Difference in adverse-event profiles between mTOR inhibitors, temsirolimus, and everolimus for advanced renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 461-461 ◽  
Author(s):  
Masahiro Nozawa ◽  
Takashi Kikuchi ◽  
Mitsutoshi Nishimoto ◽  
Yasuyuki Kobayashi ◽  
Hirotsugu Uemura
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Event ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitors ◽  
Two Agents ◽  
Significant Difference ◽  
The Difference ◽  
Grade 3

461 Background: Everolimus and temsirolimus have proven their efficacy and are used for patients with metastatic renal cell carcinoma (mRCC). They both are rapamycin derivatives and are categorized as mTOR inhibitors. There have been few reports that examined the difference between these two agents regarding adverse events. Our objective was to investigate the difference in the safety of both agents on the basis of our clinical experience. Methods: We identified patients with mRCC who had been treated with everolimus or temsirolimus at our hospital. Treatment duration, relative dose intensity, laboratory data, and adverse events during treatment with each agent were evaluated. Results: A total of 55 patients were evaluable. 43 of those had been treated with everolimus, 22 with temsirolimus, and 10 with both agents. There was no significant difference in age and gender between the two treatment groups. Median treatment durations of the everolimus and temsirolimus groups were 2.4 months and 1.8 months, respectively. Relative dose intensities of the everolimus and temsirolimus groups were 71.6 % and 75.4 %, respectively. Anemia, hyperglycemia, stomatitis, and interstitial lung disease (ILD) were detected with higher frequency in the everolimus group. In the everolimus group, 31 % of patients developed any grade of ILD including 15 % of grade 3, whereas ILD was reported in only one patient treated with temsirolimus with no grade 3 or higher. Frequencies of adverse events of grade 3 or higher were 49 % in the everolimus group and 26 % in the temsirolimus group. Conclusions: Adverse-event profiles of everolimus and temsirolimus may differ from each other. Respiratory disorders may occur more frequently and severely in patients treated with everolimus than temsirolimus. These findings suggest the difference in the pharmacodynamics, pharmacokinetics, and treatment regimen of these two agents may result in different adverse events even though they target the same molecule.

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 Nivolumab-Induced, Late-Onset, Steroid-Sensitive, High-Grade Pneumonitis and Durable Tumor Suppression in Metastatic Renal Cell Carcinoma: A Case Report

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Vincent Louie Mendiola ◽  
Meghana Kesireddy ◽  
Bagi Jana
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Event ◽  
Case Report ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Late Onset ◽  
Drug Discontinuation ◽  
Related Adverse Event ◽  
Grade 3

Nivolumab, an antiprogrammed death-1 checkpoint inhibitor, has been approved for use in unresectable/metastatic renal cell carcinoma (RCC). Nivolumab-induced pneumonitis, a rare, but often severe and potentially life-threatening immune-related adverse event, has been reported, typically, early during the treatment. Due to its low incidence, more studies are needed to better elucidate this condition and its possible effects on cancer progression. We now present a 57-year-old Hispanic male patient with metastatic RCC-clear cell type who, after his 34th cycle of nivolumab (16 months after being on nivolumab), developed a late-onset, immune-related adverse event (IRAE) including a grade 3 pneumonitis, which resolved completely, clinically, and on serial lung imaging with steroids and drug discontinuation. His cancer remained stable with no progression for 18 months despite discontinuation of nivolumab which showed tumor progression resistance. This case report is aimed at providing further information regarding the rare phenomena of a late-onset IRAE, in particular, a grade 3 nivolumab-induced pneumonitis which also responded rapidly to treatment, as well as at discussing this immunotherapy’s durable tumor suppressive effect and a possible associated factor to this phenomenon.

Comparison of quality-adjusted survival in patients with advanced renal cell carcinoma receiving first-line treatment with temsirolimus (TEMSR) or interferon-α (IFN) or the combination of IFN+TEMSR

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5049-5049 ◽  
Author(s):  
S. Parasuraman ◽  
G. Hudes ◽  
D. Levy ◽  
A. Strahs ◽  
L. Moore ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Health State ◽  
Line Treatment ◽  
First Line ◽  
Significant Difference ◽  
Grade 3 ◽  
First Line Treatment

5049 Background: In a phase 3, randomized, 3-arm study of TEMSR or IFN or the combination of TEMSR + IFN in the first-line treatment of patients with advanced renal cell carcinoma (RCC) and poor-prognostic features, TEMSR improved overall survival (p=0.0069) and progression-free survival (p=0.0001) vs. IFN (Hudes et al. J Clin Oncol. 2006;24:LBA4). Quality-adjusted survival was a pre-defined endpoint and is reported. Methods: Quality-adjusted time without symptoms and toxicity (QTWiST) was estimated by partitioning overall survival into 3 distinct health states: time with serious toxicity, time with progression, and time without symptoms and toxicity (TWiST). Survival was value-weighted when patients completed quality of life questionnaires (EQ-5D) at weeks 12 and 32, when a grade 3 or 4 adverse event (AE) was reported, upon relapse or progression, or upon withdrawal from the study. Treatment group comparisons used restricted means analyses estimated from censored survival data. Restricted means were computed for duration of each health state by truncating data at median follow-up (17.9 months). Variance and covariance were estimated using bootstrap methods. Results: All 626 randomized patients in the study were included in computation of health state durations. EQ-5D questionnaires were obtained from 260/300 (87%) upon progression and 230/570 (40%) after a grade 3/4 AE. Patients receiving TEMSR alone had 38% greater TWiST than those receiving IFN alone (TEMSR=6.5 months vs. IFN=4.7 months, p=0.00048). There was no significant difference in TWiST between the combination arm and IFN alone (IFN+TEMSR=5.4 months vs. IFN=4.7 months, p=0.1288). Patients receiving TEMSR alone had 23% greater Q-TWiST than those receiving IFN alone (TEMSR=7.0 months vs. IFN=5.7 months; p=0.0015). There was no significant difference in Q-TWiST for the combination arm compared with IFN alone (IFN+TEMSR=6.1 months vs. IFN=5.7 months, p=0.3469). Conclusions: Patients with advanced RCC receiving TEMSR alone had significantly greater quality-adjusted survival than those receiving IFN alone. No significant financial relationships to disclose.

Combination of immunotherapy and tyrosine kinase inhibitor in first-line metastatic renal cell carcinoma: A real-world Indian experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Amit Rauthan ◽  
Poonam Patil ◽  
Nitin Yashas Murthy ◽  
SP Somashekhar ◽  
Shabber Zaveri ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

e16576 Background: Immuno-oncology (IO) agents in combination with oral tyrosine kinase inhibitors (TKIs) has become a standard first line therapy in metastatic renal cell carcinoma (mRCC) patients. Various combinations such as pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvatinib have all shown better results than sunitinib. There is very limited data about this from India. Methods: This is a single center, retrospective study of mRCC patients, who received first line treatment was nivolumab or pembrolizumab with axitinib or lenvatinib. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AE). Results: Between Jan 2019 to Jan 2021, 22 patients were treated with IO + TKI combination. 12 patients received axitinib, and 10 lenvatinib. Age range was 35 to 78 years with 18 males and 4 females. IMDC risk stratification showed 3 favorable (13.6%), 13 intermediate (59%) and 6 poor risk (27.2%) patients. 2 patients (9%) achieved complete response(CR), 13 (59%) partial response (PR), 4 (18.2%) had stable disease and 3 (13.6%) progressed. The ORR was 68%. Median PFS was 22 months (1 month- 24 months). OS at 1 year was 92%, and median OS was not reached. Grade 3/4 immune related adverse events (AEs) were seen in 3 (14.2%) patients (1 colitis,1 pneumonitis,1 encephalitis), for whom the IO was discontinued. TKI related grade 3/4 AEs were seen in 8 patients (38%), and were managed with dose reductions. Conclusions: Combination IO + TKI is a very effective first line therapy in mRCC. An ORR of 68%, median PFS of 22 months and 1 year OS of 92% is the best we have seen in our patients. The efficacy of this combination is seen in all IMDC subgroups. The combination is well tolerated, and the TKI AEs are comfortably managed with dose reduction. IO combinations should be preferred over single agent TKIs (sunitinib or pazopanib) as first line therapy.

scholarly journals Temporal trends of adverse events and costs of nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma

2021 ◽  
Author(s):  
Daniel M Geynisman ◽  
Ella X Du ◽  
Xiaoran Yang ◽  
Selvam R Sendhil ◽  
Viviana Del Tejo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Individual Patient Data ◽  
Temporal Trends ◽  
Lower Grade ◽  
First Line ◽  
Unit Costs ◽  
Grade 3

Aims: To assess grade 3/4 adverse events (AEs) and costs of first-line nivolumab plus ipilimumab (NIVO + IPI) versus sunitinib in advanced or metastatic renal cell carcinoma. Methods: Individual patient data from the all treated population in the CheckMate 214 trial (NIVO + IPI, n = 547; sunitinib, n = 535) were used to calculate the number of AEs. AE unit costs were obtained from US 2017 Healthcare Cost and Utilization Project and inflated to 2020 values. Results: The proportion of patients experiencing grade 3/4 AEs decreased over time. Patients who received NIVO + IPI had lower average per-patient all-cause grade 3/4 AE costs versus sunitinib (12-month: US$15,170 vs US$20,342; 42-month: US$19,096 vs US$27,473). Conclusion: Treatment with NIVO + IPI was associated with lower grade 3/4 AE costs than sunitinib.

Comparison of efficacy and safety of checkpoint inhibitors in patients with genitourinary cancers aged below and above 75 years.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16101-e16101
Author(s):  
Gerald Bastian Schulz ◽  
Bernadett Szabados ◽  
Annabel Spek ◽  
Michael D. Staehler ◽  
Christian Stief ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Cancer Patients ◽  
Renal Cell ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
The Elderly ◽  
Genitourinary Cancers ◽  
Grade 3

e16101 Background: Checkpoint-inhibitors have recently been introduced in the treatment of patients with genitourinary cancers. However, the use in elderly patients is controversial due to putative age-associated changes including the dysregulation of the immune system. We sought to investigate the safety and efficacy of immunotherapy in patients younger and older than 75 years of age. Methods: We conducted a retrospective review of patients with renal cell carcinoma and urothelial cancer treated with different immunotherapeutic agents between August 2015 and September 2018 at a high-volume single institution. Eligible patients received at least one cycle of single agent or a combination of checkpoint inhibitors as first or following treatment line. Immune-related adverse events (irAE) were graded using the NCI CTCAE v 4.0. Clinicopathological parameters including gender, cancer entity, ECOG, adverse events, comorbidities and response to treatment were stratified by age ≥ 75 vs. < 75 years and tested with a Pearson's chi-squared test. Additionally, we evaluated the impact of irAE on oncological outcome using the log-rank test. Results: 79 patients were identified, of those 27 (34.2%) were 75 years and older (15 renal cell carcinoma and 12 urothelial cancer patients) and 52 (65.8%) were younger than 75 years (39 renal cell carcinoma and 13 urothelial cancer patients). 2 complete responses were achieved in the elderly group and 6 in the younger group (p = 0.56). Disease control rate (stable disease, partial and complete response) was 48,1% in the elderly group and 53.8% in the younger group (p = 0.631). We observed a total of 30 irAEs (18 grade 1-2 and 12 grade 3-4), with an even distribution among the groups (≥75 years: 1 grade 4 AE; < 75 years: 12 grade 3-4 AEs). Except for ECOG ≥2 (p = 0.009) and ≥2 comorbidities (p < 0.001), there was no difference when groups were stratified by age. Both disease control rate and irAE did not differ between age subgroups. Occurrence of irAE showed no impact on oncological survival. Conclusions: The study demonstrates that patients over 75 years of age with renal cell and urothelial cancer treated with checkpoint-inhibitors respond with a good toxicity profile and an efficacy comparable with the younger population. irAE seem to have no impact on prognosis.

Correlation Between the Tyrozinkinazine Inhibitor Sunitinib - Dose, Schedule of Administration and Adverse Events

2017 ◽  
Vol 68 (7) ◽  
pp. 1652-1659
Author(s):  
Dana Lucia Stanculeanu ◽  
Raluca Ioana Mihaila ◽  
Daniela Zob ◽  
Oana Catalina Toma ◽  
Raluca Ioana Mihaila ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Dose Reduction ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Dose Schedule ◽  
Prophylactic Measures ◽  
Hand Foot Syndrome

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated survival benefit in patients with metastatic renal cell carcinoma (mRCC) and is generally well tolerated with most adverse events, manifesting as mild to moderate in severity. The most frequent related adverse events include hand-foot syndrome (HFS), hypertension, proteinuria, cardiac toxicities, myelosuppression, fatigue/asthenia, hypothyroidism, diarrhea and hepatotoxicity. The study aims to determine incidence of adverse events among patients with metastatic renal cell carcinoma (mRCC) treated Sunitinib within five years from 2010 to 2015 and comparing the results with data from literature. The study included a total of 56 patients treated with Sunitinib, with a dose of 50 mg (Schedule 4/2). Due to adverse events and individual safety and tolerability, at the indication of the personal clinician, 11 patients needed dose reduction, with a continuous dose of 37.5 mg, daily and 28 patients continued the dose of 50 mg taken daily, on a different schedule (2/1 schedule). The most important toxicities were anemia, leukopenia, thrombocytopenia, gastrointestinal effects (diarrhea), fatigue and hypertension. After dose reduction or modified schedule the incidence of the most frequent toxicities (HFS, leukopenia, thrombocytopenia and fatigue) decreased, but hypertension was still observed in 30% of patients. The results are similar with data from literature. Early identification of individuals at risk and monitoring patients during Sunitinib treatment is very important and it can facilitate early intervention with prophylactic measures or supportive treatment, thus increasing quality of life and adherence to treatment. Further studies need to establish which targeted population can benefit the most from adjusted regimens and to correlate them with prognostic factors for survival.

scholarly journals Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2441
Author(s):  
Anna Caliò ◽  
Matteo Brunelli ◽  
Stefano Gobbo ◽  
Pedram Argani ◽  
Enrico Munari ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Therapy Response ◽  
Cathepsin K ◽  
Mtor Inhibitors ◽  
Predictive Marker ◽  
Predictive Biomarker ◽  
Renal Tumors ◽  
Epithelioid Angiomyolipoma

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.

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