scholarly journals Biological toxicities as surrogate markers of efficacy in patients treated with mTOR inhibitors for metastatic renal cell carcinoma

BMC Cancer ◽  
2017 ◽  
Vol 17 (1) ◽  
Author(s):  
M. Jebali ◽  
R. Elaidi ◽  
M. Brizard ◽  
J. Fouque ◽  
C. Takouchop ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitors ◽  
Surrogate Markers

scholarly journals Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma

2017 ◽  
pp. 319-329
Author(s):  
David M. Gill ◽  
Neeraj Agarwal ◽  
Ulka Vaishampayan
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Targeted Therapies ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mtor Inhibitors ◽  
Treatment Paradigm

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel–Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA’s approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.

scholarly journals The Effect and Tolerability of MTOR Inhibitors for Metastatic Renal Cell Carcinoma

2013 ◽  
Vol 24 ◽  
pp. ix71
Author(s):  
S. Tamada ◽  
T. Iguchi ◽  
H. Kawashima ◽  
T. Nakatani
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitors

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.

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.

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]

Interstitial lung diseases during treatment with sunitinib or mTOR inhibitors in metastatic renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 420-420
Author(s):  
Philipp Ivanyi ◽  
Thomas Fuehner ◽  
Meike Adam ◽  
Christian Eichelberg ◽  
Edwin Herrmann ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Dose Reduction ◽  
Metastatic Renal Cell Carcinoma ◽  
Targeted Therapies ◽  
Renal Cell ◽  
Pulmonary Function Tests ◽  
Mtor Inhibitors ◽  
Treatment Withdrawal ◽  
Steroid Pulse

420 Background: Targeted therapies are the mainstay for metastatic renal cell carcinoma (mRCC) treatment. Interstitial lung disease (ILD) represents an adverse event (AE) of such therapies while its incidence and management is poorly defined. Here, the experience on ILD with targeted agents in mRCC is reported. Methods: Retrospective analysis of mRCC patients receiving sunitinib, everolimus, or temsirolimus at three German tertiary centers between January 2006 and August 2009 was performed, accessing ILD incidence, management, and outcomes. Results: In total 26 ILD patients were identified out of 306 mRCC patients (8.5%) treated with targeted therapies. Median treatment duration to ILD diagnosis was 3.8 (range 0.98-21.5) months. ILD occurred in 6 of 204 sunitinib treated patients (2.9%), and in 20 of 102 mTOR inhibitor (mTORi) treated patients (19.6%). Cough represents the predominant symptom (69.2%, n=18). Chest CTs revealed 4 patterns: interstitial (n=13), nodular (n=3), ground glass opacities (n=8), or complex patterns (n=2). Pulmonary function tests (PFT) illustrates frequently a restrictive disorder (n=9), often accompanied by a diminished diffusion capacity (n=8). In 53.8% (n=14) a bronchoscopy with broncho-alveolar-lavage (BAL) was performed (lymphocytic cellularity n=6, eosinophilic cellularity n=4). Dose reduction (42.3%, n=11), temporary interruption (46.2%, n=12), or treatment withdrawal (53.8%, n=14) occurred frequently. Nine patients (34.6%) received steroids. Continuation of targeted therapies was maintained in 65.4% (n=17). No patient died from ILD. Conclusions: ILD represents a frequent AE with targeted therapies and also occurs in sunitinib treated patients. For diagnosis of ILD chest CTs are mandatory, whereas PFT and BALs are important subsidiary tools. Clinical relevance of ILD may vary and management of ILD ranges from watch and wait to termination of treatment and steroid pulse therapy. Severe complaints were more frequently associated with eosinophilic BAL, often required an aggressive treatment. However, in most patients, temporary interruption and/or dose reduction with subsequent continuation of targeted therapy remain sufficient to manage ILD.

Sign in / Sign up

Export Citation Format

Share Document