A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 355-355 ◽  
Author(s):  
Toni K. Choueiri ◽  
Ulka N. Vaishampayan ◽  
Jonathan E. Rosenberg ◽  
Theodore Logan ◽  
Andrea Lynne Harzstark ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Plasma Proteins ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Papillary Renal Cell Carcinoma ◽  
High Rate ◽  
Dosing Regimens

355 Background: Foretinib is an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). The aim of this study was to evaluate the efficacy and safety of 2 dosing regimens of single agent foretinib bisphosphate (foretinib) in pts with PRC and to explore modulation of plasma proteins indicative of target inhibition. Methods: Pts were enrolled in 2 cohorts with different dosing schedules of foretinib: 240 mg/day on days 1–5 of every 14 days (intermittent arm) or 80 mg/day (daily dosing arm). The primary endpoint was overall response rate (ORR) targeting an ORR of at least 25%. Pts were stratified based on status of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, chromosome 7 gain or none of these). Plasma markers reflecting potential target effects of MET and VEGFR inhibition were also analyzed. Results: Overall, 74 pts were enrolled with 37 in each dosing cohort. ORR was 13.5%, progression-free survival 9.3 months, 1 year overall survival (OS) was 70% and median OS was not reached. The median duration of response was 18.5 months. Of 68 pts with adequate tumor assessment data available, 50 experienced some reduction in the sum of the longest tumor diameters (SLD) ranging from −2% to −75%. The most frequent grade 3/4 adverse events related to foretinib were fatigue (6.8%), hypertension (50%), and diarrhea (6.8%). A high rate of non-fatal pulmonary embolism was observed (11%). There were no significant differences in efficacy or safety between the two cohorts. In both arms, plasma sMET and VEGF increased and sVEGFR2 decreased after 2 cycles indicating target inhibition, but these changes were not associated with response or PFS. Outcomes based on molecular characterization are presented separately at this meeting. Conclusions: In the largest clinical trial devoted to papillary RCC, foretinib demonstrated anti-tumor activity in patients with PRC, modulation of several target indicator plasma proteins, and a manageable toxicity profile.

DNA damage repair (DDR) pathway alteration in advanced renal cell carcinoma (RCC) is association with good progression-free survival with tyrosine kinase inhibitor (TKI) therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 346-346
Author(s):  
Wei Zhai ◽  
Junyun Wang ◽  
Ning He ◽  
Jiale Zhou ◽  
Jianfei Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Vascular Endothelial ◽  
Damage Repair ◽  
Endothelial Growth Factor

346 Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.

scholarly journals Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 5 (4) ◽  
pp. 1-5 ◽  
Author(s):  
Sharon Del Vecchio ◽  
Robert J Ellis
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Current Treatment ◽  
Phase Iii ◽  
Solid Organ ◽  
Cell Renal Cell Carcinoma ◽  
Randomised Controlled

Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma.

scholarly journals Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma

2013 ◽  
Vol 31 (2) ◽  
pp. 181-186 ◽  
Author(s):  
Toni K. Choueiri ◽  
Ulka Vaishampayan ◽  
Jonathan E. Rosenberg ◽  
Theodore F. Logan ◽  
Andrea L. Harzstark ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Response Rate ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Papillary Renal Cell Carcinoma ◽  
High Response Rate ◽  
Multikinase Inhibitor ◽  
Pathway Activation

Purpose Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. Patients and Methods Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. Conclusion Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 435-435
Author(s):  
Andrew J. Armstrong ◽  
James D. Turnbull ◽  
Julien Cobert ◽  
Tracy Jaffe ◽  
Michael Roger Harrison ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Mtor Inhibition ◽  
Grade 3

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting. Methods: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized. Results: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2). Conclusions: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

Survival outcomes associated with different sunitinib dosing regimens in metastatic renal cell carcinoma.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 417-417 ◽  
Author(s):  
Winnie Cheng ◽  
Victoria Kletas ◽  
Mario Law De Lemos ◽  
Sally Man ◽  
Christian K. Kollmannsberger
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Significant Proportion ◽  
Progression Free Survival ◽  
Survival Outcomes ◽  
Care Organization ◽  
Cancer Agency ◽  
Dosing Regimens

417 Background: Standard dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC) consists of 4 weeks treatment followed by 2-weeks rest (intermittent dosing, ID). Alternative regimens have been suggested, including continuous daily dosing (continuous dosing, CD) and non-conventional dosing (non-conventional dosing: e.g. 2 weeks on / 1-week off, ND) to provide more individualized therapy with less toxicities. It is unclear whether non-standard sunitinib dosing affects survival outcomes. Methods: mRCC patients treated with sunitinib between July 1, 2007 and July 1, 2011 were identified from the British Columbia Cancer Agency (BCCA) pharmacy database, a publicly funded cancer care organization. Medical records and dispensing data were reviewed retrospectively to categorize sunitinib dosing as ID, CD or ND. Primary outcome was to compare overall survival (OS) associated with varying regimens, with secondary outcomes of progression free survival (PFS) and incidence of treatment discontinuation due to adverse effects (AE). Results: A total of 180 patients were identified. Heng prognostic risk criteria were assessable in 162 patients. Of these, 34 (21%), 80 (49%) and 48 (30%) had low-, intermediate- and high-risk disease. Most patients received ID (120, 67%), followed by CD (32,18%) and ND (28,16%). Compared to ID, CD was associated with similar OS (median 9 vs. 13 months, HR 0.67, 95% CI 0.43-1.06, p=0.088) while ND was associated with significantly longer OS (median 9 vs. 23 months, HR 0.55, 95% CI 0.34-0.90, p=0.016). PFS was significantly better for CD (median 4 vs. 9 months, HR 0.61, 95% CI 0.40-0.94, p=0.025) and ND (median 4 vs. 10 months, HR 0.61, 95% CI 0.39-0.95, p=0.03) when compared to ID. Similar to prior sunitinib trials, a significant proportion of patients (20%) discontinued sunitinib therapy due to AE. Conclusions: In comparison to the standard ID regimen, dosing sunitinib with alternative regimens appears to be associated with improved OS and PFS in patients with mRCC. Presently, a prospective Canadian trial is underway investigating the efficacy and safety of individualized sunitinib dosing regimens.

FGFR2 expression to predict survival outcome in patients with metastatic papillary renal cell carcinoma.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 506-506 ◽  
Author(s):  
Ilya Tsimafeyeu ◽  
Alexandra Naumova ◽  
Evgenia Stepanova ◽  
Alfia Khasanova ◽  
Ilya Varlamov ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Tumor Cells ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Papillary Renal Cell Carcinoma ◽  
Survival Outcome ◽  
Primary Tumors ◽  
Metastatic Sites

506 Background: In our previous study we showed that fibroblast growth factor receptor 2 (FGFR2) mutations are rare across papillary types of renal cell carcinoma (pRCC). The aim of the present study is to test FGFR2 expression for association with survival outcome in the largest patient cohort to date. Methods: Formalin-fixed, paraffin-embedded specimens of removed primary tumors from 214 untreated metastatic pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody (Santa Cruz Biotechnology). Expression was quantified by consensus of two independent observers using a four-value intensity score (0, 1+, 2+, and 3+) and the percentage (0-100%) of the extent of reactivity. Expression was scored according to the percentage of positive cells present among all tumor cells in the section. The cytoplasmic and nuclear expression score was obtained by multiplying the intensity and reactivity extension values (range, 0-300). FGFR2 expression was tested for associations with progression-free survival (PFS), overall survival (OS) and best objective response. Results: Expression of FGFR2 was observed in 23% (49/214) of primary pRCC, mostly in cytoplasm of tumor cells. 2 of 214 (1%) patients had nuclear FGFR2 expression. Intensity was 3+ in all cases. Expression of FGFR2 was significant lower in the normal tissue of kidney (1%, P=0.001). FGFR2 expression was strongly associated with a number of metastatic sites (2 and more metastatic sites vs. 0-1), type 2 of pRCC, lower nucleolar grade (P<0.001). FGFR2-positive patients had significantly shorter OS and PFS in first-line therapy (P<0.05; Table). On multivariate analysis, FGFR2 expression, MSKCC risk group, and type of pRCC were found to be independent predictors of survival. Conclusions: In this study, we described immunohistochemical expression of FGFR2 in a large series of pRCC specimens. FGFR2 expression was found to be prognostic factor for survival in patients with metastatic pRCC. Clinical trial information: rosoncoweb2011. [Table: see text]

scholarly journals Sunitinib in the treatment of renal cell carcinoma: an update on recent evidence

2017 ◽  
Vol 9 (8) ◽  
pp. 195-207 ◽  
Author(s):  
Mimma Rizzo ◽  
Camillo Porta
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Dose Intensity ◽  
Inhibitory Effect ◽  
Complex Activity ◽  
Long Time

Sunitinib is a multitarget tyrosine kinase inhibitor endowed mainly by antiangiogenic effects, although an indirect inhibitory effect on tumor growth and, more recently, a complex activity on antitumor immune response has been described. From approval by the US Food and Drug Administration (FDA) in January 2006, sunitinib represents a key molecule in the treatment of metastatic renal cell carcinoma (mRCC) due to the peculiar molecular pathogenesis of this neoplasm. Over the past 10 years, clinical trials and real-world experiences helped clinicians to understand how, when and for how long to use sunitinib. Although a huge amount of data evidenced the relationship existing between sunitinib dose intensity and improved clinical outcome, the management of sunitinib-induced adverse events is often complex; thus, alternative schedules have been proposed over time which allow increased tolerability, without decreased daily sunitinib exposure, leading to improved clinical outcomes. To date, combinations of sunitinib with other approved targeted agents did not demonstrate any significant benefit over its single-agent use, mainly due to tolerability issues. Sunitinib has also been tested in the adjuvant setting, within the ASSURE and S-TRAC trials, with opposite results; indeed, equivocal risk-stratification criteria, as well as immature overall survival (OS) data prevent any definitive conclusion on this important issue. Despite being on the market for a long time, sunitinib still plays a role as the ‘comparator arm’ of a number of trials in the field of mRCC. Combinations with immune checkpoint inhibitors and vaccines look promising; once again, sunitinib can help us to optimize mRCC management.

Clinicopathologic features of Xp11.2 translocation renal cell carcinoma and its response to target therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16559-e16559
Author(s):  
Xieqiao Yan ◽  
Zhihong Chi ◽  
Lu Si ◽  
Chuanliang Cui ◽  
Yan Kong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Target Therapy ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Line Therapy ◽  
Xp11.2 Translocation

e16559 Background: Xp11.2 translocation renal cell carcinoma (RCC) is a unique RCC subtype with high malignant potential and poor prognosis, its natural course and response to systemic therapy are not fully understood. We analyzed the clinic features of this distinct entity and the benefit of systemic therapy in these patients. Methods: Between May 2006 and December 2019, 1113 consecutive patients diagnosed with RCC from Peking university cancer hospital (Beijing, China) were reviewed, data of the clinical characteristics and outcome of patients with metastatic Xp11.2 RCC were retrospectively collected. Tumor response to systemic therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results: Metastatic Xp11.2 translocation RCC was found in 41 cases. The median PFS and Median OS was 6.3 months (4.4 - 8.8) and 17.3 months (12.4 - 21.8) for the whole cohort, respectively. First-line treatment mainly included sunitinib (n = 12), sorafenib (n = 13), axitinib (n = 6), and pazopanib (n = 4), and the median PFS of these regimens was 5.4 months, 5.1 months, 9.4 months, 8.3 months, respectively. Twenty-three patients received subsequent therapies, the median PFS and the median OS was 4.3 months and 12 months for the second-line therapy(n = 21), 4.3 months and 14.1 months for the third-line therapy(n = 11), 2.4 months and 9.6 months for the fourth-line therapy(n = 6). Conclusions: Metastatic Xp11.2 translocation RCC is an aggressive disease. Vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) agents appeared to demonstrate some efficacy, the combination of VEGFR-TKI and immune checkpoint inhibitor (ICI) might be a useful tool for the treatment of metastatic Xp11.2 translocation RCC.

Survival outcomes associated with different sunitinib dosing regimens in metastatic renal cell carcinoma

2019 ◽  
Vol 26 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Winnie Cheng ◽  
Victoria Kletas ◽  
Christian Kollmannsberger ◽  
Mário de Lemos
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Survival Outcomes ◽  
Free Survival ◽  
Dosing Regimens ◽  
Continuous Dosing

Background Standard dosing regimen of sunitinib for metastatic renal cell carcinoma consists of four weeks treatment followed by two weeks rest (intermittent dosing). Alternative regimens have been suggested, including continuous daily dosing (continuous dosing) and non-conventional dosing (non-conventional dosing: e.g. two weeks on/one week off, non-conventional dosing), to provide more individualized therapy with less toxicities. It is unclear whether non-standard sunitinib dosing affects survival outcomes. Patients Metastatic renal cell carcinoma patients treated with sunitinib between 1 July 2007 and 1 July 2011 at our institution. Methods Medical records and dispensing data were reviewed retrospectively to categorize sunitinib dosing as intermittent dosing, continuous dosing, or non-conventional dosing. Primary outcome was to compare overall survival associated with varying regimens, with secondary outcomes of progression-free survival and incidence of treatment discontinuation due to adverse effects. Results A total of 180 patients were identified. Most patients received intermittent dosing ( n = 120, 67%), followed by continuous dosing ( n = 32, 18%) and non-conventional dosing ( n = 28, 16%). Compared to intermittent dosing, continuous dosing was associated with similar overall survival (median 9 vs. 13 months, HR 0.67, 95% CI: 0.43–1.06, p = 0.088) while non-conventional dosing was associated with significantly longer overall survival (median 9 vs. 23 months, HR 0.55, 95% CI: 0.34–0.90, p = 0.016). Progression-free survival was significantly better for continuous dosing (median 4 vs. 9 months, HR 0.61, 95% CI: 0.40–0.94, p = 0.025) and non-conventional dosing (median 4 vs. 10 months, HR 0.61, 95% CI: 0.39–0.95, p = 0.03) when compared to intermittent dosing. Similar to prior sunitinib trials, a significant proportion of patients (20%) discontinued sunitinib therapy due to adverse effects. Conclusions Based on retrospective, real-world data, alternative sunitinib dosing regimens appear to be viable options for patients with metastatic renal cell carcinoma.

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