Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study.

BACKGROUND: FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. METHODS: The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. FINDINGS: Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. INTERPRETATION: RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. FUNDING: Janssen Research & Development.

Repurposed Therapeutic Agents Targeting the Ebola Virus: A Systematic Review.

BACKGROUND: The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD. OBJECTIVE: We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy. METHODS: We conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial. RESULTS: We identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence. CONCLUSIONS: Several established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.

The Safety, Tolerability, and Preliminary Efficacy of a Gemcitabine-releasing Intravesical System (TAR-200) in American Urological Association-defined Intermediate-risk Non-muscle-invasive Bladder Cancer Patients: A Phase 1b Study.

Background and objective: Patients with intermediate-risk non-muscle-invasive bladder cancer (IR NMIBC) have a high risk of recurrence and need effective therapies to reduce the risk of disease recurrence or progression. This phase 1b study (NCT02720367) assessed the safety and tolerability of TAR-200, an intravesical drug delivery system, in participants with IR NMIBC. Methods: Participants with recurrent IR NMIBC were eligible. Participants received either two 7-d or two 21-d TAR-200 dosing cycles over a 4-6-wk period in a marker lesion/ablation design. TAR-200 was placed in the window between the cystoscopy showing recurrent papillary disease and the subsequent complete transurethral resection of the bladder tumour. The primary endpoint was TAR-200 safety. The secondary endpoints included TAR-200 tolerability, pharmacokinetics, and preliminary efficacy. Key findings and limitations: Twelve participants received TAR-200 treatment. No TAR-200-related serious or grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred. Nine participants had grade ≤ 2 TAR-200-related TEAEs, with urgency, dysuria, and haematuria being most common. Two participants refused a second dosing cycle due to urinary urgency and frequency. Insertion and removal of TAR-200 was successful in all cases. Plasma gemcitabine concentrations remained below the lower limit of detection. Five participants (42%) had complete response (CR): four had pathological CR and one had CR based on visual assessment. Conclusions and clinical implications: TAR-200 appears to be safe and well tolerated, with encouraging preliminary efficacy in participants with IR NMIBC. This study lays the groundwork for the multiple phase 2 and 3 global studies that are currently on-going for TAR-200. Patient summary: In this study, researchers evaluated the safety of the novel drug delivery system TAR-200 in participants with intermediate-risk non-muscle-invasive bladder cancer. They concluded that TAR-200 was safe and well tolerated with promising antitumour activity.

Adherence Measures for Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate plus Prednisone: Results of a Prospective, Cluster-Randomized Trial.

Residual androgen production causes tumor progression in metastatic, castration-resistant prostate cancer (mCRPC) patients. Abiraterone acetate (AA), a prodrug of abiraterone, is an oral CYP-17 inhibitor that blocks androgen production. It was hypothesized that adherence-enhancing measures (AEM) might be beneficial for mCRPC patients receiving abiraterone acetate plus prednisone (AA + P). This multicenter, prospective, 2-arm trial allocated mCRPC patients who were progressive after docetaxel-based chemotherapy or asymptomatic/mildly symptomatic after failure of an androgen deprivation therapy to Arm A (with AEM) or Arm B (without AEM) by center-based cluster-randomization. The primary objective was to assess the influence of AEM on discontinuation rates and medication adherence in mCRPC patients treated with AA + P. A total of 360 patients were allocated to Arm A, and 315 patients to Arm B. At month 3, the rate of treatment discontinuation, not due to disease progression or the start of new cancer therapy, was low in both arms (A: 9.0% vs. B: 7.3%, OR = 1.230). Few patients had a medium/low Morisky Medication Adherence Scale (MMAS-4) score (A: 6.4% vs. B: 9.1%, OR = 0.685). The results obtained did not suggest any clear adherence difference between Arm A and Arm B. In patients with mCRPC taking AA + P medication, adherence seemed to be generally high.

Physicians in the pharmaceutical industry: their roles, motivations, and perspectives.

Although physicians occupy a significant number of key positions in the pharmaceutical industry, practicing clinicians are often unaware of the variety of career paths within this industry, or of the structure of a pharmaceutical company. Here, we address questions that practicing clinicians frequently ask their colleagues in the pharmaceutical industry. In addition to providing an overview of the common roles occupied by physicians in pharma, we also describe the various motivations for transitioning into the industry and discuss different scenarios regarding the timing of the career change. Furthermore, we outline the characteristics and skills that enable physicians to have a successful career in pharma.

Limb-Salvage Surgery of Soft Tissue Sarcoma with Sciatic Nerve Involvement.

BACKGROUND: The surgical resection of soft tissue sarcomas (STS) with sciatic nerve involvement presents a significant surgical and oncological challenge. Current treatment strategies pursue a multimodal approach with the aim of limb preservation. We aim to evaluate the outcomes of limb-sparing surgery of STS in a patient cohort and to propose a classification for STS with sciatic nerve involvement. METHODS: Patients receiving limb-preserving resections for STS with sciatic nerve involvement between 01/2010 and 01/2017 were included. Clinical and oncological data were prospectively collected in a computerized database and retrospectively analyzed. Sciatic nerve involvement in STS was classified preoperatively as follows: type A for nerve encasement; type B for nerve contact; and type C for no nerve involvement. RESULTS: A total of 364 patients with STS were treated, of which 27 patients had STS with sciatic nerve involvement. Eight patients with type A tumors (29.6%) underwent sciatic nerve resection, and 19 patients with type B tumors (70.4%) received epineural dissections. Disease progression was observed in 8 patients (29.6%) with a local recurrence of 11.1% and distant metastasis in 29.6%. The type of nerve resection significantly influenced leg function but had no impact on disease recurrence or overall survival. CONCLUSION: In a cohort of carefully selected patients with STS and sciatic nerve involvement, the extent of sciatic nerve resection had no significant impact on disease recurrence or survival. Precise classification of neural involvement may therefore be useful in selecting the appropriate degree of nerve resection, without compromising oncological outcome or unnecessarily sacrificing leg function.

Repurposed therapeutic agents targeting the Ebola virus: a protocol for a systematic review.

BACKGROUND: The recent Ebola epidemic in western Africa developed into an acute public health emergency of unprecedented level in modern times. The treatment provided in most cases has been limited to supportive care, as no approved therapies are available to date. Several established, licenced drugs have been suggested as potential repurposed therapeutic agents for Ebola. However, scientific data on their efficacy in treating Ebola is limited. The purpose of this review is to systematically assess scientific evidence on potential drugs targeting Ebola. In specific, we aim to (1) identify drug library screens involving therapeutic agents targeting the Ebola virus, (2) list potential approved drugs identified from drug screens and review their mechanism of action against the Ebola virus and (3) summarise the outcome of preclinical and clinical trials investigating approved drugs targeting the Ebola virus. METHODS/DESIGN: We will develop comprehensive systematic search strategies and will perform a systematic literature search in MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). Two authors will independently screen the titles, abstracts and the references of all selected articles on the basis of inclusion criteria. These include any available drug screening, preclinical studies and clinical studies examining the efficacy of approved therapeutic agents targeting the Ebola virus. There will be no restrictions on the type of participants, the type of comparator, time or setting. Data extraction and quality assessment will be undertaken by two review authors working independently. DISCUSSION: This systematic review will provide systematic knowledge on potential repurposed therapeutic agents targeting Ebola. It aims to help guide future investigations on repurposed drugs and avoid repetitive studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024349.

Ischemic colitis: who will survive?

BACKGROUND: Operative treatment for acute ischemic colitis is associated with a high morbidity and mortality. These patients often have a prolonged postoperative stay in the intensive care unit with an uncertain outcome. In this study, we aimed to develop a predictive risk score for perioperative mortality and to examine long-term follow-up of patients with acute ischemic colitis. METHODS: All patients (n = 177) undergoing surgical treatment for acute ischemic colitis in our institution from 2002 to 2008 were prospectively included in this study. Independent predictors of perioperative mortality and poor long-term survival were assessed by uni- and multivariate analysis. RESULTS: A risk score including various perioperative variables (nonocclusive ischemic colitis, acute renal failure, extent of bowel ischemia, serum lactate, and duration of catecholamine therapy) was defined being highly predictive for postoperative mortality of patients having undergone an operation for acute ischemic colitis. Mesenteric atherosclerosis in the surgical specimen is an independent prognostic factor for poor long-term survival (52 vs 40 months with mesenteric atherosclerosis; P = .027). CONCLUSION: This study for the first time presents a risk score highly predictive of postoperative mortality of patients undergoing an operation for ischemic colitis. Our score may help to further select and modify therapeutic management in patients with acute ischemic colitis on the basis of validated data. Furthermore, we could demonstrate a significant influence of mesenteric atherosclerosis on long-term survival of patients with acute ischemic colitis.