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24th February 2023
Data presented at the 2023 American Society for Clinical Oncology (ASCO) genitourinary cancer symposium, showed that pembrolizumab monotherapy in patients with Bacillus Calmette-Guerin (BGC) unresponsive, high-risk, non-muscle invasive bladder cancer, showed notable anti-tumour activity after roughly 45 months of follow-up.
The vast majority (75 to 80%) of newly diagnosed bladder cancers are categorised as non-muscle invasive cancers (NMIBC). BCG has been used in the treatment of NMIBC for many years although in roughly half of high-risk patients, intra-vesical BCG treatment fails and NMIBC persists or recurs early. In an earlier Phase II study (KEYNOTE-057), patients with histologically confirmed BCG-unresponsive carcinoma in situ with or without papillary tumours, treated with pembrolizumab monotherapy showed that the drug was both tolerable and demonstrated promising anti-tumour activity.
The data presented at the ASCO symposium relates to a second patient cohort from KEYNOTE-057 who had papillary tumours but without carcinoma in situ. These individuals received pembrolizumab at a dose of 200 mg every three weeks for less than 35 cycles. The primary endpoint as 12-month disease-free survival (DFS) as determined by central pathology and radiology review. Other outcomes explored included the 12-month DFS of any disease, progression-free survival (PFS) to worsening of grade, stage, or death as well as PFS to muscle invasion, metastasis, or death and finally, overall survival (OS).
Pembrolizumab and disease-free survival
A total of 132 patients with a median age of 72 years were included and who had received a median of 10 prior BCG instillations. The median follow-up was 45.4 months.
The 12-month DFS rate was 43.5 % and the median DFS was 7.7 months (95% CI 6.5 – 13.6). In addition, for any level of disease recurrence, the 12 month DFS was estimated as 41.7% with a median DFS of 6 months. The 12-month PFS to either invasive or metastatic disease or death was 88.2% with a median PFS of 46.2 months and the estimated overall survival rate at 12 months was 96.2%.
The authors concluded that patients with BCG unresponsive, non-carcinoma in situ papillary high risk NMIBC may benefit from pembrolizumab monotherapy.
Citation
Necchi A et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. Abstract LBA442, GuCS 2023
23rd February 2023
In a phase 2 trial of adding talimogene laherparepvec (T-VEC) to neoadjuvant chemotherapy (NAC) in patients with triple negative breast cancer, researchers from the Moffitt Cancer Center, Florida, observed an improved estimated pathological complete response rate.
Triple negative breast cancer accounts for 10 to 15% of all breast cancers and chemotherapy has become the established treatment for both early and advanced disease. In a phase 1 trial reported in 2021 among 9 women with stage II to III triple negative breast cancer, use of T-VEC in combination with neoadjuvant chemotherapy, led to a complete response rate of 55%. The rational for T-VEC is based on the notion that the oncolytic virus selectively replicates within tumour cells and produces granulocyte-macrophage colony-stimulating factor which enhances both the local and systemic anti-tumour response. In fact, T-VEC (brand name Imlygic) is already licensed for the treatment of adult patients with unresectable melanoma which has become both regionally and distantly metastatic but without bone, brain, lung or other visceral disease.
Following the success of the phase 1 trial, the US researchers continued to explore the utility of this therapeutic approach by undertaking a phase 2 trial of T-VEC in patients with stage II to III triple negative breast cancer, followed by doxorubicin and cyclophosphamide chemotherapy prior to surgery, to assess residual the cancer burden index. Eligible patients received a total of five doses of intra-tumoral T-VEC injection, given initially at week 1, followed by four subsequent doses on weeks 4, 6, 8 and 10 concurrently with intravenous once-weekly paclitaxel. The primary outcome of interest was a pathological complete response (RCB0), defined as no residual invasive disease in the breast or sampled nodes after completion of NAC. The secondary endpoint was the RCB0-1 rate.
T-VEC and pathological complete response
A total of 37 women with a median age of 49 years, the majority of whom (84%) had stage II disease were included in the study.
A total of 16 women had a pathological complete response with an estimated RCB0 response of 45.9%. In addition, 8 patients had RCB1 minimal residual disease, giving a descriptive RCB0-1 rate of 65%. The authors added that the 2-year disease-free event rate was equal to 89% with no recurrence in RCB0-1 patients.
The researchers concluded that the use of T-VEC when added to NAC may increase RCB0-1 rates and called for continued investigation of this strategic approach in women with triple negative breast cancer.
Citation
Soliman H et al. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial. Nat Med 2023
Hemgenix (etranacogene dezaparvovec) has been granted a conditional marketing authorisation by the European Commission for the treatment of severe and moderately severe haemophilia B (congenital Factor IX deficiency) in adults without a history of Factor IX inhibitors.
Haemophilia B is an inherited and life-threatening rare disease affecting 1 in 40,000 live males which is about 15% of cases of haemophilia. It is a caused by missing or defective clotting protein, factor IX and sufferers are particularly vulnerable to bleeds in joints, muscles, and internal organs leading to pain, swelling and ultimately joint damage.
Patients with haemophilia B require lifelong treatment with intravenous infusions of Factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and wellbeing. HEMGENIX® is an adeno-associated virus five (AAV5)-based gene therapy that is given as a one-time treatment for moderately severe to severe haemophilia B patients. HEMGENIX® uses a specific type of AAV, called AAV5, as its vector. The AAV5 vector carries the naturally occurring Padua gene variant of Factor IX (Factor IX-Padua), which generates Factor IX proteins that are 5 to 8 times more active than normal.
Hemgenix clinical data
The main clinical study with Hemgenix is the HOPE-B trial which is an ongoing, multinational, open-label, single-arm study, designed to evaluate the safety and efficacy of HEMGENIX®. Fifty-four adult haemophilia B patients classified as having a diagnosis of moderately severe or severe haemophilia B and requiring prophylactic Factor IX replacement therapy, were enrolled in a prospective, six-month observational period during which time they continued to use their current standard of care therapy to establish a baseline Annual Bleeding Rate (ABR). After the six-month lead-in period, patients received a single intravenous administration of HEMGENIX® with 53 patients completing at least 18 months of follow-up. The primary endpoint in the pivotal HOPE-B study was 52-week ABR after achievement of stable Factor IX expression compared with the six-month lead-in period.
Results from the pivotal HOPE-B study demonstrated that HEMGENIX® produced mean Factor IX activity of 36.9 IU/dL at 18 months post infusion. At 24 months follow-up, Factor IX activity remained stable at 36.7 IU/DL. After the six-month lead-in period post-infusion, the adjusted annualized bleeding rate (ABR) (1.51) for all bleeds was reduced by 64 percent (p = 0.0002) and all Factor IX-treated bleeds was reduced by 77 percent (3.65 to 0.83; p<0.0001) over months seven to 18. From day 21 through to months 7 to 24, 52 of 54 (96.3%) treated patients remained free of continuous routine Factor IX prophylaxis. The mean consumption of Factor IX replacement therapy significantly decreased by 248,392.6 IU/year/patient (96.52%; 1-sided p< 0.0001) between month 7 to 24 following treatment with HEMGENIX® compared to standard of care routine Factor IX prophylaxis during the lead-in period.
Fortunately, there were no serious adverse reactions identified. One death resulting from urosepsis and cardiogenic shock in a patient at 65 weeks following dosing was considered unrelated to treatment by investigators and the company sponsor. A serious adverse event of hepatocellular carcinoma was determined to be unrelated to treatment with HEMGENIX® by independent molecular tumour characterization and vector integration analysis. No inhibitors to Factor IX were reported.
In the press release, Professor Wolfgang Miesbach, Head of Coagulation Disorders at the Comprehensive Care Centre, University Hospital of Frankfurt, said “this approval marks an important step forward in the treatment of haemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints and internal organs, alleviating the burden of lifelong intravenous infusions of Factor IX products,” They added that “data from the HOPE-B study demonstrate the potential of HEMGENIX® to remove the need for routine prophylaxis, by providing durable Factor IX activity, as well as improved bleeding outcomes and quality of life for people with haemophilia B.”
21st February 2023
An international team of researchers have found that combining darolutamide with androgen-deprivation therapy and docetaxel improved overall survival in men with metastatic hormone sensitive prostate cancer.
Darolutamide is a potent androgen-receptor inhibitor which has been shown to improve survival in men with non-metastatic, castration-resistant prostate cancer when used alongside androgen-deprivation therapy. Furthermore, the ARASENS trial published in 2022 in the New England Journal of Medicine, found that in men with metastatic, hormone-sensitive prostate cancer, use of oral darolutamide (600 mg twice daily), androgen-deprivation therapy (ADT) and docetaxel (DOC) significantly improved overall survival compared to a placebo group without the drug but with both ADT and DOC.
In the current analysis, researchers undertook a post hoc analysis of ARASENS and focused on the effect of darolutamide in various subgroups. Participants were categorised into those with high-volume disease (defined by visceral metastases and or > 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis) or high-risk disease, which was a Gleason score > 8 and > 3 bone lesions and the presence of visceral metastases. The team also investigated those with both low risk and low volume disease, i.e., not meeting the high volume/risk criteria. For their analysis the primary endpoint was set as overall survival.
Darolutamide and overall survival in subgroups
A total of 1,305 participants of whom 1,005 (77%) had high-volume disease and 912 (70%) high-risk disease were included in the analysis.
Treatment with darolutamide improved overall survival compared to placebo in those with high volume disease by 31% (hazard ratio, HR = 0.69, 95% CI 0.57 – 0.82) and by a similar amount in those with high-risk disease (HR – 0.71, 95% CI 0.58 – 0.86). There were also broadly similar improvements in overall survival among those with low volume and low risk disease.
In terms of safety, grade 3 or 4 adverse events occurred in a similar proportion of patients (64.9% vs 64.2% darolutamide vs placebo group) in the high volume subgroup and the incidence was similar across all subgroups.
The authors concluded that in men with hormone sensitive metastatic prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel led to an increased OS and with a similar adverse effect profile in the subgroups.
Citation
Hussain M et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. J Clin Oncol 2023
20th February 2023
A significant five-year overall survival rate has been observed with the use of neoadjuvant nivolumab in resectable non-small cell lung cancer.
In a 2018 global study, lung cancer was found to be the most commonly diagnosed cancer (11.6% of all cases) as well as the leading cause of cancer deaths. The most common form of lung cancer is non-small cell lung cancer (NSCLC) which accounts for around 80-85% of all cancers. The use of programmed death 1 (PD-1) protein inhibitors as a treatment for patients with advanced NSCLC have been shown to produce a durable response and encouraging survival rates. Until recently, the value of PD-1 blockage in patients with resectable NSCLC has been unclear. However, in a 2018 trial it was found that two preoperative doses of nivolumab in adults who had early, i.e. stage I, II of IIIA, surgically resectable NSCLC, did not cause a delay to surgery and was able to induce a major pathological response in nearly half (45%) of resected tumours. While these were impressive, there was uncertainty over the longer term outcome of such patients.
In the current study, a team from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, US, provided the longest known follow-up study of patients given neoadjuvant nivolumab therapy with any type of cancer. The patient cohort was derived from the team’s earlier 2018 trial described above. Eligible participants received two doses of nivolumab (3mg/kg bodyweight) every two weeks with surgical resection planned for roughly four weeks after the first dose. In this follow-up, the researchers examined exploratory endpoints such as recurrence-free survival (RFS) and overall survival (OS) from the date of the patient’s surgery. They also considered the proportion achieving a major pathological response (MPR).
A total of 20 patients were included and followed for a median of 63 months. The five-year RFS rate was 60% and the OS 80%. In addition, the researchers reported that the use of nivolumab was associated with few side effects and did not delay surgery.
At the time the analysis was undertaken, the hazard ratio (HR) for the presence of a MPR, though not significant, was in the direction of improved RFS (HR = 0.61, 95% CI 0.15 – 2.44). In fact, at the five-year follow-up, eight of nine patients with a MRP were alive and free of disease. In contrast six of the 11 patients without MRP at a tumour relapse, three of whom died.
The authors concluded that five years, the clinical outcomes associated with neoadjuvant therapy were comparatively favourable to the earlier observed response. They added that while there was a trend towards improved RFS, it was difficult to draw any firm conclusions due to the small sample size.
Citation
Rosner S et al. Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res 2023
19th February 2023
A study analysing hospital admissions for both chronic obstructive pulmonary disease (COPD) and asthma from 1999 to 2020, has revealed a significant increase for both conditions despite a considerable increase in prescribed treatments for these diseases.
Both COPD and asthma are common respiratory diseases. In a recent global systematic review it was estimated that some 391·9 million people had COPD in 2019 and the World Health Organization (WHO) estimates than in 2019, there were 3.23 million global deaths from COPD. Asthma also affects a huge number of people and WHO estimated that in 2019, the disease affected some 262 million people across the world and led to 455,000 deaths. With both diseases leading to a considerable number of deaths, in the present study, a team of Saudi Arabian researchers examined the trends in hospital admissions and which could result in death, for both COPD and asthma between 1999 and 2020. The researchers extracted information from the hospital episode statistics database in England and the corresponding database was Wales. In addition to hospital admissions data, the team also collected information on COPD and asthma-related medicines prescribed between 2004 and 2020.
Hospital admissions for COPD and asthma
The total annual number of admissions for the two conditions rose by 82.2% between 1999 and 2020 which represented a 59.1% increase in the hospital admission rate over this period of time (p < 0.05).
The most common reason for COPD admission (38.7%) was in combination with an acute lower respiratory tract infection and which increased by 198.5% between 1999 and 2020. In contrast, acute exacerbations of COPD alone, accounted for a quarter of admissions (25.5%) and this rate had actually reduced by 4.8% between 1999 and 2020. As with COPD, asthma additions also increased by 46.1% over the 21-year period.
Just over a third (34.7%) of COPD and asthma admissions occurred in those age 75 years and older with just under a quarter (23.5%) in those aged 15 – 59 years. Interestingly, slightly more than half (53.8%) of admissions for both conditions occurred in women.
When looking at prescriptions, the researched observed a 42.2% increase the absolute number of COPD and asthma-related dispensed medicines between 2004 and 2020, which represented a 27.2% increase between the two periods of time (p < 0.05).
The authors concluded that while the data showed a clear rise in hospital admissions for both conditions the reasons behind these increases were unclear and they called for further research to try and better understand the factors responsible for these higher rates.
Citation
Alwafi H et al. Trends in hospital admissions and prescribing due to chronic obstructive pulmonary disease and asthma in England and Wales between 1999 and 2020: an ecological study. BMC Pulm Med 2023
18th February 2023
Having autoimmune diseases (AIDs) seems to increase the risk of developing atrial fibrillation according to the findings of a prospective study by Dutch researchers.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and data from 2017 suggests that globally, there were 3.046 million new cases.
Although the underlying cause of AF remains uncertain, there is a suggestion of a mechanistic link with inflammatory processes. Moreover, a feature of autoimmune diseases such as rheumatoid arthritis is inflammation and one meta-analysis found a 29% higher risk of AF among those with rheumatoid arthritis. Nevertheless, the link between AF and other autoimmune disorders is less clear.
As a result, in the current study, the Dutch team turned to data held in the UK Biobank and looked for those diagnosed rheumatic fever, gastrointestinal AIDs and other AIDs e.g. those affecting the musculoskeletal, connective tissues and neurological systems. Such individuals were monitored over time for the development of AF. In addition, the team collected data on cardiovascular risk factors such as hypertension, type 2 diabetes, body mass index etc and which were adjusted for in regression models.
A total of 494,072 individuals with a median age of 58 (54.8% female) were followed for a median of 12.8 years and during this time 5.5% of the cohort developed AF.
In fully adjusted models, among those with rheumatic fever but no cardiac involvement, there was a 47% higher risk of developing AF (hazard ratio, HR = 1.47, 95% CI 1.26 – 1.72).
Similarly, there were elevated risks for those with several autoimmune diseases including Crohn’s disease (HR = 1.23), ulcerative colitis (HR = 1.17), rheumatoid arthritis (HR = 1.39) systemic lupus erythematosus (HR = 1.82) and systemic sclerosis (HR = 2.32).
When analysed by gender, the researchers found that for many of these disorders, there was a higher risk among women although the risk was higher among men but only for ulcerative colitis.
The authors concluded that whilst their data showed how autoimmune diseases were associated with the development of AF, further evidence was need to support the clinical translation of these findings.
Citation
Tilly MJ et al. Autoimmune diseases and new-onset atrial fibrillation: a UK Biobank study. Eurospace 2022.
The use of glucagon-like peptide-1 (GLP-1) agonists in patients who have type 2 diabetes and are overweight is associated with a small but significant weight loss after 72 weeks, according to a retrospective analysis of electronic health records by US researchers.
It has long been recognised that obesity is an independent risk factor for cardiovascular disease. In addition, cardiovascular disease is often present in those with type 2 diabetes and presents a major cause of death among such patients.
Despite this elevated risk, lifestyle modification, in particular weight loss, has been shown to be associated with better control of diabetes and and a reduction in cardiovascular risk factors.
Clinical trials in overweight, type 2 diabetic patients have demonstrated that drugs such as semaglutide, which is one of the GLP-1 agonists, achieves superior and clinically meaningful reductions in body weight in comparison to placebo.
However, most of the weight loss clinical trials have included a lifestyle intervention to support patients but in the absence of such support, GLP-1 agonist-associated weight loss is no better than that achieved with other agents such as metformin.
In the current study, US researchers from the University of Pittsburgh, wanted to understand the degree to which GLP-1 agonists induced weight loss when used as a part of routine clinical care, i.e. in the absence of a specific behavioural weight loss intervention.
The team retrospectively examined the electronic health records of those prescribed any drugs from the GLP-1 agonist class and the subsequent weight loss after 72 weeks of therapy.
Outcomes were available for 2,405 participants with a mean age of 48 years (47.4% male) and of whom, 92.1% had type 2 diabetes and a mean baseline body mass index of 37.
Only eight weeks after the first dispensing of a GLP-1 agonist, the mean weight loss was 1.1% and this increased to 2.2% after 72 weeks.
However, some patients did even better. For instance, 11.2% had lost at least 5% of their body weight after eight weeks, but after 72 weeks, this proportion increased to just over a third (33.3%).
In fact, at the 72 week mark, nearly half of the entire cohort (42.7%) had lost weight, with a small proportion of patients (10.5%) managing to lose 10% or more of their body weight.
The authors concluded that the use of GLP-1 agonists prescribed at standard doses led to a modest degree of weight loss in a real-world setting and in the absence of any specific patient support.
Citation
White GE et al. Real-world weight-loss effectiveness of glucagon-like peptide-1 agonists among patients with type 2 diabetes: A retrospective cohort study. Obesity (Silver Spring) 2023.
17th February 2023
In a randomised controlled trial, an international group of researchers showed that the CAR T-cell therapy, Ide-cel (idecabtagene vicleucel) gave rise to greater progression-free survival than any of five other standard regimens in heavily pre-treated patients with relapsed or refractory multiple myeloma.
Although treatments for multiple myeloma have improved in recent years, evidence suggests that around 16% of patients relapse after 8 months of treatment. Nevertheless, while CD38-targeting monoclonal antibodies have made a significant impact to the treatment of patients with multiple myeloma (MM), those who a refractory to this regime have a poor prognosis. The use of CAR T-cell therapies directed against the B-cell maturation antigen (BCMA) expressed on myeloma cells, have proven to be effective in MM. In fact, one Phase II trial in which Ide-cel was given to relapsed or refractory MM patients, generated a response in over 70% of patients, with 33% experiencing a complete response. While CAR T-cell therapy clearly works in relapsed/refractory MM, there is an absence of comparative studies of the treatment compared to other regimes.
In the current study, researchers recruited MM patients who were refractory to between two and four prior regimes. Eligible participants were then randomised 2:1 to Ide-cel or one of five standard regimens and which included immunomodulatory agents, proteasome inhibitors and daratumumab. The primary endpoint was set as progression-free survival whereas secondary endpoints included the overall response and survival.
Ide-cel and progression-free survival
A total of 386 patients with a median age of 63 years (60.5% male) received either Ide-cel (254) or one of the standard regimes. Among the entire cohort, 66% had triple-class refractory disease and 95% daratumumab-refractory disease.
After a median of 18.6 months follow-up, the median progression-free survival in the Ide-cel group was 13.3 months compared to 4.4 months in the standard regime groups (hazard ratio for disease progression or death, HR = 0.49, 95% CI 0.38 – 0.65, p < 0.001). In fact, 12-month progression-free survival was 55% for Ide-cel but only 30% in the standard regimen. Furthermore, a complete response occurred in 39% of the intervention group and on 5% in the standard therapy group. Data on overall survival were immature. In addition, adverse effects of either grade 3 or 4 were more frequent in the Ide-cel group (93% vs 75).
Based on these results, the authors concluded that Ide-cel gave rise to an improved response compared to standard therapy in patients who failed to respond to two to four prior regimens.
Citation
Rodriguez-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med 2023
Older residents in a care home (CH) are at a potentially higher risk of medication error and adverse drug reactions due to both polypharmacy and aged-related alterations in drug pharmacokinetics and pharmacodynamics.
Moreover, data from a 2009 study found that in a home of 259 residents, taking a mean of eight different medicines, 69.5% had one or more errors. Given this high level of errors, various interventions have been developed to optimise prescribing for elderly CH residents.
Nevertheless, despite numerous studies employing a range of different interventions, a 2016 Cochrane review concluded that it was not possible to draw robust conclusions because of the variability in study designs, interventions, results and reported outcomes. However, the authors of the Cochrane review did call for high-quality, cluster-randomised controlled trials that measured well-defined, important, resident-related outcomes.
Consequently, the current trial was designed to estimate the effectiveness of using an independent pharmacist prescriber in care homes. The pharmacists provided pharmaceutical care plans to approximately 20 residents in one to three care homes through weekly visits over a 6-mont period.
For the control arm, residents received their usual general practitioner care and any pharmacist input ranged from medicine supply (i.e. via a community pharmacy) or visits by a primary care pharmacist undertaking medication reviews. The primary outcome of interest was the fall rate per person over the six month period and which was based on findings from a feasibility study of the intervention.
Pharmacist care home intervention and fall rates
A total of 876 residents with a mean age of 85.3 years (30.4% male) and taking a median of 6 medicines, were included and of these, 449 were randomised to the pharmacist intervention.
During the period of study, 697 falls were documented in the intervention group and 538 in the control arm, although this difference in fall rate was not statistically significant (risk ratio, RR = 0.91, 95% CI 0.66 – 1.26) even after adjustment for various factors.
Other secondary outcomes which included quality of life, hospital admissions and mortality were not significantly different between the two groups, with the exception of the drug burden index, which significantly favoured the intervention (RR = 0.83, 95% CI 0.74 – 0.92, p < 0.001).
The authors suggested that the lack of difference in the primary outcome could have arisen due to the short duration of the study and concluded that the significant reduction in the drug burden index was predicted to yield future clinical benefits to patients.
Citation
Holland R et al. Evaluation of effectiveness and safety of pharmacist independent prescribers in care homes: cluster randomised controlled trial. BMJ 2023.
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