scholarly journals Extended Disease Control with Unconventional Cabozantinib Dose Increase in Metastatic Renal Cell Carcinoma

Kidney Cancer ◽  
2021 ◽  
pp. 1-10
Author(s):  
Akanksha Sharma ◽  
Roy Elias ◽  
Alana Christie ◽  
Noelle S. Williams ◽  
Ivan Pedrosa ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Dose Escalation ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Medical Center ◽  
Treatment Options ◽  
Good Tolerability

BACKGROUND: Cabozantinib is among the most potent tyrosine kinase inhibitors (TKIs) FDA-approved for metastatic renal cell carcinoma (mRCC). Effective treatments after progression on cabozantinib salvage therapy are limited. Dose escalation for other TKIs has been shown to afford added disease control. OBJECTIVE: We sought to evaluate whether dose escalation of cabozantinib (Cabometyx®) from conventional doses in selected patients with limited treatment options offered additional disease control. We asked how cabozantinib dose increases may affect circulating drug levels. METHODS: We identified patients with mRCC at the University of Texas Southwestern Medical Center who were treated with cabozantinib dose escalation to 80 mg after progressing on conventional cabozantinib 60 mg. We then queried leading kidney cancer investigators across the world to identify additional patients. Finally, we reviewed pharmacokinetic (PK) data to assess how higher doses impacted circulating levels by comparison to other formulations (Cometriq® capsules). RESULTS: We report six patients treated at two different institutions with cabozantinib-responsive disease and good tolerability, where cabozantinib was dose escalated (typically to 80mg, but as high as 120 mg) after progression on 60 mg, a strategy that resulted in added disease control (median duration, 14 months; 95% Confidence Interval [CI]: 8 –Not Estimable[NE]). Four patients (66.7%) had disease control lasting at least 1 year. No grade III/IV adverse events were identified. A comparison of PK data to FDA-approved cabozantinib 140 mg capsules suggest that cabozantinib 80 mg tablets results in comparable exposures. CONCLUSIONS: mRCC patients with cabozantinib responsive disease and reasonable tolerability may benefit from dose escalation at progression.

scholarly journals Dose escalation of axitinib on disease progression as a strategy in the treatment of metastatic renal cell carcinoma

ESMO Open ◽  
2018 ◽  
Vol 3 (7) ◽  
pp. e000445 ◽  
Author(s):  
Gary Joseph Doherty ◽  
Deirdre Lynskey ◽  
Athena Matakidou ◽  
Kate Fife ◽  
Tim Eisen
Keyword(s):  
Renal Cell Carcinoma ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Disease Progression ◽  
Metastatic Renal Cell Carcinoma ◽  
Dose Escalation ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Drug Label ◽  
Entire Cohort

IntroductionThe AXIS trial established axitinib as a standard of care treatment for patients with metastatic renal cell carcinoma (mRCC) after failure of a prior tyrosine kinase inhibitor. Axitinib dosing begins at 5  mg twice daily, with escalation of doses to 7  and 10  mg after consecutive 2-week intervals if tolerated (as per the drug label). Given clinical concerns about drug-related toxicity, we have used a pragmatic strategy where dose escalations were made only after disease progression or where rapid responses were clinically required.MethodsWe performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for >2 weeks at Addenbrooke’s Hospital, Cambridge, UK, over a 37 -month period to determine the clinical and radiological effects of dose escalations made according to the above strategy.Results42 patients fitting these criteria were identified, 29 having ≥1  dose escalation event (DEE). 60 DEEs were identified (median of two per patient), and the objective radiological consequences of 53 DEEs could be evaluated. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% vs 70%). 56.6 % of all DEEs and 63.6 % of DEEs made as a result of disease progression resulted in disease control. The median OS from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 16.5 months for the entire cohort. The mean dose (for all patients) at 90 days after starting axitinib was 5.92  mg.ConclusionThese data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and this may be a preferred option in patients in whom there are particular concerns about drug-related toxicity, quality of life optimisation or healthcare-associated costs.

A novel strategy for axitinib dosing in the treatment of metastatic renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 464-464
Author(s):  
Gary Doherty ◽  
Deirdre Lynskey ◽  
Athena Matakidou ◽  
Kate Fife ◽  
Tim Eisen
Keyword(s):  
Renal Cell Carcinoma ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Disease Progression ◽  
Metastatic Renal Cell Carcinoma ◽  
Dose Escalation ◽  
Survival Data ◽  
Renal Cell ◽  
Drug Exposure ◽  
Dosing Strategy

464 Background: The AXIS trial established axitinib as an effective second line treatment for patients with metastatic renal cell carcinoma (mRCC). The dosing schedule of axitinib in this trial begins at 5mg twice daily, with escalation of individual doses to 7mg and 10mg after consecutive 2 week intervals if tolerated. We observed significant drug-related toxicity using this dosing strategy, particularly after dose escalations, while clinical responses were often observed at the starting dose. We therefore switched to a pragmatic strategy where dose escalations were made only after disease progression or where a rapid response was deemed clinically pertinent. Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for greater than 2 weeks at Addenbrooke’s Hospital, Cambridge, UK (a tertiary referral center), over a 40 month period to determine the clinical and radiological effects of dose escalations made according to the above strategy. Results: 42 patients fitting these criteria were identified; of these, 29 had at least one dose escalation event (DEE). A total of 58 DEEs were identified, with a median of 2 per patient, and the objective radiological consequences of 50 of these could be determined. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% versus 70%). 56% of all DEEs, and 62.5% of DEEs made as a result of disease progression, resulted in disease control. The median overall survival from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 6.7 months for non-dose-escalated patients. The median survival for dose-escalated patients with a higher than median time on a prior tyrosine kinase inhibitor has not been reached at the time of data cut-off. The mean dose (for all patients) at 90 days after starting axitinib was 5.92 mg. Conclusions: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and may reduce toxicity through lower drug exposure. Our survival data compares favourably to the AXIS trial in a real practice population.

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 426-426 ◽  
Author(s):  
Toni K. Choueiri ◽  
M Dror Michaelson ◽  
Edwin M. Posadas ◽  
Guru Sonpavde ◽  
David F. McDermott ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Dose Escalation ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Tumor Regression ◽  
Low Grade ◽  
Vegf Receptor ◽  
Dose Escalation Study

426 Background: Resistance to VEGF-targeted therapy is a major challenge in contemporary treatment of metastatic renal cell carcinoma (mRCC), and endoglin (CD105) activation may be an important mechanism leading to resistance. Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and mRCC cancer stem cells that is upregulated following VEGF inhibition. TRC105 is an anti-endoglin monoclonal antibody that potentiates bevacizumab (Bev) and VEGF receptor tyrosine kinase inhibitors (VEGFR TKI) in preclinical models. Methods: Heavily-pretreated mRCC pts with ECOG PS 0-1, and acceptable organ function were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg PO BID and then escalated per patient tolerance to a maximum of 10 mg PO BID). Results: Eighteen mRCC pts (median age=61.5; M:F 16:2; median number of prior therapies=3, including >1 VEGFR TKI, clear cell=13, prior axitinib allowed) were treated. TRC105 dose escalation proceeded from 8 mg/kg (n=3) to 10 mg/kg (n=15) without dose limiting toxicity. Low grade AEs characteristic of each drug were not increased in frequency or severity at the recommended phase 2 doses of the two drugs. Three pts (18%) were PR by RECIST and 8 of 17 pts (47%) exhibited >10% tumor reduction. Median PFS is not mature and is at least 5.8 months in the overall population and at least 5.9 months in ccRCC pts. The single patient who progressed on axitinib immediately prior to study entry remains progression free at month 5 with minor tumor regression. Conclusions: TRC105 at 8 and 10 mg/kg was well tolerated with axitinib in mRCC pts with signs of activity. A multicenter randomized phase II trial of axitinib +/- TRC105 is accruing at this time. Clinical trial information: NCT01806064.

Risk of toxicity with immunotherapy–tyrosine kinase inhibitors for metastatic renal cell carcinoma: a meta-analysis of randomized controlled trials

2021 ◽  
Author(s):  
Alessandro Rizzo ◽  
Veronica Mollica ◽  
Matteo Santoni ◽  
Matteo Rosellini ◽  
Andrea Marchetti ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Relative Risks

Aim: Few data are available regarding the safety profile of immunotherapy–tyrosine kinase inhibitor (IO-TKI) combinations in metastatic renal cell carcinoma. The authors investigated all-grade and grade 3–4 (G3–4) adverse events in trials comparing IO-TKI combinations with sunitinib monotherapy. Methods: The relative risks of several all-grade and G3–4 adverse events were analyzed. Results: Relative risks were similar between patients receiving IO-TKI combinations versus sunitinib monotherapy. However, the use of IO-TKI combinations was associated with a higher risk of all-grade and G3–4 diarrhea, all-grade hypothyroidism, G3–4 decreased appetite, all-grade and G3–4 aspartate transaminase increase and all-grade and G3–4 alanine transaminase increase. Conclusion: The results of the authors' meta-analysis suggest that risks of treatment-related adverse events should be carefully considered when choosing IO-TKI combinations in metastatic renal cell carcinoma patients.

scholarly journals Treatable causes of diarrhoea in patients on tyrosine kinase inhibitors for metastatic renal cell carcinoma

2019 ◽  
Vol 30 (1) ◽  
pp. 150-151
Author(s):  
S.V. Lightowlers ◽  
B. Greef ◽  
T. Eisen ◽  
A. Matakidou ◽  
K. Fife ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors
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