scholarly journals Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells—A View towards Second Line Renal Cell Carcinoma Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1630
Author(s):  
Eva Juengel ◽  
Pascal Schnalke ◽  
Jochen Rutz ◽  
Sebastian Maxeiner ◽  
Felix K.-H. Chun ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cyclin A ◽  
Second Line ◽  
Human Endothelial Cells ◽  
First Line ◽  
Line Therapy

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance.

Sunitinib versus sorafenib as first-line therapy followed by sorefenib and sunitinib for patients with metastatic renal cell carcinoma (RCC) with clear cell histology: A multicenter randomized trial, CROSS-J-RCC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 469-469 ◽  
Author(s):  
Yoshihiko Tomita ◽  
Sei Naito ◽  
Naoto Sassa ◽  
Atsushi Takahashi ◽  
Tsunenori Kondo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Second Line ◽  
First Line ◽  
Standard Dosage ◽  
Line Therapy ◽  
Significant Difference

469 Background: SWITCH, a prospective, randomized sequential trial to evaluate SU/SO versus SO/SU, revealed no difference in first-line or total PFS or OS, but no direct comparison was obtained between 1st line sunitinib (SU) and sorafenib (SO) for clear cell (CC) metastatic renal cell carcinoma (mRCC). Methods: Treatment-naïve patients with CC mRCC, ECOG PS 0/1 and MSKCC favorable or intermediate risk were randomized to receive open-label SU/SO or SO/SU at the standard dosage and schedule. The primary endpoint was 1st line PFS, and secondary endpoints were total PFS and OS. The calculated sample size was 59 per group, with α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 patients enrolled in this study from February 2010 to July 2012 from 39 institutions, 120 could be evaluated (SU/SO, 57 and SO/SU, 63). Baseline patients' characteristics in the SU/SO and SO/SU groups were as follows: favorable risk, 21% and 22%; and presence ofnephrectomy, 88% and 89%, respectively. First-line mPFS was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (HR, 0.67; 95% CI, 0.42–1.08; p= 0.095). There was no statistically significant difference in total (T)-PFS, 27.8 M, and 22.6 m (HR 0.73, CI 0.428-1.246; p=0.247), or OS 38.4 m and 30.9 m (HR 0.934, CI 0.588-1.485; p=0.773). Subgroup analyses showed that T-PFS was NR and 27.8 m (p=0.021) in the favorable risk, and 38.4 m and 16.1 m (p=0.009) in with less than 5 metastatic sites, 6.5 m and 13.6 m (p=0.025) without nephrectomy in the SU/SO and SO/SU groups, respectively. The most common adverse events (AEs) in case of first-line SU or SO (all grade, all cause) were hand–foot syndrome (71% vs. 86%), hypothyroidism (70% vs. 33%), fatigue (57% vs. 40%), hypertension (55% vs. 44%), and diarrhea (23% vs. 38%). AEs were generally lower during second-line therapy. Conclusions: There was no significant difference in first-line PFS, T-PFS, and OS between the two sequential treatments. Although fewer patients received second-line treatment in the SU/SO group, OS in this group was numerically longer than that in the SO/SU group. Clinical trial information: 01481870.

scholarly journals Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3634
Author(s):  
Nicola Longo ◽  
Marco Capece ◽  
Giuseppe Celentano ◽  
Roberto La Rocca ◽  
Gianluigi Califano ◽  
...  
Keyword(s):  
Systematic Review ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Group Performance ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy

A high percentage of patients with metastatic renal cell carcinoma (mRCC) require a second-line option. We aimed to summarize available evidences about the clinicopathological profile of mRCC patients who receive a second-line therapy. A systematic review was performed in August 2020. We included papers that met the following criteria: original research; English language; human studies; enrolling mRCC patients entering a second-line therapy. Twenty-nine studies enrolling 7650 patients (73.5% male, mean age: 55 to 70 years) were included. Clear cell histology was reported in 74.4% to 100% of cases. Tyrosine kinase inhibitors, immunotherapy, bevacizumab, mTOR inhibitors, and chemotherapy were adopted as first line option in 68.5%, 29.2%, 2.9%, 0.6%, and 0.2% of patients, respectively. Discontinuation of first-line therapy was due to progression and toxicity in 18.4% to 100% and in 17% to 48.8% of patients, respectively. Eastern Cooperative Oncology Group performance status score was 0 or 1 in most cases. Most prevalent prognostic categories according to the International Metastatic RCC Database Consortium and Memorial Sloan–Kettering Cancer Centre score were intermediate and good. About 77.8% of patients harboured ≥2 metastatic sites. In conclusion, patients who enter a second-line therapy are heterogeneous in terms of a clinical-pathological profile. Tailoring of second-line treatment strategies is strongly advocated.

scholarly journals Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma

2015 ◽  
Vol 26 (2) ◽  
pp. 378-385 ◽  
Author(s):  
R. Elaidi ◽  
A. Harbaoui ◽  
B. Beuselinck ◽  
J.-C. Eymard ◽  
A. Bamias ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy

Real world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 615-615 ◽  
Author(s):  
Igor Stukalin ◽  
J Connor Wells ◽  
Jeffrey Graham ◽  
Takeshi Yuasa ◽  
Benoit Beuselinck ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Real World ◽  
Renal Cell ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy

615 Background: The immuno-oncology (IO) checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor (TKI) cabozantinib have both been shown in phase III clinical trials to be effective in metastatic renal cell carcinoma (mRCC) after progression on first-line therapy. We sought to explore the real-world efficacy of these therapies in second-line mRCC. Methods: Using the IMDC database, a retrospective analysis was performed on mRCC patients treated with second-line nivolumab or cabozantinib. Baseline characteristics and IMDC risk factors were collected. Overall survival (OS), time to treatment failure (TTF), and response rates were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences. Results: 225 patients were treated with nivolumab and 53 with cabozantinib. There was no significant difference in OS identified, with a mOS for nivolumab of 22.1 months (95% CI 17.18 – NR) and 23.7 months (95% CI 15.52 vs. NR) for cabozantinib, p = 0.6053. The TTF was also similar, with 6.90 months (95% CI 4.60 – 9.20) for nivolumab versus 7.39 months (95% CI 5.52 – 12.85) for cabozantinib, p = 0.1983. The adjusted hazard ratio (HR) for nivolumab vs. cabozantinib was 1.297 (95% CI – 0.728 – 2.312), p = 0.3775. Conclusions: Nivolumab and cabozantinib appear to have similar efficacy in terms of OS and TTF in this real-world patient population, thus both novel agents are reasonable therapeutic options for patients progressing after initial first-line therapy. [Table: see text]

191 Association of immune related adverse events with the efficacy of immune checkpoint inhibitors in metastatic renal cell carcinoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A205-A206
Author(s):  
Vasilii Bushunow ◽  
Leonard Appleman ◽  
Roby Thomas
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Kaplan Meier

BackgroundImmune checkpoint inhibitors (ICI) are first-line therapy for tumors including metastatic renal cell carcinoma (mRCC). Use of ICI is complicated by diverse immune-related adverse events (irAEs), which can add significant morbidity but are also associated with improved efficacy of therapy.1 2 Risk factors for development of irAE are still poorly understood. We hypothesized that patients with mRCC treated with ICI as first-line therapy have higher rates of developing irAE’s than patients previously treated with other therapies.MethodsWe conducted a single-institution, retrospective medical record review of patients with mRCC treated with immune-checkpoint inhibitors from March 2011 through April 15, 2020. We identified therapy duration, and presence, severity, and treatment of adverse events. We defined overall survival as time elapsed from date of diagnosis until death or until completion of study. We classified severity of adverse events according to CTCAE guidelines. Statistical methods included univariate Cox proportional hazards and logistic regression models, and Kaplan-Meier curves were plotted for subgroups.ResultsA total of 64 unique charts were reviewed. 18 patients (28%) of patients were treated with ICI as first-line therapy. 28 patients (44%) experienced immune-related adverse events with a total of 40 irAE’s identified. Most irAE were grade I-II (78%), with 7 (17%) grade III and 1 (2.4%) grade IV irAE’s. Most common sites were skin (29%), thyroid (20%) and gastrointestinal (15%). Patients with irAE had increased survival compared to those who did not have irAE (median survival not reached, vs 139 weeks, p=0.0004) (figure 1). This finding remained after excluding patients who had only experienced dermatologic irAE (median survival not reached in non-derm irAE subgroup, vs 144 weeks for dermatologic or no irAE, p=0.01) (figure 2). Patients treated with ICI as first line therapy had greater rates of developing irAE (72%) than those who had prior therapies (32%) (OR 5.4; p = 0.006). There was no association between histology type and rate of irAE.Abstract 191 Figure 1Kaplan-Meier survival plot of OS between patients with any irAE and those without any irAEAbstract 191 Figure 2Kaplan-Meier survival plot of OS between patients with non-dermatologic irAE and those without any irAE or only dermatologic irAEConclusionsThe development of irAE’s in patients with mRCC treated with ICI is associated with longer survival. This study joins the growing body of evidence showing that presence of irAE’s is associated with increased treatment efficacy. Use of ICI as first-line therapy is associated with higher risk of irAE. Given growing use of ICI as first-line therapy, further study to predict onset and severity of irAE’s is required.AcknowledgementsHong Wang, PhD, for statistical support.Ethics ApprovalThis study was approved by the University of Pittsburgh Institutional Review Board. Approval number STUDY19100386.ReferencesElias R, Yan N, Singla N, Levonyack N, Formella J, Christie A, et al. Immune-related adverse events are associated with improved outcomes in ICI-treated renal cell carcinoma patients. J Clin Oncol 2019;37(7):S645.Verzoni E, Cartenì G, Cortesi E, et al. Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer 2019;7(1):99.

Comparison of First-line Pazopanib and Sunitinib in Metastatic Renal Cell Carcinoma: Experiences of the Urologic Cancer Centre for Research and Innovation

2019 ◽  
Author(s):  
Emily C.L. Wong ◽  
Camilla Tajzler ◽  
Gaurav Vasisth ◽  
Amanda Zhu ◽  
Mathilda Chow ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Side Effects ◽  
Cell Carcinoma ◽  
Disease Progression ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Significant Difference

Abstract Background: Sunitinib and pazopanib are orally-administered tyrosine kinase receptor inhibitors (TKIs) approved as first-line therapy for the treatment of metastatic renal cell carcinoma (mRCC). The IMDC criteria are a predictive prognostic model for patients with mRCC when stratified into three prognosis groups: favourable, intermediate and poor. We retrospectively compared the efficacy and safety of sunitinib and pazopanib as first-line therapy for patients with mRCC in our single institution database. Methods: Retrospective analysis was done to compare progression-free survival (PFS) and side effects of sunitinib and pazopanib as first-line therapy in patients with mRCC. Patients were stratified into prognosis groups according to IMDC criteria. Disease assessment was performed on measurable aspects of disease based on computed tomography or magnetic resonance imaging reports. Survival analysis was performed using the Kaplan-Meier method and Cox regression, with disease progression as the endpoint.Results: Data was obtained from 228 patients with mRCC who were treated with either pazopanib (n=57) or sunitinib (n=171). No significant difference in PFS was found between sunitinib and pazopanib (HR for disease progression or all-cause death, 1.10; 95%CI: 0.76-1.57, p=0.62). Median PFS time for patients receiving sunitinib was 9.4 months and for pazopanib, 8.5 months. Median PFS for patients with intermediate-risk disease was similar between groups (9.4 months vs. 9.2 months, respectively, p=0.93). However, patients treated with sunitinib experienced a greater number of side effects compared to pazopanib. Conclusions: Sunitinib and pazopanib are similarly efficacious as first-line therapy for mRCC. However, adverse events are lower with pazopanib.

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