Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal ...cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.
We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.
Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 52%), and diarrhoea (38 34%). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five 4%) and hypertension (four 4%). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 22%) and MET (11 20%) with responses seen irrespective of mutational status.
While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.
None.
Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, ...advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study.
A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS).
Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R
= 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate OR 3.31 (95% CI 1.01-10.83), P = 0.048, PFS HR 0.55 (0.28-1.07), P = 0.08, and OS HR 0.42 (0.21-0.85), P = 0.02. Serious adverse event rates were similar in the unmatched and matched groups.
Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies.
I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.
A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key ...dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.
Abstract Background The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). Objective To analyze outcomes based on the presence of ...bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. Design, setting, and participants We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. Outcome measurements and statistical analysis We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. Results and limitations The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively ( p < 0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) ( p = 0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval CI, 1.22–1.62) for BMs, 1.42 (95% CI, 1.17–1.73) for LMs, and 1.82 (95% CI, 1.47–2.26) for both BMs and LMs compared with other metastatic sites ( p < 0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p < 0.0001). Data in this analysis were collected retrospectively. Conclusions The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
Abstract
Visceral metastasis (VM) and a higher number of bone metastasis generally define high volume/risk in patients with metastatic castration-sensitive prostate cancer (mCSPC). Subgroup analysis ...of pivotal trials did not show a clear benefit of second-generation non-steroidal anti-androgens (NSAAs) in patients with VM. However, subgroup analysis of the trial assessing abiraterone acetate, a CYP 17 inhibitor, plus prednisone (AAP) showed an improved overall survival (OS) in patients with mCSPC with VM. We searched MEDLINE, Web of Science, and congress abstracts for the phase III randomized controlled trials of second-generation NSAAs and AAP in patients with mCSPC. In this pooled analysis, we included 6485 patients from the 6 phase III trials. The rate of patients with VM was 15.2%. Interestingly, in contrast to NSAAs, AAP seems to be effective in improving OS among patients with VM (hazard ratio, HR: 0.89, 95% CI, 0.72-1.11, P = .30 for second-generation NSAAs; HR: 0.58, 95% CI, 0.40-0.84, P = .004 for AAP). In contrast, both second-generation NSAAs (HR: 0.63, 95% CI, 0.57-0.70, P < .001) and AAP (HR: 0.68, 95% CI, 0.57-0.81, P < .001) improved OS in patients without VM. In this pooled analysis, we demonstrate that while AAP provided an OS improvement in patients with VM, second-generation NSAAs did not demonstrate a similar OS benefit in this population.
This review evaluates the pooled data from phase III trials of androgen-receptor signaling inhibitors in patients with metastatic castration-sensitive prostate cancer to dissect the impact of abiraterone acetate plus prednisone versus non-steroidal anti-androgens on overall survival for metastatic castration-sensitive prostate cancer with visceral metastasis.
Antibacterial compounds that reduce extracellular polymeric substances (EPS) are needed to avoid bacterial biofilms in water pipelines. Herein, green one-pot synthesis of α-aminophosphonates (α-Amps) ...A-G was achieved by using ionic liquid (IL) as a Lewis acid catalyst. The synthesized α-Amp analogues were tested against different bacteria such as Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. The representative B analogue showed an efficient antibacterial effect with MIC values of 3.13 μg/mL for E. coli, P. aeruginosa, and 6.25 μg/mL for B. subtilis. Additionally, a strong ability to eliminate the mature bacterial biofilm, with super-MIC values of 12.5 μg/mL for E. coli, P. aeruginosa, and 25 μg/mL for B. subtilis. Moreover, bacterial cell disruption by ROS formation was also tested, and the compound B revealed the highest ROS level compared to other compounds and the control, and efficiently destroyed the extracellular polymeric substances (EPS). The docking study confirmed strong interactions between B analogue and protein structures with a binding affinity of −6.65 kCal/mol for the lyase protein of gram-positive bacteria and −6.46 kCal/mol for DNA gyrase of gram-negative bacteria. The results showed that α-Amps moiety is a promising candidate for developing novel antibacterial and anti-biofilm agents for clean water supply.
Display omitted
•α-aminophosphonates were synthesized and their antibacterial activity was tested.•Minimum inhibitory concentration values reached in the range of 3.13–6.25 μg/mL.•Compound B showed efficient eradication of extracellular polymeric substances.•Molecular docking revealed that compounds B bind strongly to protein structures.•α-Amps moiety is promising to develop new antibacterial and anti-biofilm agents.
PDF
