. Median PFS for second-line therapy was 4.6 mo (95% confidence interval [CI], 3.8-5.4), 4.1 mo (95% CI, 3.4-4.9) for rTKI treatment, and 5.4 mo (95% CI, 2.7-8.1) for mTORi treatment (p=0.400). No differences in PFS were observed among third-line therapy groups (3.6 mo for mTORi; 3.7 mo for rTKI). Treatment duration following first VEGFi failure (combined second- and third-line PFS) was 10.0 mo for VEGFi-rTKI-mTORi and 12.2 mo for VEGFi-mTORi-rTKI (p=0.103). No significant differences in OS were observed among sequence groups (33.7 mo [95% CI, 30.4-37.1] for VEGFi-rTKI-mTORi; 38.7 mo [95% CI, 24.4-52.9] for VEGFi-mTORi-rTKI). Primary resistance on first-line therapy was an independent predictor of OS, but type of sequence was not. Limitations are the retrospective design and limited numbers of cases. The sequence therapies VEGFi-mTORi-rTKI and VEGFi-rTKI-mTORi with the currently available agents appear to be equally efficacious in terms of PFS, OS, and response rate, with no apparent beneficial effect with an early use of mTORi.

Busch J ，Seidel C ，Erber B ，Issever AS ，Hinz S ，Kempkensteffen C ，Magheli A ，Miller K ，Grünwald V ，Weikert S ... -  《-》

Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors.

The activity of systemic agents after progression when using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in patients with metastatic renal cell carcinoma (mRCC) is poorly characterized. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has a broad US Food and Drug Administration label and National Comprehensive Cancer Network guideline level 2b recommendation in this setting; we thus explored our institutional experience in this population. We conducted a retrospective analysis of patients with mRCC who were treated with bevacizumab in the second- and/or third-line settings; the primary endpoint was progression-free survival (PFS). Overall response rates (ORR), overall survival (OS), and toxicity were analyzed. Twenty-one patients were treated with bevacizumab: the median age was 63 years old; 80% were white and 14% were black; 80% had clear cell histology. All the patients had prior VEGFR TKI therapy; 43% had prior mTOR inhibitor; the median number of prior therapies was 3. The median PFS was 4.4 months (95% CI, 2.8-9.6 months), and the median OS was 19.4 months (95% CI, 9.9-NR months). ORR was 9.5%; 52% of subjects had stable disease as best response, and 52% had disease progression. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4 and 13.2 months, respectively. Grade 3 to 4 toxicities included fatigue (29%), dehydration (24%), failure to thrive (10%), constipation (10%), and muscle weakness (10%). Single-agent bevacizumab has acceptable toxicity and moderate disease-stabilizing activity in selected patients with mRCC who have failed prior VEGFR TKI and mTOR inhibitors. These data support clinical benefit to continued ongoing VEGF inhibition. Further prospective studies of bevacizumab alone or with alternative targeted agents in previously treated populations with mRCC are warranted.

Turnbull JD ，Cobert J ，Jaffe T ，Harrison MR ，George DJ ，Armstrong AJ ... -  《-》