BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of
alterations. Patients (
= 67) who were ...unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.
BJG398 is active in patients with alterations in
, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status.
.
The approval and use of molecular targeted agents for the first-line treatment of metastatic renal cell carcinoma (mRCC) has substantially improved the clinical outcome of patients. Although ...eventually all patients progress, hopes have been renewed with the approval of everolimus for patients who progress on or after treatment with tyrosine kinase inhibitors. In order to improve the prognosis for these patients, it is imperative to understand the reasons why patients with mRCC fail on first-line treatment. Currently, progression is assessed on the basis of the Response Evaluation Criteria in Solid Tumors, but it is known that targeted agents tend to cause disease stabilization rather than a significant decrease in tumor mass. Therefore, it may be time to evaluate the need to incorporate additional diagnostic methods in the assessment of disease response. Equally important is the study of the factors that determine the success or failure of second-line therapy in order to increase the chances of delivering the most effective and personalized therapy possible. In this article, we review the evidence related to the evaluation of patients with mRCC who fail on first-line treatment with targeted agents, including the systems to assess response and progression, the prognostic factors, the prognostic models that have been created based on these factors, and what is known about predictive biomarkers of disease outcome.
Abstract The field of urothelial carcinoma has shown considerable advances in terms of diagnosis, staging, and treatment. The increasing knowledge of molecular pathways and genes involved in the ...occurrence of this tumor has encouraged the search for new, more effective and less toxic therapies, and has prompted the design and development of clinical trials. However, the speed at which results are published makes it difficult for clinicians to cover the vast amount of information available. Moreover, in clinical practice some gaps remain concerning treatment options for patients who have progressed after first-line cisplatin-based combinations, who cannot tolerate cisplatin-based chemotherapy, or who have received platinum-based neoadjuvant or adjuvant therapy, and thus cannot be offered this option on disease progression. The purpose of this review is to issue a series of recommendations on the optimal management of early and advanced urothelial carcinoma based on current evidence and the available updated guidelines.
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•Cabozantinib is approved for use in patients with advanced renal cell carcinoma.•Cabozantinib is associated with high interpatient variability in drug clearance.•Patients may require ...dose reduction to achieve optimal cabozantinib exposure.•Exposure-response models predict that dose reductions improve tolerability.•Appropriate dose reductions are predicted to have minimal impact on efficacy.
Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.
Este artículo es el resultado de una investigación cuyo enfoque es cuali-cuantitativo. El propósito fue recolectar información y datos teóricos para entender y explicar cómo la Programación ...Neurolingüística (PNL) puede a través de los nuevos estudios de la Didáctica de la Lengua y la Literatura (DLL) contribuir en su desarrollo. Se pretende lograr que los maestros lleguen a vincularse con el mundo de los estudiantes. Las estrategias de la PNL han sido adaptadas a las clases de Lengua de una manera didáctica y se toma en cuenta el papel de las emociones en el desarrollo del proceso de enseñanza-aprendizaje. Los datos estadísticos obtenidos mediante una encuesta descriptiva ayudaron a conocer la forma en la que los maestros trabajan con los estudiantes y cómo ellos responden al modelo de aprendizaje aplicado. Por lo tanto, se concluyó que este modelo no responde a las necesidades actuales. La propuesta planteada brinda nuevas herramientas al docente para alcanzar un aprendizaje significativo tomando en cuenta las necesidades e intereses de los alumnos. Para esto el estudio se centra en las diferentes técnicas de la PNL, aplicables en el aula como: conocimiento de los sistemas representacionales que existen para sentir y conocer el mundo que nos rodea, cómo funcionan los niveles de pensamiento lógico y cómo afectan a la conducta, estrategias de rapport para sintonizar en grupo e incluso estrategias para mejorar la ortografía con la PNL.
Summary Background Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for ...all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma. Methods TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete. Findings Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5–34·8), 39 (36%, 90% CI 28–44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24–40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3–4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 7% of 207 patients), colitis (13 6%), and diarrhoea (13 6%). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia. Interpretation In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy. Funding Bristol Myers Squibb.
The PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact ...on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib.
This was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders.
22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders.
Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.
The mTOR pathway is frequently altered in UC and is crucial in regulating immune responses. This phase 2 trial investigated the role of the combination of sapanisertib (mTOR inhibitor) and paclitaxel in patients who progressed to standard therapies. About 22 patients were enrolled. ORR was 18.2%. Median OS was 6.1 months (95% CI: 1.8-13.4). 86% of patients had grade 3-4 adverse events (AE).
•ECCO Essential Requirements for Quality Cancer Care (ERQCC) are position papers on delivering high-quality care.•Each paper focuses on a cancer type, in this case prostate cancer.•Prostate cancer is ...a major healthcare burden and has complex treatment options.•High-quality care can only be a carried out in specialised units or centres.•The essential, multidisciplinary details for such centres are set out by the ERQCC expert group.
ECCO Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give oncology teams, patients, policymakers and managers an overview of essential care throughout the patient journey.
Prostate cancer is the second most common male cancer and has a wide variation in outcomes in Europe. It has complex diagnosis and treatment challenges, and is a major healthcare burden.
Care must only be a carried out in prostate/urology cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals. Such units are far from universal in European countries.
To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.
Purpose
To describe the incidences of hypogonadism, hypertension, and dyslipidaemia in patients with stage 1 seminoma (S1S) testicular cancer (TC) treated with a risk-adapted strategy.
Methods
A ...retrospective analysis from 2000 to 2020 was conducted. Active surveillance (AS), carboplatin one cycle, and carboplatin two cycles were offered according to risk factors. Cumulative incidences and relapse-free survival (RFS) were estimated.
Results
Of the 145 patients, 8 (5.4%) were excluded due to bilateral TC or hypogonadism at diagnosis. Median follow-up time was 8.2 years. Eighty-four, 30, and 33 patients were treated with AS, carboplatin one cycle, and carboplatin two cycles, respectively. In the overall population, the 5-year and 10-year cumulative incidences were 1.6% and 5.3% for hypogonadism; 2.0% and 8.6% for hypertension; and 12.4% and 25.1% for dyslipidaemia. No statistically significant differences were found in the incidences among the three adjuvant strategies. Five-year and 10-year RFS were 85.9% and 83.3% for AS; 92.4% and 84.0% for carboplatin one cycle; and 96.7% at both times for carboplatin two cycles.
Conclusion
There were no statistically differences in cumulative incidences of hypogonadism, hypertension, and dyslipidaemia in S1S patients treated with a risk-adapted strategy.
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