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European Urology Oncology Jun 2023The comparative efficacy and health-related quality of life (HRQoL) outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib as first-line treatments...
BACKGROUND
The comparative efficacy and health-related quality of life (HRQoL) outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib as first-line treatments for advanced renal cell carcinoma (aRCC) have not been assessed in head-to-head trials.
OBJECTIVE
To assess the efficacy and HRQoL outcomes of nivolumab plus cabozantinib versus pembrolizumab plus axitinib.
DESIGN, SETTING, AND PARTICIPANTS
Patient-level data for nivolumab plus cabozantinib from the CheckMate 9ER trial and published data for pembrolizumab plus axitinib from the KEYNOTE-426 trial were used. CheckMate 9ER data were reweighted to match the key baseline characteristics as reported in KEYNOTE-426.
INTERVENTION
Nivolumab (240 mg every 2 wk) plus cabozantinib (40 mg once daily) and pembrolizumab (200 mg every 3 wk) plus axitinib (5 mg twice daily, initially).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Hazard ratios (HRs) for progression-free survival (PFS), duration of response, overall survival (OS), and deterioration in HRQoL were assessed using weighted Cox proportional-hazard models, with sunitinib as a common anchor. Objective response rates (ORRs) and changes in HRQoL scores from baseline were assessed as difference-in-differences for the two treatments relative to sunitinib.
RESULTS AND LIMITATIONS
After balancing patient characteristics between the trials, nivolumab plus cabozantinib was associated with significantly improved PFS (HR [95% confidence interval {CI}] 0.70 [0.53-0.93]; p = 0.01) and a significantly decreased risk of confirmed deterioration in HRQoL (Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-related Symptoms: HR [95% CI] 0.48 [0.34-0.69]) versus pembrolizumab plus axitinib. OS was similar between treatments (HR [95% CI] 0.99 [0.67-1.44]; p = 0.94). Nivolumab plus cabozantinib was associated with numerically greater ORRs (difference-in-difference [95% CI] 8.4% [-1.7 to 18.4]; p = 0.10) and longer duration of response (HR [95% CI] 0.79 [0.47-1.31]; p = 0.36) than pembrolizumab plus axitinib. Comparative studies using data with a longer duration of follow-up are warranted.
CONCLUSIONS
Nivolumab plus cabozantinib significantly improved PFS and HRQoL compared with pembrolizumab plus axitinib as first-line treatment for aRCC.
PATIENT SUMMARY
This study was conducted to indirectly compare the results of two immunotherapy-based combinations-nivolumab plus cabozantinib versus pembrolizumab plus axitinib-for patients who have not received any treatment for advanced renal cell carcinoma. Patients who received nivolumab plus cabozantinib had a significant improvement in the length of time without worsening of their disease and in their perceived physical and mental health compared with pembrolizumab plus axitinib; patients remained alive for a similar length of time from the start of either treatment. This analysis further adds to our current knowledge of the relative benefits of these two treatment regimens and will help with physician and patient treatment decisions.
Topics: Humans; Carcinoma, Renal Cell; Nivolumab; Axitinib; Sunitinib; Antineoplastic Agents; Kidney Neoplasms; Quality of Life
PubMed: 36842942
DOI: 10.1016/j.euo.2023.01.012 -
Cancer Medicine Sep 2021Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes...
Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second-line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). This study was aimed at comparing the efficacy of two TKIs-axitinib and sunitinib-in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first-line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression-free survival (PFS), cause-specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab-treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first-line therapy in mRCC patients. Thus, from among VEGFR-TKIs, axitinib might be a possible option for application in the middle of IO drug-based treatment sequences.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Sunitinib; Young Adult
PubMed: 34313025
DOI: 10.1002/cam4.4130 -
Clinical Genitourinary Cancer Oct 2021Combined axitinib and immuno-oncology (IO) therapy is approved for first-line advanced renal cell carcinoma. Overlapping toxicities represent a clinical challenge.... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Combined axitinib and immuno-oncology (IO) therapy is approved for first-line advanced renal cell carcinoma. Overlapping toxicities represent a clinical challenge. Calculating the time to resolution (TTR) of common axitinib-related adverse events (AEs) after treatment interruption may help to identify AE etiology and determine appropriate management strategies.
MATERIALS AND METHODS
Data from 5 randomized or single-arm axitinib monotherapy or combination studies were analyzed. Patients with histologically confirmed clear cell advanced renal cell carcinoma were pooled into 3 cohorts based on treatment received: axitinib monotherapy, axitinib + IO, and other tyrosine kinase inhibitor (TKI). Any grade and grade ≥3 treatment-emergent diarrhea, fatigue, hypertension, nausea, and palmar-plantar erythrodysesthesia syndrome were assessed. TTR was defined as the time from treatment interruption/discontinuation to resolution.
RESULTS
The axitinib monotherapy cohort comprised 532 patients, the axitinib + IO cohort 541 patients, and the other TKI cohort 882 patients. Median TTR for all AEs (any grade) in the axitinib monotherapy cohort ranged from 1 to 3 days, except for fatigue (8 days). For diarrhea, hypertension, nausea, and palmar-plantar erythrodysesthesia syndrome, median TTRs were longer in the axitinib + IO (4-11 days) and other TKI (7-8 days) cohorts versus the monotherapy cohort. Results were similar when only AEs of grade ≥3 were considered.
CONCLUSIONS
The TTR of monotherapeutic axitinib-related AEs is ≤3 days, except for fatigue, and generally shorter than for other single-agent TKIs and axitinib + IO. This has important implications for identifying AE etiology with combined axitinib-IO therapy and implementation of appropriate management strategies. ClinicalTrials.org identifiers: NCT00678392, NCT00920816, NCT02493751, NCT02684006, NCT02853331.
Topics: Axitinib; Carcinoma, Renal Cell; Hand-Foot Syndrome; Humans; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 33947608
DOI: 10.1016/j.clgc.2021.03.019 -
The Lancet. Oncology Oct 2019Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include...
BACKGROUND
Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor.
METHODS
We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811.
FINDINGS
Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2).
INTERPRETATION
Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting.
FUNDING
Pfizer.
Topics: Aged; Algorithms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Axitinib; Carcinoma, Renal Cell; Dehydration; Diarrhea; Fatigue; Female; Humans; Hypertension; Ipilimumab; Kidney Neoplasms; Male; Middle Aged; Nivolumab; Progression-Free Survival; Response Evaluation Criteria in Solid Tumors; Retreatment
PubMed: 31427205
DOI: 10.1016/S1470-2045(19)30513-3 -
Asia-Pacific Journal of Clinical... Aug 2020To evaluate predictive factors which associated with oncological outcomes to first-line axitinib for metastatic renal cell carcinoma (mRCC).
AIM
To evaluate predictive factors which associated with oncological outcomes to first-line axitinib for metastatic renal cell carcinoma (mRCC).
METHODS
A retrospective chart review was conducted patients who had been treated with axitinib as first-line therapy for the treatment of mRCC from September 2013 to February 2018. Axitinib was given by single daily oral administration at a dose of 10 mg, which was reduced according to adverse events (AEs). We investigated progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and AEs.
RESULTS
Thirty-eight mRCC patients were enrolled. The median follow-up duration of axitinib treatment was 11.3 months (range = 1.0-56.9). ORR was 28.9%. Median PFS and OS was 12.8, and 17.9 months, respectively. In univariate analysis, baseline lactate dehydrogenase (LDH), neutrophil, corrected calcium (Ca), platelets (Plt) and time from diagnosis were selected as potential predictive factors. Multivariate Cox's proportional hazards model analysis showed that the number of risk factors were associated with PFS (P = 0.03) and OS (P = 0.02).
CONCLUSION
Baseline LDH, neutrophil, Ca, Plt and time from diagnosis are predictive factors for both PFS and OS in first-line treatment with axitinib for metastatic renal cell carcinoma.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Survival Rate; Treatment Outcome
PubMed: 32129940
DOI: 10.1111/ajco.13323 -
Retinal Cases & Brief Reports May 2021Axitinib (Inlyta, New York, NY) is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one previous systemic therapy. A case...
PURPOSE
Axitinib (Inlyta, New York, NY) is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one previous systemic therapy. A case of bilateral retinal hemorrhages and cotton wool spots associated with axitinib is reported.
METHODS
A 62-year-old woman with a 4-year history of renal cell carcinoma with metastases was treated with axitinib at a maximum oral daily dose of 8 mg. Soon after beginning higher dose therapy, she developed blurred vision, floaters, and photopsias.
RESULTS
Funduscopic examination of both eyes revealed cotton wool spots and retinal hemorrhages that improved with cessation of therapy.
CONCLUSION
Axitinib may be associated with microangiopathic retinal toxicity.
Topics: Axitinib; Carcinoma, Renal Cell; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kidney Neoplasms; Middle Aged; Protein Kinase Inhibitors; Retina; Retinal Hemorrhage; Visual Acuity
PubMed: 30015771
DOI: 10.1097/ICB.0000000000000771 -
Future Oncology (London, England) Jan 2021Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved...
Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase III trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab and ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Safety; Survival Rate
PubMed: 33016119
DOI: 10.2217/fon-2020-0079 -
Bulletin Du Cancer Dec 2018HOW TO CHOOSE THE APPROPRIATE SECOND-LINE TREATMENT?: The treatment of advanced or metastatic renal cell cancer (RCC) has dramatically improved in the past ten years. In... (Review)
Review
HOW TO CHOOSE THE APPROPRIATE SECOND-LINE TREATMENT?: The treatment of advanced or metastatic renal cell cancer (RCC) has dramatically improved in the past ten years. In the second-line setting, for patients who progressed on prior antiangiogenic therapy (mainly the VEGFR tyrosine kinase inhibitors (TKI) sunitinib or pazopanib), axitinib and everolimus have been recommended. Since 2015, other drugs have proven their efficacy and are currently considered the standard of care: cabozantinib (TKI that targets VEGFR, MET and AXL) and nivolumab (first anti-PD-1 check point inhibitor). Lenvatinib has also demonstrated promising results in association with everolimus, but this combination is not available in France. The optimal treatment choice for a given patient is challenging for the clinician when facing multiple options. In this article, we review the efficacy, safety and quality of life results of the main pivotal clinical studies involving advanced or metastatic RCC in the second-line setting, to help clinicians in selecting the most appropriate treatment. Beyond that, it is important to define all the sequencing strategy for patients to successively receive all the drugs that have demonstrated an increase in overall survival.
Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Immunotherapy; Indazoles; Kidney Neoplasms; Nivolumab; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Sulfonamides; Sunitinib
PubMed: 30595153
DOI: 10.1016/S0007-4551(18)30379-5 -
International Journal of Urology :... Sep 2023The objective of this study was to assess the clinical outcomes following combined treatment with pembrolizumab and axitinib as first-line therapy for patients with...
OBJECTIVES
The objective of this study was to assess the clinical outcomes following combined treatment with pembrolizumab and axitinib as first-line therapy for patients with advanced RCC.
METHODS
This study retrospectively included 47 consecutive Japanese patients who were diagnosed with advanced RCC and subsequently received pembrolizumab and axitinib between February 2020 and January 2022. Efficacy and safety of this combined therapy in these patients were comprehensively investigated.
RESULTS
The 47 included patients were classified into the following 3 groups by the IMDC system: favorable, 7 (14.9%); intermediate, 24 (51.1%) and poor, 16 (34.0%). Responses to this combined therapy in the 47 patients were as follows: CR, 8 (17.0%); PR, 20 (42.6%); SD, 16 (34.0%) and PD, 3 (6.4%); thus, the ORR was 59.6%. During the observation period, disease progression and death occurred in 19 (40.4%) and 9 (19.1%) patients, respectively, and the median PFS and OS were 18 months and not reached, respectively. Univariate analyses identified the following significant predictors for poor prognostic outcomes: lack of nephrectomy, liver metastasis, bone metastasis, elevated CRP and IMDC poor risk for PFS; and lack of nephrectomy, non-CCC and elevated CRP for OS. AEs and those corresponding to grade ≥ 3 occurred in all (100%) and 30 (63.8%) patients, respectively.
CONCLUSIONS
To our knowledge, this is the first study focusing on real-world outcomes following pembrolizumab and axitinib for treatment-naïve advanced Japanese RCC patients, which showed the efficacy and safety of this combined therapy being similar or even superior to those in clinical trial.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Kidney Neoplasms; Japan; Retrospective Studies
PubMed: 37345413
DOI: 10.1111/iju.15230 -
Future Oncology (London, England) Jun 2017To study patient characteristics and treatment patterns in real-world axitinib use for metastatic renal cell carcinoma.
AIM
To study patient characteristics and treatment patterns in real-world axitinib use for metastatic renal cell carcinoma.
PATIENTS & METHODS
We conducted a retrospective analysis of second- or third-line axitinib use between 1 January 2012 and 31 October 2014 in 135 metastatic renal cell carcinoma patients using the US Oncology Network database.
RESULTS
Overall, 86.7% had clear cell histology, 57.8% had stage III/IV disease at diagnosis and 55.6% were poor risk by Heng criteria. Median treatment duration was 4.6 months (range: 0.03-35.49); 80.7% initiated axitinib at 5 mg/day twice daily, and 67.4% maintained this dose. Overall, 77.8% discontinued treatment, mainly due to disease progression (50.5%) and toxicity (21.9%).
CONCLUSION
Axitinib usage patterns were consistent with the National Comprehensive Cancer Network Guidelines. Ease of use among community oncologists and patient tolerance are key features of axitinib.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Community Health Centers; Female; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Male; Medical Oncology; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome; United States
PubMed: 28485672
DOI: 10.2217/fon-2016-0566