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Cancer Medicine Aug 2023Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome.
PATIENTS AND METHODS
Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA).
RESULTS
In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R Y score = 0.89, Q Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found.
CONCLUSION
TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.
Topics: Humans; Metabolomics; Colorectal Neoplasms; Metabolome; Triazines; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37329221
DOI: 10.1002/cam4.6248 -
Journal of Cancer 2023Ovarian cancer (OC) represents the seventh most lethal female tumors worldwide. The combination of PARP inhibitor (PARPi) and angiogenic inhibitor has been shown to be...
Ovarian cancer (OC) represents the seventh most lethal female tumors worldwide. The combination of PARP inhibitor (PARPi) and angiogenic inhibitor has been shown to be effective as a first-line or second-line maintenance regimen to synergistically exert antitumor effects, which prompts us to further evaluate the therapeutic effect of the combination of PARP inhibitor Niraparib and anti-angiogenic Brivanib on OC. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay were applied to evaluate the anti-proliferative effect of Niraparib, Brivanib, or the combination treatment on OC cells. The Annexin V-FITC/PI apoptotic assay was adopted to detect cell apoptosis. Tumor xenograft experiment and immunohistochemical (IHC) analysis were performed to evaluate the effect of single or combination treatment on the tumorigenicity of OC . Our current findings revealed that OC cells harboring BRAC1/2 mutations were more sensitive to Niraparib treatment compared to those with BRAC wild-type, and the addition of Brivanib enhanced programmed cell death (PCD) to sensitize OC cells with BRAC mutations to Niraparib treatment . Our work illustrates that the combination regimen of PARPi and angiogenic inhibitor treatment should be beneficial for the OC patients with BRAC mutations, at least partially owing to the induction of multiple forms of programmed cell death (PCD).
PubMed: 38021157
DOI: 10.7150/jca.89082 -
Clinical Colorectal Cancer Dec 2023Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity.
METHODS
The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m intravenously followed by weekly maintenance of 250 mg/m, plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables.
RESULTS
Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea.
CONCLUSION
The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS.
Topics: Humans; Cetuximab; Proto-Oncogene Proteins p21(ras); Disease-Free Survival; Colorectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37704538
DOI: 10.1016/j.clcc.2023.08.006 -
Frontiers in Oncology 2023Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with...
Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with unresectable hepatocellular carcinoma (HCC) have yielded inconsistent results.
METHODS
In this work, a systematic review and meta-analysis was performed to compare the TACE+MKI combination therapy versus TACE monotherapy in HCC patients with time to progression (TTP) adopted as primary outcome.
RESULTS
A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI significantly prolonged TTP (hazard ratio [HR] 0.74, 95% CI 0.62-0.89, p=0.001) versus TACE monotherapy. Subgroup analysis suggested MKI administration before TACE might be preferable to post-TACE MKI for TTP. TACE+MKI also increased objective response rate (ORR) (risk ratio [RR] 1.17, 95% CI 1.03-1.32, p=0.01), but failed to improve overall survival (OS) (HR 0.98, 95% CI 0.86-1.13, p=0.82) and progression-free survival (PFS) (HR 0.75, 95% CI 0.50-1.12, p=0.16). The incidence of any adverse event (AE) did not significantly differ between TACE+MKI and TACE groups (RR 1.17, 95% CI 0.96-1.42, p=0.01), while serious AEs showed significant difference (RR 1.41, 95% CI 1.26-1.59, p<0.0001). Nevertheless, these AEs showing significant difference were mainly associated with MKI toxicities rather than TACE.
CONCLUSIONS
TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design.
PubMed: 37361570
DOI: 10.3389/fonc.2023.1139025