scholarly journals Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors

2010 ◽  
Vol 4 ◽  
pp. CMO.S1590 ◽  
Author(s):  
Sumanta Kumar Pal ◽  
Robert A. Figlin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Treatment Options ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Phase Iii

The agents currently approved for use in metastatic renal cell carcinoma (mRCC) can be divided broadly into two categories: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.

scholarly journals Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206

2010 ◽  
Vol 28 (13) ◽  
pp. 2137-2143 ◽  
Author(s):  
Brian I. Rini ◽  
Susan Halabi ◽  
Jonathan E. Rosenberg ◽  
Walter M. Stadler ◽  
Daniel A. Vaena ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Interferon Alfa ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Grade 3

Purpose Bevacizumab is an antibody that binds vascular endothelial growth factor and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN-α) is the historic standard initial treatment for RCC. A prospective, randomized, phase III trial of bevacizumab plus IFN-α versus IFN-α monotherapy was conducted. Patients and Methods Patients with previously untreated, metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN-α (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN-α monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety. Results Seven hundred thirty-two patients were enrolled. The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-α and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-α monotherapy (unstratified log-rank P = .097). Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = .069) favoring bevacizumab plus IFN-α. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-α. Patients who developed HTN on bevacizumab plus IFN-α had a significantly improved PFS and OS versus patients without HTN. Conclusion OS favored the bevacizumab plus IFN-α arm but did not meet the predefined criteria for significance. HTN may be a biomarker of outcome with bevacizumab plus IFN-α.

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.

Cytogenetic changes in metastatic renal cell carcinoma: Basis for sensitivity and resistance to everolimus.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15050-e15050
Author(s):  
Imogen Rose Caldwell ◽  
Paul Oei ◽  
Daniel Ng ◽  
Beth Caudwell ◽  
Peter C.C. Fong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
In Situ Hybridisation ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Fluorescence In Situ Hybridisation ◽  
Cytogenetic Changes

e15050 Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to benefit from these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of benefit from everolimus therapy. Methods: 10 pts with clear cell mRCC treated with everolimus therapy were enrolled. 2 pts had both primary & metastatic specimens. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) & clinical data including Progression-free Survival (PFS) (RECIST 1.1) were obtained. The gene probes chosen for this analysis were: VHL, FHIT, PDGFβ, PDGFRβ, FGFR1, FGFR3, EGFR, MYC, PTEN & IGH@. Results: Results are displayed in the table. The median PFS was 7.5 months (mo), including 4 pts who remain on treatment. 8 pts were treated 1st-line, one 2nd-line & one 3rd-line. The longest responder (PFS 28 mo, 3rd-line) had a normal VHL status but loss of FHIT. 2 pts with the longest PFS had gain of both PDGFβ & PDGFRβ. Changes were observed between the primary & metastatic specimens including the acquisition of gain of PDGFβ & MYC (these pts remain progression-free on treatment). Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFβ & PDGFRβ was observed in 5 pts including 2 with prolonged benefit. Acquisition of gains in gene status suggests evolution of genetic changes between primary & metastatic specimens. [Table: see text]

First-line sunitinib versus pazopanib in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 544-544 ◽  
Author(s):  
Jose Manuel Ruiz Morales ◽  
J Connor Wells ◽  
Frede Donskov ◽  
Georg A. Bjarnason ◽  
Jae-Lyun Lee ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line

544 Background: Sunitinib (SU) and Pazopanib (PZ) have been compared head-to-head in the first-line phase III COMPARZ study in metastatic renal cell carcinoma (mRCC). We compared SU versus PZ, to confirm outcomes and subsequent second-line therapy efficacy in a population-based setting. Methods: We used the IMDC to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS2 and PFS2 were also evaluated. Results: We obtained data from 3,606 patients with mRCC treated with either first line SU (n=3226) or PZ (n=380) with an overall median follow-up of 43.5 months (m) (CI95% 41.4 – 46.4). IMDC risk group distribution for favorable prognosis was 440 (17.3%) for SU vs 72 (25%) for PZ, intermediate prognosis 1414 (55.6%) for SU vs 153 (53%) for PZ, poor prognosis 689 (27.1%) for SU vs 62 (22%) for PZ, p= 0.0027. We found no difference between SU vs. PZ for OS (20.1 [CI95% 18.76-21.42] vs. 23.68 m [CI95% 19.54 - 28.81] p=0.19), PFS (7.22 [CI95% 6.76 - 7.78] vs. 6.83 m [CI95% 5.58 - 8.27] p=0.49). The RR was similar in both groups (Table 1). Adjusted HR for OS and PFS were 0.952 (CI95% 0.788 – 1.150 p=0.61) and 1.052 (CI95% 0.908 – 1.220 p = 0.49), respectively. We also found no difference in any second-line treatment between either post-SU vs. post-PZ groups for OS2 (12.88 [CI95% 11.89 – 14.19] vs. 12.91 m [CI95% 10.3 – 19.1] p=0.47) and PFS2 (3.67 [CI95% 3.38 – 3.87] vs. 4.53 m [CI95% 3.08 – 5.35] p=0.4). There was no statistical difference in OS2 and PFS2 if everolimus was used after SU or PZ (p = 0.33 and p = 0.41, respectively) or if axitinib was used after SU or PZ (p = 0.73 and p = 0.72, respectively). Conclusions: We confirmed in real world practice, that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. [Table: see text]

Treatment Strategies in Metastatic Renal Cell Carcinoma

2010 ◽  
Vol 06 (02) ◽  
pp. 41
Author(s):  
Alain Ravaud ◽  
Jean Christophe Bernhard ◽  
Marine Gross-Goupil ◽  
◽  
◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mammalian Target Of Rapamycin ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Clinical Effects ◽  
Improved Outcomes ◽  
Endothelial Growth Factor

Metastatic renal cell carcinoma (mRCC) is associated with a poor clinical outcome. Until recently, treatment recommendations were limited to immunotherapy and nephrectomy; however, an increased understanding of the molecular biology of RCC has led to the advent of targeted therapies directed against vascular endothelial growth factor/receptor (VEGF/VEGFR) or the mammalian target of rapamycin (mTOR) pathways, both major mediators of tumour growth and progression. These targeted agents have significantly improved outcomes in patients with mRCC, revolutionising treatment. These treatments have overlaps and important distinctions in terms of clinical effects, toxicity and patient populations in which they have been investigated. Concerns in terms of the appropriate sequencing of these agents, their combined use and their role in the context of nephrectomy have emerged as clinically relevant and are being actively investigated.

scholarly journals Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Rachna Raman ◽  
Daniel Vaena
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Immune Therapies ◽  
Localized Renal Cell Carcinoma ◽  
Metastatic Rcc

Localized renal cell carcinoma (RCC) is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR) inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer) has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

scholarly journals Bevacizumab Demonstrates Prolonged Disease Stabilization in Patients with Heavily Pretreated Metastatic Renal Cell Carcinoma: A Case Series and Review of the Literature

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Nicole M. Agostino ◽  
Rebecca Gingrich ◽  
Joseph J. Drabick
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Single Agent ◽  
Interleukin 2 ◽  
Case Series ◽  
Growth Factor Receptor ◽  
Mtor Inhibitors ◽  
Heavily Pretreated

There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC). These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR) via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months) with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.

scholarly journals Eligibility criteria and endpoints in metastatic renal cell carcinoma trials.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 465-465
Author(s):  
Sarah Wong ◽  
David I. Quinn ◽  
Georg A. Bjarnason ◽  
Scott A. North ◽  
Srikala S. Sridhar
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Phase Iii Trials ◽  
The One ◽  
Meta Analyses

465 Background: Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In Sept 2015, DATECAN published recommendations for time-to-event endpoints in mRCC trials. The success of their efforts to harmonize endpoints has not yet been assessed. Methods: We assessed eligibility criteria and endpoints from 18 Phase III mRCC trials starting from 2003 onwards. We also assessed 4 Phase III trials submitted after Sept. 2015 for compliance with DATECAN recommendations. Results: Among the 18 trials, consistent criteria were: absolute neutrophil count ≥1,500/µL, platelet count ≥100,000/µL, and bilirubin ≤1.5xULN. However, the following differed in requirements and measures used: see table.The 4 newer trials did not entirely follow DATECAN’s recommendations. Although their primary endpoint is progression free survival (PFS) as recommended, 3/4 trials do not define PFS, and the one that does includes death from any cause instead of DATECAN’s “death from kidney cancer.” Conclusions: Key eligibility criteria were somewhat inconsistent across phase III mRCC trials, and newer trials’ endpoints did not align with DATECAN’s recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN’s recommendations, greater promotion and enforcement of recommendations is needed to harmonize trial design and improve comparability.[Table: see text]

scholarly journals Cabozantinib in metastatic renal cell carcinoma: latest findings and clinical potential

2017 ◽  
Vol 9 (10) ◽  
pp. 627-636 ◽  
Author(s):  
Melissa Bersanelli ◽  
Sebastiano Buti
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Endothelial Growth Factor

Since the advent of immunotherapy revolutionized the treatment of metastatic renal cell carcinoma (mRCC), the attention of oncologists has been unavoidably shifted from tyrosine kinase inhibitors (TKIs) to immune checkpoint blockade, with the associated risk of listing cabozantinib as just one of many available TKIs. On the contrary, we think that cabozantinib represents a very good option for mRCC treatment, with outstanding outcomes in terms of response rate, progression-free survival, overall survival and quick time to treatment response. Its safety profile is acceptable and its discontinuation rate, due to toxicity, is similar to those of other TKIs. It is still not clear if the effectiveness of this drug is justified by its wide spectrum of multikinase activity, extended to the MET and AXL kinases, or by the simple maintenance of a ‘vascular endothelial growth factor receptor pressure’ after another previous TKI. Early-phase studies are currently ongoing to investigate the potential activity and safety of cabozantinib in association with immunotherapy, albeit with the risk of an overly toxic combination. Thus, future opportunities to improve the clinical use of this drug will probably be represented by a smart treatment sequence.

Tivozanib in patients treatment-naive for metastatic renal cell carcinoma: A subset analysis of the phase III TIVO-1 study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4513-4513 ◽  
Author(s):  
Cora N. Sternberg ◽  
Tim Eisen ◽  
Piotr Tomczak ◽  
Andrew Louis Strahs ◽  
Brooke Esteves ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Common Adverse Event ◽  
Phase Iii ◽  
Treatment Naïve ◽  
Prior Systemic Therapy

4513 Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR=0.797, 95% CI 0.639–0.993; P=0.042; ORR: 33% vs 23%, P=0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N=517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR=0.756, 95% CI 0.580–0.985, P=0.037). ORR was 34% for T vs 24% for S (P=0.038). The most common adverse event (AE; All grades/Grade ≥3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatment-related reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.

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