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Clinical Cancer Research : An Official... Dec 2023Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a...
PURPOSE
Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).
EXPERIMENTAL DESIGN
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
RESULTS
VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.
CONCLUSIONS
By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
Topics: Animals; Humans; Carcinoma, Renal Cell; Axitinib; Tyrosine Kinase Inhibitors; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 37733811
DOI: 10.1158/1078-0432.CCR-23-1182 -
Der Urologe. Ausg. A Sep 2020
Topics: Humans; Antibodies, Monoclonal, Humanized; Axitinib; Carcinoma, Renal Cell; Kidney Neoplasms; Sunitinib
PubMed: 32865647
DOI: 10.1007/s00120-020-01298-3 -
Therapeutics and Clinical Risk... 2022Until recently, the approved first-line treatment for metastatic RCC (mRCC) consisted of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth... (Review)
Review
Until recently, the approved first-line treatment for metastatic RCC (mRCC) consisted of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor receptors (VEGFR) monotherapy. The landscape of first-line treatment has been transformed in the last few years with the advent of immune checkpoint inhibitors (ICI) or VEGFR TKI plus ICI combinations. This article focuses on the profile of one of these ICI plus VEGFR TKI combination, avelumab plus axitinib. We detail the characteristics of each drug separately, and then we explore the rationale for their association, its efficacy and the resulting toxicity. Finally, we examine the factors associated with avelumab plus axitinib outcomes, and their impact on therapeutic strategy.
PubMed: 35837579
DOI: 10.2147/TCRM.S263832 -
Expert Opinion on Biological Therapy Jan 2020: The systemic therapy in metastatic renal cell carcinoma (mRCC) is moving from tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors to... (Review)
Review
: The systemic therapy in metastatic renal cell carcinoma (mRCC) is moving from tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors to immune checkpoint inhibitors and its combination with TKIs.: This review provides a general overview using immune checkpoint inhibition for the treatment of RCC. Clinical results from conducted and ongoing clinical trials are summarized and checkpoint inhibition is reviewed in the context to other available systemic therapies such as TKIs for mRCC based on the different International Metastastic RCC Database Consortium (IMCD) risk groups. Furthermore, prospects for the use of predictive biomarkers in the decision-making process of chosen therapy will be given.: Using checkpoint inhibition in mRCC has demonstrated a superior efficacy for patients with IMDC intermediate and poor risk for ipilimumab combined with nivolumab. Furthermore, therapeutic regimes with tyrosine kinase inhibition plus immune checkpoint-inhibition were recently presented and demonstrated superiority in all risk groups for axitinib plus pembrolizumab in overall survival and progression-free survival (PFS) and axitinib plus avelumab in PFS compared to sunitinib monotherapy. Novel biomarkers of response to further optimize therapeutic selection and patient outcomes are ongoing medical objectives.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 31587590
DOI: 10.1080/14712598.2020.1677601 -
Romanian Journal of Morphology and... 2023The formation, proliferation, and evolution of glioblastoma (GB) are significantly influenced by pathological angiogenesis. This is supported by several growth factor...
The formation, proliferation, and evolution of glioblastoma (GB) are significantly influenced by pathological angiogenesis. This is supported by several growth factor receptors, such as the vascular endothelial growth factor receptor (VEGFR). In this experiment, we examined how the Food and Drug Administration (FDA) approved VEGFR blockers Sorafenib and Axitinib affect the viability of GB cells in vitro. Cells were cultivated in 96-well culture plates for the experiments, afterwards Sorafenib and Axitinib were administered at doses ranging from 0.3 μM to 80 μM. 2,5-Diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the impact of VEGFR inhibition on high-grade glioma (HGG) cell lines. To observe the morphological changes in cell shape, we used a 10× magnification microscopy. Our results showed that both Axitinib and Sorafenib retarded GB1B culture proliferation in a dose- and time-dependent manner in comparison to control cohorts that had not received any treatment. The half maximal inhibitory concentration (IC50) value for Axitinib was 3.5839 μM after three days of drug administration and 2.2133 μM after seven days of drug administration. The IC50 value for Sorafenib was 3.5152 μM after three days of drug administration and 1.6846 μM after seven days of drug administration. After the treatment with Axitinib or Sorafenib, very few cells became rounded and detached from the support, others remained adherent to the culture substrate, but acquired a larger, flatter shape. Our results indicate that VEGFR might serve as a key target in the treatment of GB. Although it is known that in vitro some drugs block the VEGFR more potently, clinical evidence is required to show whether this actually translates to better clinical outcomes.
Topics: Humans; Axitinib; Sorafenib; Glioblastoma; Cell Survival; Vascular Endothelial Growth Factor A; Indazoles; Antineoplastic Agents
PubMed: 37518874
DOI: 10.47162/RJME.64.2.07 -
Frontiers in Pharmacology 2023This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment... (Review)
Review
This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.
PubMed: 37745049
DOI: 10.3389/fphar.2023.1223929 -
Therapeutic Advances in Medical Oncology 2020The treatment landscape of metastatic renal cell carcinoma (mRCC) has been transformed with the advent of antiangiogenics, notably tyrosine kinase inhibitors (TKIs)... (Review)
Review
The treatment landscape of metastatic renal cell carcinoma (mRCC) has been transformed with the advent of antiangiogenics, notably tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR), and immune checkpoint inhibitors (ICIs). Both treatment options have improved outcomes of patients and modified the natural history of mRCC. Clinical investigations have focused on evaluating combination regimens containing ICIs and VEGFR-directed TKIs. Namely, the combinations of axitinib plus pembrolizumab (KEYNOTE-426) and axitinib plus avelumab (JAVELIN RENAL 101) have shown improved outcomes compared with sunitinib in treatment-naïve patients with mRCC. In this review, we discuss the clinical data of single-agent TKIs and ICIs in mRCC and the rationale for the combination ICIs and TKIs based on preclinical and clinical evidence. We also explore the current challenges for regimen selection and development of predictive biomarkers.
PubMed: 32215057
DOI: 10.1177/1758835920907504 -
Hematology/oncology and Stem Cell... Apr 2023Renal cell carcinoma (RCC) is the most common kidney cancer in adults (approximately 90%), and clear cell RCC (ccRCC) is the most frequent histologic subtype... (Review)
Review
Renal cell carcinoma (RCC) is the most common kidney cancer in adults (approximately 90%), and clear cell RCC (ccRCC) is the most frequent histologic subtype (approximately 75%). We reviewed the safety and efficacy of checkpoint inhibitors (CPIs) in ccRCC, identifying 5927 articles in PubMed, Embase, Cochrane, and Web of Science. Ten randomized control (N = 7765) and 10 non-randomized (N = 572) studies were included. Overall, 4819 patients treated with CPI combinations were compared with everolimus, sunitinib, or placebo. Overall response rates (ORR) were 9-25% with nivolumab (niv), 42% with niv + ipilimumab (ipi), 55.7% with niv + cabozantinib, 56% with niv + tivozanib vs. 5% with everolimus. ORR was 51.5-58% with avelumab + axitinib vs. 25.5% with sunitinib. ORR was 59.3-73% with pembrolizumab + tyrosine kinase inhibitor vs. 25.7% with sunitinib. ORR was 32-36% with atezolizumab + bevacizumab vs. 29-33% with sunitinib. In patients with PD-L1+ve and -ve ccRCC, niv, atezolizumab, ipi, and pembrolizumab were safe and effective alone and when combined with cabozantinib, tivozanib, axitinib, levantinib, and pegilodecakin. Atezolizumab + bevacizumab was safe and effective in ccRCC with high PD-L1 expression. Pembrolizumab was safe and effective in preventing recurrence in ccRCC patients with nephrectomy. Additional randomized, double-blind, multicenter clinical trials are needed to confirm these results.
Topics: Adult; Humans; Carcinoma, Renal Cell; Sunitinib; Axitinib; Everolimus; B7-H1 Antigen; Bevacizumab; Kidney Neoplasms; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37023219
DOI: 10.56875/2589-0646.1027 -
European Urology Oct 2022In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC).
OBJECTIVE
To evaluate health-related quality of life (HRQoL) in KEYNOTE-426.
DESIGN, SETTING, AND PARTICIPANTS
A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease-Related Symptoms (FKSI-DRS) questionnaires.
RESULTS AND LIMITATIONS
Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (-0.79% improvement vs sunitinib; 95% confidence interval [CI] -7.2 to 5.6), QLQ-C30 (7.5% improvement vs sunitinib; 95% CI 1.0-14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2-17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82-1.3; TTfD HR 0.82; 95% CI 0.69-0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87-1.3; TTfD HR 0.98; 95% CI 0.83-1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95-1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1-1.7). Patients were assessed during the off-treatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL.
CONCLUSIONS
Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS.
PATIENT SUMMARY
Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Quality of Life; Sunitinib
PubMed: 35843776
DOI: 10.1016/j.eururo.2022.06.009 -
Clinical Genitourinary Cancer Apr 2023Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib,...
INTRODUCTION
Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib, are approved for first-line treatment of metastatic renal cell carcinoma (mRCC). Pembrolizumab/axitinib is associated with superior progression free survival (PFS), objective response rate (ORR), and overall survival over sunitinib. However, to date, the activity and safety of pembrolizumab/axitinib in later lines of therapy has not been reported.
MATERIALS AND METHODS
Clinical data of consecutive patients receiving pembrolizumab/axitinib in the second-line or beyond for mRCC at Yale-New Haven Hospital were retrospectively collected. Best objective response was assessed using RECIST 1.1 criteria. Kaplan-Meier function was used to analyze survival.
RESULTS
Thirty-eight patients were included. Median age was 64, 92.1% had clear cell mRCC, 18.4% had sarcomatoid dedifferentiation; 94.7% had prior ICI and 39.5% had prior VEGF-R-TKI. Pembrolizumab/axitinib was administered as second-line therapy in 21 (55.5%) patients, third-line in 5 (13.2%) and beyond in 12 (30.2%). Adverse events (AEs) occurred in 86.8% of patients. Grade 3-4 AEs attributed to pembrolizumab and axitinib were seen in 18.4% and 6.4% of patients, respectively. No grade 5 AEs occurred. At a median follow up of 17.1 months, median PFS was 9.7 months (95% CI, 4.1-15.3). Amongst 36 response evaluable patients, the ORR was 25.0% (all partial) and disease control rate (including stable disease for at least 6 months) was 66.6%. The most frequent treatment sequence was first-line nivolumab/ipilimumab followed by second-line pembrolizumab/axitinib (n = 17, 44.7%); among this cohort, median PFS with pembrolizumab/axitinib was 11.1 (95% CI, 8.4-13.7) months, with an ORR of 31.4%.
CONCLUSION
Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line. Prospective studies evaluating ICI-VEGF-R-TKI combinations beyond first-line are warranted to identify the most beneficial treatment sequencing in mRCC.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Vascular Endothelial Growth Factor A; Kidney Neoplasms; Prospective Studies; Retrospective Studies
PubMed: 36681606
DOI: 10.1016/j.clgc.2023.01.002