Activity of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 364-364 ◽  
Author(s):  
Toni K. Choueiri ◽  
Sumanta Kumar Pal ◽  
David F. McDermott ◽  
David A. Ramies ◽  
Stephanie Morrissey ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Primary Objective ◽  
Risk Category ◽  
Efficacy Evaluation ◽  
Prior Therapy

364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts with a median of 2 prior regimens; 17/25 (68%) RCC pts had received ≥ 2 lines of prior therapy and 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. All pts were intermediate (24/25) or poor (1/25) risk category per Heng et al prognostic strata (JCO 2009). Related AEs ≥ Grade 3 severity: hypophosphatemia 8 (32%), PE 3 (12%; all were incidental / resolved) and diarrhea 3 (12%). Preliminary PK data suggest that clinically relevant doses of cabo do not markedly alter the Cmax or AUC0-24h of rosi consistent with lack of inhibition of CYP2C8. RCC pts with confirmed PR by mRECIST: 6/25 (24%). Additionally, 1 pt had an unconfirmed PR. Disease control rate (PR + SD): 68% at 16 weeks; 18/21 (86%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 – 63% reduction in measurements). 14/25 (56%) remain on cabo with a median follow-up of 4 months. Median PFS and OS have not been reached. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated pts with RCC with a toxicity profile similar to that of other TKIs. Preliminary data suggest no DDI between cabo and rosi (CYP2C8 substrate).

Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4504-4504 ◽  
Author(s):  
Toni K. Choueiri ◽  
Sumanta Kumar Pal ◽  
David F. McDermott ◽  
David A. Ramies ◽  
Stephanie Morrissey ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Primary Objective ◽  
Heavily Pretreated ◽  
Cell Components ◽  
Anti Tumor Activity

4504 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity was also evaluated. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Cabo was given daily at a dose of 140 mg free base (equivalent to 175 mg salt form) starting at Day 2. Rosi (4 mg) was given Day 1 and Day 22 to complete PK assessment for DDI. Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts; 17/25 (64%) RCC pts had received ≥ 2 prior agents; 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. The majority of pts were in an intermediate (21/25) or poor (3/25) prognostic category (1/25 in favorable category) per Heng et al (JCO, 2009, v27, p5794). ORR by mRECIST: 7/25 (28%). Disease control rate (PR + SD): 72% at 16 weeks; 19/21 (90%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 - 63% reduction in measurements). 10/25 (36%) pts remain on cabo. Median PFS is 14.7 months (95% CI: 7.3, upper limit not reached) with a median follow-up of 7.7 months. AEs ≥ Grade 3 severity: hypophosphatemia (36%), hyponatremia (20%), and fatigue (16%). PK data suggest that clinically relevant doses of cabo do not alter the Cmax or AUC0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated RCC pts with a toxicity profile similar to that of other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).

Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up.

1993 ◽  
Vol 11 (7) ◽  
pp. 1368-1375 ◽  
Author(s):  
L M Minasian ◽  
R J Motzer ◽  
L Gluck ◽  
M Mazumdar ◽  
V Vlamis ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factors ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Interferon Alfa ◽  
Advanced Renal Cell Carcinoma ◽  
Survival Duration

PURPOSE Three trials were conducted to define the efficacy and toxicity of interferon alfa-2a in the treatment of metastatic renal cell cancer. Univariate and multivariate analyses were performed to identify prognostic factors for survival. PATIENTS AND METHODS Prospectively, 159 patients were treated with interferon alfa-2a. In the first trial, 42 patients received 50 x 10(6) U/m2 intramuscularly three times per week. In the second trial, 64 patients received gradually escalating doses of interferon alfa-2a from 3 to 36 x 10(6) U subcutaneously administered daily. The third trial was randomized; 25 patients received daily interferon alfa-2a alone and 28 were treated with daily interferon alfa-2a and 0.15 mg/kg vinblastine every 3 weeks. RESULTS The overall response proportion was 10% (two complete and 14 partial responses). The median response duration was 12.2 months. The median survival duration was 11.4 months, with 3% of patients alive at 5 or more years. A univariate statistical analysis showed that a Karnofsky performance status > or = 80, prior nephrectomy, and interval from diagnosis to treatment of longer than 365 days were significant prognostic factors for survival. In a multivariate analysis, only prior nephrectomy and Karnofsky performance status > or = 80 were shown to be independent predictors of survival. CONCLUSION Interferon alfa-2a had minimal antitumor activity in patients with advanced renal cell carcinoma and long-term survival was achieved in a small proportion of patients. The need for continued investigation and the identification of more effective therapy for advanced renal cell carcinoma is evident from the poor overall survival rate observed in these 159 patients. The investigation of new agents and of interferon alfa-2a in combination with other agents remains a priority.

Outcome Predictors of Gamma Knife Radiosurgery for Renal Cell Carcinoma Metastases

Neurosurgery ◽  
2011 ◽  
Vol 69 (6) ◽  
pp. 1232-1239 ◽  
Author(s):  
Hideyuki Kano ◽  
Aditya Iyer ◽  
Douglas Kondziolka ◽  
Ajay Niranjan ◽  
John C. Flickinger ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Brain Metastases ◽  
Cell Carcinoma ◽  
Stereotactic Radiosurgery ◽  
Median Survival ◽  
Renal Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Gamma Knife Radiosurgery ◽  
Tumor Control

Abstract BACKGROUND Although whole-brain radiation therapy (WBRT) has been a standard palliative management for brain metastases from renal cell carcinoma, its benefit has been elusive because of radiobiological resistance. OBJECTIVE To evaluate the role of stereotactic radiosurgery (SRS) in the management of brain metastases from renal cell carcinoma. METHODS We reviewed records from 158 consecutive patients (men = 111, women = 47) who underwent SRS for 531 brain metastases from renal cell carcinoma. The median patient age was 61 years (range, 38-83 years), and the median number of tumors per patient was 1 (range, 1–10). Seventy-nine patients (50%) had solitary brain metastasis. Fifty-seven patients (36%) underwent prior WBRT. The median total tumor volume for each patient was 3.0 cm3 (range, 0.09-47 cm3). RESULTS The overall survival after SRS was 60%, 38%, and 19% at 6, 12, and 24 months, respectively, with a median survival of 8.2 months. Factors associated with longer survival included younger age, longer interval between primary diagnosis and brain metastases, lower recursive partitioning analysis class, higher Karnofsky performance status, smaller number of brain metastases, and no prior WBRT. Median survival for patients with > 2 brain metastases, higher Karnofsky performance status (> 90), and no prior WBRT was 12 months after SRS. Sustained local tumor control was achieved in 92% of patients. Symptomatic adverse radiation effects occurred in 7%. Overall, 70% of patients improved or remained neurologically stable. CONCLUSION Stereotactic radiosurgery is an especially valuable option for patients with higher Karnofsky performance status and smaller number of brain metastases from renal cell carcinoma.

Treatment of Advanced Renal Cell Carcinoma: Recent Advances and Current Role of Immunotherapy, Surgery, and Cryotherapy

2016 ◽  
Vol 103 (1) ◽  
pp. 15-21 ◽  
Author(s):  
Alessia Mennitto ◽  
Elena Verzoni ◽  
Giuseppina Calareso ◽  
Carlo Spreafico ◽  
Giuseppe Procopio
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Cancer Control ◽  
Multimodality Treatment ◽  
Palliative Surgery ◽  
Recent Advances ◽  
Systemic Treatments

Renal cell carcinoma (RCC) is the 10th most common cancer in Western countries. The prognosis of metastatic disease is unfavorable but may be different according to several risk factors, such as histology and clinical features (Karnofsky performance status, time from nephrectomy, hemoglobin level, neutrophils and thrombocytes count, lactate dehydrogenase and calcium serum value, sites and extension of the disease). In this review, we focused on some recent developments in the use of immunotherapy, surgery and cryotherapy in the treatment of advanced disease. While RCC is unresponsive to chemotherapy, recent advances have emerged with the development of targeted agents and innovative immunotherapy-based treatments. Surgical resection remains the standard of care for patients with small renal lesions but in patients with significant comorbidities ablative therapies such as cryoablation and radiofrequency ablation may lead to local cancer control and avoid surgical complications and morbidity. In the setting of metastatic RCC, radical nephrectomy, or cytoreductive nephrectomy, is considered a palliative surgery, usually part of a multimodality treatment approach that requires systemic treatments.

Multi-Institutional Study of the Angiogenesis Inhibitor TNP-470 in Metastatic Renal Carcinoma

1999 ◽  
Vol 17 (8) ◽  
pp. 2541-2541 ◽  
Author(s):  
Walter M. Stadler ◽  
Timothy Kuzel ◽  
Charles Shapiro ◽  
Jeffery Sosman ◽  
Joseph Clark ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Regression ◽  
Angiogenesis Inhibitor ◽  
Term Therapy ◽  
Prior Therapy ◽  
Previously Treated Patients ◽  
Long Term Therapy

PURPOSE: Renal cell carcinoma is resistant to most chemotherapy, and only a minority of patients respond to immunotherapy. Its highly vascular nature suggests that antiangiogenesis therapy might be useful. We thus performed a phase II study of the fumigillin analog TNP-470 in previously treated patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Metastatic renal cell carcinoma patients with good organ function were entered onto the study through five separate institutions. There were no exclusion criteria for prior therapy. All patients were treated at a dose of 60 mg/m2 of TNP-470 infused over 1 hour three times per week. RESULTS: Thirty-three patients were enrolled. Therapy was generally well tolerated, but asthenia, fatigue, vertigo, dizziness, sense of imbalance, and loss of concentration were common and severe enough to lead to therapy discontinuation in five patients. There was only one partial response of short duration (response rate, 3%, 95% confidence interval, 0% to 16%), but six patients (18%) remained on study for 6 or more months without toxicity or disease progression. CONCLUSION: Long-term therapy with TNP-470 has manageable toxicities and is feasible in patients with metastatic renal cell carcinoma but does not lead to any significant objective responses. Further studies in this population using TNP-470 schedules that produce more prolonged drug levels and clinical trial end points other than objective tumor regression may be indicated.

Prognostic Impact of Trial-Eligibility Criteria in Patients with Metastatic Renal Cell Carcinoma

2021 ◽  
pp. 1-8
Author(s):  
Hiroki Ishihara ◽  
Hidekazu Tachibana ◽  
Hironori Fukuda ◽  
Kazuhiko Yoshida ◽  
Hirohito Kobayashi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Real World ◽  
Renal Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Prognostic Impact ◽  
Eligibility Criteria

<b><i>Objective:</i></b> The aim of the study was to evaluate the prognostic impact of trial-eligibility criteria on outcome in real-world metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). <b><i>Patients and Methods:</i></b> mRCC patients treated with TKIs as first-line systemic therapy were retrospectively evaluated. The patients were determined as trial-ineligible when they met at least 1 following trial-ineligible criteria; Karnofsky performance status score &#x3c;70, hemoglobin &#x3c;9.0 g/dL, creatinine &#x3e;2.4 mg/dL (male) or &#x3e;2.0 mg/dL (female), calcium &#x3e;12.0 mg/dL, platelet &#x3c;100,000 /μL, neutrophil &#x3c;1,500 /μL, nonclear-cell histology, and brain metastasis. <b><i>Results:</i></b> Of 238 patients, 101 patients (42%) were determined as trial-ineligible. Progression-free survival (PFS) and overall survival (OS) after the TKI initiation were significantly shorter in the trial-ineligible patients than in the trial-eligible patients (median PFS: 5.53 vs. 15.8 months, <i>p</i> &#x3c; 0.0001; OS: 13.8 vs. 43.4 months, <i>p</i> &#x3c; 0.0001). Objective response rate was also significantly lower in the trial-ineligible patients (15% vs. 37%, <i>p</i> = 0.0003). Multivariate analysis further showed that the trial-eligibility was an independent factor for PFS (hazard ratio [HR]: 2.46, <i>p</i> &#x3c; 0.0001) and OS (HR: 2.39, <i>p</i> &#x3c; 0.0001). In addition, the number of trial-ineligible factors were negatively correlated with PFS and OS. <b><i>Conclusions:</i></b> In real-word, the substantial number of mRCC patients did not meet the trial-eligibility criteria, and their outcome was worse than that in the trial-eligible patients. Further studies focusing on the outcome in real-world trial-ineligible patients in the immune checkpoint inhibitor era are warranted.

Randomized clinical trials and real life studies: Comparison of baseline characteristics of patients in oral target therapies for renal cell carcinoma

2021 ◽  
pp. 107815522110055
Author(s):  
Ruggero Lasala ◽  
Fiorenzo Santoleri ◽  
Alessia Romagnoli ◽  
Felice Musicco ◽  
Paolo Abrate ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Randomized Clinical Trials ◽  
Performance Status ◽  
Relevant Literature ◽  
Real Life ◽  
Ecog Performance Status ◽  
Target Therapies ◽  
Baseline Characteristics

Introduction Pivotal Randomized Controlled Trials (RCTs) constitute scientific evidence in support of therapeutic choices when a drug is authorized in the market. In RCTs, patients are selected in a rigorous manner, in order to avoid bias that may influence efficacy assessments. Therefore, patients who take the drug in Real Life Studies (RLSs) are not the same as those participating in RCTs, which, in turn, leads to low data transferability from RCTs to RLS. The objective of this study was to evaluate the differences between RCTs and RLS, in terms of patient baseline characteristics. Materials and Methods Our study includes all oral target therapies for RCC (Renal Cell Carcinoma) marketed in Europe before March 31, 2019. For each treatment, we considered both RCTs and RLSs, the former gathered from Summary of Product Characteristics published on the European Medicine Agency (EMA) website, and the latter yielded by our search in relevant literature. For each drug considered, we then compared the baseline characteristics of patients included in the RCT samples with those of the samples included in the RLSs using the Chi-squared and Mann-Whitney tests. Results We considered six medicines, for a total of 9 pivotal RCTs and 31 RLSs. RCTs reported the same type of patient baseline characteristics, whereas RLSs are more varied in reporting. Some patient baseline characteristics (metastases, previous treatments, etc.) were significantly different between RCTs and RLs. Other characteristics, such as ECOG Performance Status, brain metastases, and comorbidities, liver and kidney failure, are comprised in exclusion criteria of RCTs, though are included in RLS. Discussion and Conclusion: While evaluating equal treatments for the same indications, RCTs and RLSs do not always assess patients with the same characteristics. It would be necessary to produce evidence from RLSs so as to have an idea of treatment effectiveness in patients groups that are not eligible or underrepresented in RCTs.

scholarly journals Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma

2021 ◽  
pp. 100267
Author(s):  
Hui-wen Lue ◽  
Daniel S. Derrick ◽  
Soumya Rao ◽  
Ahna Van Gaest ◽  
Larry Cheng ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Tumor Regression ◽  
Cell Renal Cell Carcinoma ◽  
Induce Tumor Regression

Nephrectomy Followed by Interferon Alfa-2b Compared With Interferon Alfa-2b Alone for Metastatic Renal Cell Cancer

2021 ◽  
pp. 113-118
Author(s):  
Christopher Weight
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Performance Status ◽  
Cell Cancer ◽  
Interferon Alfa ◽  
Cytoreductive Nephrectomy

This chapter summarizes the findings of a landmark trial of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma performed in the interferon era. All enrolled patients had a good performance status. It found overall survival extended by about 3 months in the cytoreductive-nephrectomy-plus-interferon arm versus the interferon-only arm.

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